Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans

Definitions

• a method can comprise administering to a subject a therapeutically effective amount of a pharmaceutical composition to treat the multifactorial neurological disease.
• a pharmaceutical composition can comprise: a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, GT Docket No.199260-717601 D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.
• E is D-Ser, D-
• the peptide or the salt thereof can be D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr or a salt thereof.
• the derivative of I can be esterified, glycosylated, or amidated at the C terminus.
• the multifactorial neurological disease can be a vascular dementia.
• the administering is daily.
• the multifactorial neurological disease can be a LBVAD.
• the vascular dementia can comprise a subcortical vascular dementia or a multi-infarct dementia.
• the pharmaceutical composition can be in unit dose form.
• the pharmaceutical composition can be in a form of a pill or a liquid.
• a second therapy can be administered concurrently or consecutively.
• the second therapy can comprise a carbidopa, a levodopa, a cholinesterase inhibitor, a N-methyl D-aspartate antagonist, a catechol O-methyltransferase (COMT) inhibitor, a MAO-B inhibitor, an aducanumab, a lecanemab, a remternetug, a high blood pressure medication, a high cholesterol medication, an anticoagulant medication, a diabetes medication, a salt of any of these, or any combination thereof.
• CCT catechol O-methyltransferase
• the peptide can comprise at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D- Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.
• E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D- Leu, or a derivative of any of these
• the disease can be selected from the group consisting of: a postural instability, a gait disturbance, a balance issue, a post-traumatic stress disorder (PTSD), an urinary incontinence, and any combination thereof.
• the peptide, the derivative thereof, or the salt thereof can comprise at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I.
• A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D- Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly or a derivative of any of these.
• the pharmaceutical composition can further comprise an excipient, a diluent, a carrier, or a combination thereof.
• a method can comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease.
• the pharmaceutical composition comprises: a peptide, a derivative thereof, or a salt thereof.
• the peptide can comprise: i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH 2 (SEQ ID NO: 1) or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers and the N-terminal amino acid is an amide; ii) [D- Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 2)or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof.
• the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these; and II) a lecanemab, a derivative thereof, a
• the peptide, the derivative thereof, or the salt thereof can comprise at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F- GT Docket No.199260-717601 G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D- Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Thr, D
• the pharmaceutical composition can be administered by: an oral route, an injection route, a sublingual route, a buccal route, a rectal route, a vaginal route, an ocular route, an otic route, a nasal route, an internasal route, an inhalation route, a cutaneous route, a subcutaneous route, an intramuscular route, an intravenous route, a systemic route, a local route, a transdermal route, or any combination thereof.
• the pharmaceutical composition can be formulated for oral administration or for intravenous administration.
• the pharmaceutical composition can be in a form of a pill or a liquid.
• the pharmaceutical composition can be in a form of a liquid.
• the pharmaceutical composition can comprise: a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises: i) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 (SEQ ID NO: 1) or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Thr- Asn-Tyr-Thr (SEQ ID NO: 2) or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof; and a lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these.
• SEQ ID NO: 1 [D-Ala1]-Ser-Thr-Thr-Thr-Asn-T
• the disease can be a mild cognitive impairment or a mild dementia.
• the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg
• the peptide, the derivative thereof, or the salt thereof comprises at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I
• the peptide or the salt thereof can be D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr or a salt thereof.
• I can be esterified, glycosylated, or amidated at the C terminus.
• the pharmaceutical composition can further comprise an: excipient, a diluent, a carrier, or a combination thereof.
• the pharmaceutical composition can GT Docket No.199260-717601 comprise the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these.
• the pharmaceutical composition can comprise the aducanumab, the derivative thereof, the biosimilar thereof, or the salt of any of these.
• the pharmaceutical composition can comprise the remternetug, the derivative thereof, the biosimilar thereof, or the salt of any of these.
• the pharmaceutical composition can be in unit dose form.
• the pharmaceutical composition can comprise the peptide, the derivative thereof, or the salt thereof in an amount of from about 0.005 mg to about 1000 mg.
• the pharmaceutical composition can comprise the lecanemab, the aducanumab, the remternetug, the derivative thereof, the biosimilar thereof, or the salt of any of these in an amount of from about 1 mg to about 500 mg.
• the pharmaceutical composition can comprise the lecanemab, the aducanumab, the remternetug, the derivative thereof, the biosimilar thereof, or the salt of any of these in an amount of about 10 mg/kg.
• the pharmaceutical composition can be formulated for intravenous delivery or for oral delivery.
• pharmaceutical composition can be in a form of a pill or a liquid. [11] Also disclosed herein are pharmaceutical compositions.
• kits comprising the pharmaceutical compositions disclosed herein and a container.
• a kit can comprise: I) a peptide, a derivative thereof, or a salt thereof.
• the peptide can comprise at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D- Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D- Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D- Arg, or Gly,
• the method can comprise administering to the subject a therapeutically effective amount of: I) a peptide, a derivative thereof, or a salt thereof.
• the peptide can comprise at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-
• the peptide, the derivative thereof, or the salt thereof can comprise at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B- C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D- Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D- Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative of any of these; H is
• the peptide, the derivative thereof, or the salt thereof can be in unit dose form.
• the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these can be in unit dose form.
• the pharmaceutical composition can be administered by: an oral route, an injection route, a sublingual route, a buccal route, a rectal route, a vaginal route, an ocular route, an otic route, a nasal route, an internasal route, an inhalation route, a cutaneous route, a subcutaneous route, an intramuscular route, an intravenous route, a systemic route, a local route, a transdermal route, or any combination thereof.
• the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these can be in an amount of from about 1 mg to about 500 mg. In some embodiments, the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these can be administered for about: one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, or for life.
• the peptide, the derivative thereof, or the salt thereof can be administered for about: one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, or for life.
• the administering of the peptide, the derivative thereof, or the salt thereof can be daily, weekly, or monthly.
• FIGS.3A-3E shows RAP-103 prevents A ⁇ oligomer-induced spine loss on rodent neurons.
• Projection images of 23 DIV mouse hippocampal neurons immunolabeled for MAP2, PSD95 and VGLUT were taken.
• FIG. 3A shows MAP2 channel in this overexposed image shows weakly labeled dendrites (see arrows).
• FIG. 3B shows inverted deconvolved projection image of overlayed MAP2 (light gray) with PSD95 (dark gray puncta). Most PSD95 puncta align with dendrites even though some MAP2 positive dendrites (see FIG.3A, arrows) are too faint to show up on the deconvolved overlays.
• FIG. 3C shows enlarged boxed region from FIG.
• FIG. 3B shows Many spines are MAP2 positive but PSD95 puncta along dendrites could be in spines w/o MAP2.
• FIG. 3D shows quantitative analysis of spines (PSD95 puncta) normalized to MAP2 area from multiple fields of multiple coverslips shows A ⁇ d/t reduces spines but that reduction is inhibited by RAP- GT Docket No.199260-717601 103. *p ⁇ 0.05.
• FIG. 3E shows number of synapses per 20 um of dendrites. Synapses were quantified per 20 ⁇ m segment of 5 secondary dendrites per field from ⁇ 50 fields from each of 4 coverslips (205-230 segments) per treatment. [18] FIGS.
• FIG. 4A-4B show RAP-103 prevents A ⁇ oligomer-induced synapse and spine loss on human neurons.
• FIG. 4A shows a sample confocal image of day 55 human neurons. Inset of immunolabel for vGlut (dark gray) and PSD95 (light gray) shows several synapses in which immunolabeling of markers are in contact or overlap. Treatment with A ⁇ d/t ⁇ RAP-103 (1 nM) is 5 days. A significant drop in synapses or spines (as shown in FIG.4B) with A ⁇ d/t normalized for the total dendrite area per field (MAP2-immunolabel) is eliminated by RAP-103 but not control peptide 3, which didn’t block rods . [19] FIGS.
• FIG. 5A-5B shows RAP-103 reverses A ⁇ induced cofilin rods in hippocampal neurons. Hippocampal neurons were treated with A ⁇ (1nM) to induce rods. After overnight incubation, rods (shown in the white box) were followed at 4 min intervals by fluorescence microscopy with treatment of 0.1 nm RAP-103 or 50 nM AMD3100.
• FIG.5A shows selected images of fluorescent rods from the RAP-103 treated cells throughout the time course.
• FIG. 5B shows the time course of the rod area over more than 150 minutes of treatment. The Y-axis shows the percent of initial rod area, while the X-axis shows the time in minutes.
• FIGS.6A-6D show RAP-103 prevents memory impairment in morris water maze (MWM) testing of Thy1-aSyn mice.
• FIG.6A shows the total distance swimming was the same in the alpha synuclein compared to WT and RAP-103 did not have an adverse or activating effect on swimming.
• FIGS.6B-D show that RAP-103 treated alpha synuclein mice maintained their ability to remember the location of the platform by three assessments; FIG.6B shows distance in target; FIG. 6C shows time in target; and FIG.
• FIGS. 7A-7B show the effect of peptides on rods induced by other initiators.
• FIG. 7A shows glutamate-induced rod formation is not inhibited by RAP-310 at concentrations that completely inhibit A ⁇ d/t-induced rods.
• FIG.7B shows rods induced in day 55 human neurons treated on DIV 54 with IL-6 are inhibited GT Docket No.199260-717601 in a dose-dependent manner by RAP-103 with an EC50 of about 0.1 pM. ** p ⁇ 0.01.
• This data shows the peptides herein can be used to treat IL-6 associated diseases such as multifactorial neurological diseases.
• FIG.8 shows quantification of the percentage of neurons with rods (fold change relative to control) after 7 days of growth in vitro (DIV 7).
• Hippocampal neurons were pre-treated with control (PBS) or 1 ⁇ g/ml of alpha synuclein preformed fibrils (PFFs) and with a control (H2O) or 50 pM of RAP-103 for 24h.
• FIG. 8 shows the quantification of the rod index (shown as fold change of number of rods relative to control) after 14 days of growth in vitro (DIV 14) of hippocampal neurons pre-treated with control (PBS) or 1 ⁇ g/ml alpha synuclein PFFs and with a control (H2O) or 50 pM of RAP-103 for 24h.
• FIG.9A-9D shows RAP-103 and RAP-310 inhibited formation of A ⁇ d/t-induced rods in a dose-dependent manner in both rodent and human neurons.
• FIG.10A-10B shows effect of RAPs on rods induced by other initiators.
• FIG.10A shows rod formation induced by adenoviral-mediated overexpression of PrPC in rat hippocampal neurons infected with AdPrPC and treated with RAP-103 [50 pM] at the same time (4 day) or on DIV 5 (1 day).
• FIG. 11 shows inhibition by RAP-103 (1nM) of TNF-alpha release by pre-formed fibrils (PFF) of A ⁇ and alpha synuclein.
• the Y-axis shows the level of TNF-alpha release by cultured THP.1 human monocytes.
• the X-axis shows the different treatments (e.g., A ⁇ (Abeta), aSyn (alpha synuclein), A ⁇ and aSyn) in the two conditions of media only (left bar) or media plus RAP- 103 (right bar).
• a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
• description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
• the term ‘about’ a number can refer to that number plus or minus 10% of that number.
• the term ‘about’ a range can refer to that range minus 10% of its lowest value and plus 10% of its greatest value.
• a sample includes a plurality of samples, including mixtures thereof.
• determining means “determining”, “measuring”, “evaluating”, “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement and include determining if an element may be present or not (for example, detection). These terms may include quantitative, qualitative or quantitative, and qualitative determinations. Assessing may be alternatively relative or absolute. “Detecting the presence of” includes determining the amount of something present, as well as determining whether it may be present or absent.
• a “subject” may be a biological entity.
• the biological entity may be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
• the subject may be GT Docket No.199260-717601 tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro.
• the subject may be a mammal.
• the mammal may be a human.
• the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject may not be necessarily diagnosed or suspected of being at high risk for the disease.
• the term “at least partially” may refer to a qualitative condition that exhibits a partial range or degree of a feature or characteristic of interest.
• at least partially reducing postural instability in a subject may comprise a reduction in postural instability that is at least about: 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% reduced relative to a subject being untreated.
• the term “in vivo” may be used to describe an event that takes place in a subject’s body.
• the term vivo may be used to describe an event that takes place outside of a subject’s body. An “ex vivo” assay may not be performed on a subject.
• an “ex vivo” assay performed on a sample may be an “in vitro” assay.
• the term “in vitro” may be used to describe an event that takes place contained in a container for holding laboratory reagent such that it may be separated from the living biological source organism from which the material may be obtained.
• In vitro assays may encompass cell-based assays in which cells alive or dead are employed.
• In vitro assays may also encompass a cell-free assay in which no intact cells are employed.
• treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient such as preventing symptoms of a multifactorial neurological disease.
• beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
• a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
• a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement may be observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
• a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
• a prophylactic benefit a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
• a “dose” can refer to a measured quantity of a therapeutic agent to be taken at one time.
• unit dose or “dosage form” may be used interchangeably and may be meant to refer to pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components or excipients, in a particular configuration, and apportioned into a particular dose to be delivered.
• unit dose may also sometimes encompass non-reusable packaging. More than one unit dose may refer to distinct pharmaceutical drug products packaged together, or to a single pharmaceutical drug product containing multiple drugs and/or doses.
• unit dose may also sometimes refer to the particles comprising a pharmaceutical composition, and to any mixtures involved. Types of unit doses may vary with the route of administration for drug delivery, and the substance(s) being delivered.
• a solid unit dose may be the solid form of a dose of a chemical compound used as a pharmaceutically acceptable drug or medication intended for administration or consumption.
• pharmaceutically acceptable salt may refer to pharmaceutical drug molecules, which may be formed as a weak acid or base, chemically made into their salt forms, most frequently as the hydrochloride, sodium, or sulfate salts. Drug products synthesized as salts may enhance drug dissolution, boost absorption into the bloodstream, facilitate therapeutic effects, and increase its effectiveness. Pharmaceutically acceptable salts may also facilitate the development of controlled-release dosage forms, improve drug stability, extend shelf life, enhance targeted drug delivery, and improve drug effectiveness.
• composition or vehicle such as a liquid or solid filler, diluent, excipient, carrier, solvent or encapsulating material.
• agent or “biologically active agent” may refer to a biological, pharmaceutical, or chemical compound or a salt of any of these. Non-limiting examples may include a simple or complex organic or inorganic molecule, a peptide, a protein, a nucleotide such as an engineered RNA, an engineered DNA, an alternative nucleic acid, a protein, a carbohydrate, a toxin, or a chemotherapeutic compound.
• the terms “effective amount” or “therapeutically effective amount” of a drug used to treat a disease may be an amount that may reduce the severity of a disease, reduce the GT Docket No.199260-717601 severity of one or more symptoms associated with the disease or its treatment, or delay the onset of more serious symptoms or a more serious disease that may occur with some frequency following the treated condition.
• time to peak plasma concentration can refer to the time required for a drug to reach peak concentration in plasma. Peak concentration in plasma can be defined as the plasma concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose.
• the term “substantially” or “essentially” can refer to a qualitative condition that exhibits an entire or nearly total range or degree of a feature or characteristic of interest.
• substantially can refer to a total range or degree of a feature or characteristic of interest by about plus or minus: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 7
• substantially can refer to at least about: 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of the total range or degree of a feature or characteristic of interest.
• HPLC can refer to high-performance liquid chromatography (formerly referred to as high-pressure liquid chromatography), which is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. HPLC can be a common technique used in pharmaceutical development, as it can be a method to ensure product purity.
• the terms peptide and polypeptide can be used interchangeably herein.
• fragment may be a portion of a sequence, a subset that may be shorter than a full-length sequence.
• a fragment may be a portion of a gene.
• a fragment may be a portion of a peptide or protein.
• a fragment may be a portion of an amino acid sequence.
• a fragment may be a portion of an oligonucleotide sequence.
• a fragment may be less than about: 20, 30, 40, 50 amino acids in length.
• a fragment may be about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60% or about 70% of the total length of an amino acid sequence or a nucleotide sequence.
• compositions e.g., pharmaceutical formulations
• methods of treatment of a disease e.g., a diagnostic to detect the disease, or a kit comprising a pharmaceutical formulation.
• the compositions and formulations herein can be used to treat a subject with a multifactorial neurological disease.
• compositions and formulations herein can be used to treat a Lewy Body variant of Alzheimer’s disease (LBVAD).
• LVAD Lewy Body variant of Alzheimer’s disease
• compositions and formulations herein can be used to treat an Alzheimer’s Disease Related Dementia (ADRD). In some cases, compositions and formulations herein can be used to treat a vascular dementia. In some cases, compositions and formulations herein can be used to treat a frontotemporal dementia.
• ADRD Alzheimer’s Disease Related Dementia
• compositions and formulations herein can be used to treat a vascular dementia. In some cases, compositions and formulations herein can be used to treat a frontotemporal dementia.
• a ⁇ and ⁇ -syn can act synergistically to promote the aggregation and accumulation of each other, as well as promoting neurofibrillary tangles (NFTs) to create a more severe pathology in dementias that is not simply additive. Treatments are needed to address the causes and effects of mixed-proteinopathies as they define dementia patient populations more precisely than clinical impressions.
• RAP-103 and the other peptides disclosed herein unexpectedly can block the combined effects of amyloid-beta and alpha-synuclein on TNF ⁇ secretion by monocytes.
• the results herein show that when both amyloid-beta and alpha-synuclein are present, as occurs in mixed-dementias, a synergistic release of neurotoxic TNF ⁇ secretion by human monocytes occurs. Not being bound to any theories, this may occur due to the formation of a novel combined oligomeric toxic species formed from the interactions of both oligomers.
• RAP-103 has an unexpected effect on a neurotoxic process (e.g., reducing TNF ⁇ secretion) occurring in patients with mixed-proteinopathies that contributes to accelerated cognitive decline.
• the peptides herein can be used to treat subjects with a mixed proteinopathy.
• the peptides herein can directly block the individual direct effects of amyloid- beta and alpha-synuclein on neuronal synapse formation.
• the peptides herein may directly block the combined effects of amyloid-beta and alpha-synuclein on neuronal synapse formation.
• compositions and formulations herein can be used to treat other diseases and/or conditions such as a postural instability, a gait disturbance, a balance issue, a loss of bladder control, an urinary incontinence, or any combination thereof.
• GT Docket No.199260-717601 In certain instances, the compositions herein can be used to treat postural instability. In some cases, postural instability can be described as the inability to maintain equilibrium under dynamic and static conditions such as preparation of movements, perturbations, and quiet stance.
• ADRD Alzheimer Disease Related Dementia
• a peptide herein can lower neurodegenerative cytokines including IL-1, IL-6, IL-8 and TNF-alpha as compared to the cytokine level before treatment.
• a peptide can block microglial, astrocyte activation and infiltration of immune cells into CNS.
• a peptide herein can antagonize a cluster of chemokine receptors to promote neuro regeneration of spines and synapses.
• a peptide herein can reduce the synergistic effect of amyloid beta (A ⁇ ) and alpha synuclein ( ⁇ -Syn).
• a ⁇ amyloid beta
• ⁇ -Syn alpha synuclein
• a peptide herein can reduce cytokine (e.g., TNF-alpha) release in monocytes exposed to A ⁇ and ⁇ -Syn by at least about: 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, GT Docket No.199260-717601 95%, or 100% as compared to monocytes not exposed to A ⁇ and ⁇ -Syn.
• cytokine e.g., TNF-alpha
• a peptide herein can reduce cytokine (e.g., TNF-alpha) release in monocytes exposed to A ⁇ and ⁇ -Syn by about: 5% to about 100%, 5% to about 25%, 10% to about 30%, 40% to about 60%, 30% to about 70%, 45% to about 75%, 50% to about 80%, 60% to about 75%, 60% to about 70%, 65% to about 80%, 70% to about 80%, 80% to about 90%, 85% to about 95%, or about 90% to about 100% as compared to monocytes not exposed to A ⁇ and ⁇ -Syn.
• cytokine e.g., TNF-alpha
• a peptide herein may comprise up to eight or more than eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D- Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof, and
• a peptide herein can comprise at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D- Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; wherein F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; wherein G is D-Thr, D-Ser, D-Asn, D-Arg, D- Gln, D-Lys, or D-Trp, or a derivative of any of these; wherein H is D-Tyr, or a derivative thereof; and wherein I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these.
• peptides in a composition may be used to reverse loss of synapses and/or dendritic spines.
• peptides in a composition may be used to induce growth of a synapse.
• peptides in a composition may be used to induce growth of a dendritic spine.
• peptides in a composition may be used to induce growth of a neuronal growth cone.
• peptides in a composition may be used to prevent and/or reverse actin rod formation.
• peptides in a composition may be used to prevent and/or reverse cofilin rod formation.
• peptides in a composition may be used to prevent actin and cofilin rod formation. In some cases, peptides in a composition may be used to reverse actin and cofilin rod formation.
• RAP peptides can inhibit rod formation by targeting the PrPC-lipid raft enlargement and/or NOX recruitment that is mediated by binding of A ⁇ d/t and/or other rod inducers. In some cases, a peptide herein can inhibit rod formation by targeting the PrPC-lipid raft enlargement and/or NOX recruitment that is mediated by binding of A ⁇ d/t and/or other rod inducers.
• the multi-chemokine receptor antagonist peptide RAP-103 (All D-peptide- Thr-Thr-Asn- Tyr-Thr (SEQ ID NO: 3)) is being developed to provide a treatment for multifactorial neurological diseases and other disease. Treatment with a peptide disclosed herein surprisingly and unexpectedly led to improvement in cognitive function and improved postural stability of a subject with an advanced dementia and postural instability. In some cases, RAP-103 and the other peptides disclosed herein can be used to treat a multifactorial neurological diseases and/or other disease.
• Peptides [60] As used herein, amino acids can be referenced by their one or three letter codes, which are shown in Table 1.
• Amino acid nfiguration at the alpha carbon can be D or L – r non-identical substituents on its alpha carbon atom.
• the designations D and L should not be confused with one letter amino acid codes.
• D amino acids are designated with a D in front of the amino acid (e.g., D-Ser, dA). If the amino acid has four non-identical substituents on its alpha carbon atom, and the amino acid is not designated with a D in front of the amino acid, the amino acid can be of the L configuration.
• GT Docket No.199260-717601 The amino acid glycine, lacking four non-identical substituents on its alpha carbon atom, may not be D or L.
• Peptides herein can include peptides in Table 2.
• Table 2 Peptide sequences Peptide Sequences n 1) o [63] Wherein in the tab e, pept des N (S Q NO: 3) ( -103), SSTYR (SEQ ID NO: 4), STNYT (SEQ ID NO: 5) and ASTTTNYT (SEQ ID NO: 8) (RAP-310) are all D-peptides such that each amino acid in the peptide is in the D configuration. Wherein in the table, each amino acid of peptide NTSYG (SEQ ID NO: 6), except for glycine, is in the D configuration.
• each amino acid of peptide ETWYS (SEQ ID NO: 9) is in the D configuration.
• dASTTTNYT (SEQ ID NO: 2) the alanine is in the D configuration, and all other amino acids in peptide 5 are in the L configuration.
• dASTTTNYT-NH2 (SEQ ID NO: 1) the alanine is in the D configuration, and all other amino acids in peptide 5 are in the L configuration.
• a peptide such as TTNYT (SEQ ID NO: 3) can comprise a N- terminal methyl group (e.g., N-methyl-TTNYT (SEQ ID NO: 10)).
• a peptide can comprise an amide.
• ASTTTNYT SEQ ID NO: 8
• ASTTTNYT-amide SEQ ID NO: 7
• Peptide Compositions GT Docket No.199260-717601 [64]
• a composition which comprises a peptide wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; wherein F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; wherein G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; wherein H
• E can be D-Thr. In some instances, F can be D-Thr. In some instances, E can be D-Thr and F can be D-Thr. In some instances, G can be D-Asn. In some instances, F can be D-Thr and G can be D-Asn. In some instances, E can be D-Thr, F can be D-Thr, and G can be D-Asn. In some instances, H can be D-Tyr. In some instances, E can be D-Thr and H can be D- Tyr. In some instances, G can be D-Asn and H can be D-Tyr. In some instances, I can be D- Thr.
• E can be D-Thr
• F can be D-Thr
• G can be D-Asn
• H can be D-Tyr
• I can be D-Thr.
• the peptide may comprise at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln,
• A can be D-Ala.
• B can be D-Ser. In some instances, B can be D-Thr. In some instances, A can be D-Ala and B can be D-Ser. In some instances, A can be D-Ala and B can be D-Thr. In some instances, C can be D-Ser. In some instances, C can be D- Thr. In some instances, B can be D-Ser and C can be D-Ser. In some instances, B can be D-Thr and C can be D-Ser. In some instances, B can be D-Thr and C can be D-Ser. In some instances, B can be D-Thr and C can be D-Thr. In some instances, E can be D-Thr. In some instances, F can be D-Thr.
• E can be D-Thr and F can be D-Thr.
• G can be D-Asn.
• F can be D-Thr and G can be D- Asn.
• E can be D-Thr
• F can be D-Thr
• G can be D-Asn.
• H can be D-Tyr.
• E can be D-Thr and H can be D-Tyr.
• G can be D-Asn and H can be D-Tyr.
• I can be D-Thr.
• E can be D- Thr
• F can be D-Thr
• G can be D-Asn
• H can be D-Tyr
• I can be D-Thr.
• E can be D- Thr
• F can be D-Thr
• G can be D-Asn
• H can be D-Tyr
• I can be D-Thr.
• a peptide at the C terminus can be esterified, glycosylated, or amidated at the C terminus.
• I or a derivative thereof can be esterified, glycosylated, or amidated at the C terminus.
• the peptide sequence can comprise a sequence of ASTTTNYT (SEQ ID NO: 11), where each amino acid, individually, can be of the L or of the D configuration; in some instances, all amino acids in the sequence ASTTTNYT (SEQ ID NO: 12) can be in the L configuration; in some instances, all amino acids in the sequence ASTTTNYT (SEQ ID NO: 8) can be of the D configuration.
• the peptide sequence can comprise a sequence of SSTYR (SEQ ID NO: 13), where each amino acid, individually, can be of the L or of the D configuration; in some instances, all amino acids in the sequence SSTYR (SEQ ID NO: 14) can be in the L configuration; in some instances, all amino acids in the sequence SSTYR (SEQ ID NO: 4) can be of the D configuration.
• the peptide sequence can comprise a sequence of NTSYG (SEQ ID NO: 17), where each amino acid, individually, can be of the L or of the D configuration; in some instances, all amino acids in the sequence NTSYG (SEQ ID NO: 18) can be in the L configuration; in some instances, all amino acids in the sequence NTSYG (SEQ ID NO: 19) can be of the D configuration.
• the peptide sequence can comprise a sequence of TTNYT (SEQ ID NO: 20), where each amino acid, individually, can be of the L or of the D configuration; in some instances, all amino acids in the sequence TTNYT (SEQ ID NO: 21) can be in the L configuration; in some instances, all amino acids in the sequence TTNYT (SEQ ID NO: 3) can be of the D configuration. In some cases, all amino acids in the sequence TTNTY (SEQ ID NO: 22) can be of the D configuration.
• ASTTTNYT-NH2 (SEQ ID NO: 23), where each amino acid, individually, can be of the L or of the D configuration; in some instances, all amino acids in the sequence ASTTTNYT-NH2 (SEQ ID NO: 24) can be in the L configuration; in some instances, all amino acids in the sequence ASTTTNYT-NH 2 (SEQ ID NO: 7) can be of the D configuration.
• the A in the sequence ASTTTNYT-NH2 (SEQ ID NO: 1) can be in the D configuration GT Docket No.199260-717601 and all other amino acids in this sequence can be in the L configuration.
• the peptide sequence is a multi-chemokine receptor antagonist RAP-103 (R103) (All D-peptide- Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 3)) as shown in FIGS.1 and 2.
• RAP-103 RAP-103
• the peptide described herein can be in the form of a pharmaceutically acceptable salt, such as acetate.
• compositions An active pharmaceutical ingredient may be any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances may be intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body.
• compositions herein comprise peptides as an active pharmaceutical ingredient. In some cases, compositions herein comprise pharmaceutical compositions.
• the peptide can be formulated as a pill.
• a peptide herein can be formulated as a pharmaceutical composition with an additional therapy.
• the additional therapy can comprise an GT Docket No.199260-717601 aducanumab, a lecanemab, a remternetug, a derivative of any of these, a biosimilar of any of these, or a salt of any of these.
• a peptide herein can be formulated as a first pharmaceutical composition and an additional therapy can be formulated as a second pharmaceutical composition.
• Representative Acids for Salts [78]
• the pharmaceutically acceptable salt of the peptide can be formed from the peptide and an acid.
• the acid can be at least one of: 1-hydroxy-2- naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D),
• a salt herein can comprise a pharmaceutically acceptable salt.
• the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′- dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate,
• a salt of a peptide or derivative thereof or a compound can be a Zwitterionic salt.
• the pharmaceutical composition comprising the salt of the pharmaceutically active ingredient, wherein the salt comprises an organic salt, an inorganic salt, or any combination thereof.
• an organic salt may comprise a phosphinate (e.g., sodium hypophosphite), a hydrazinium salt, a urate, a diazonium salt, an oxalate salt, a tartrate, a choline chloride.
• an inorganic salt may be sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, potassium chloride, sodium sulfate, calcium carbonate, calcium phosphate, or any combination thereof.
• the pharmaceutical composition comprising the salt of the pharmaceutically active ingredient, wherein the salt comprises an HCl salt, an ascorbic acid salt, a mandelic acid salt, an aspartic acid salt, a carbonic acid salt, a citric acid salt, a formic acid salt, a glutamic acid salt, a lactic acid salt, a lauric acid salt, a maleic acid salt, a borate salt, a bitartrate salt, a palmitic acid salt, a phosphoric acid salt, or any combination thereof.
• the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′- dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as
• a carrier, a diluent, and/or an excipient can include pharmaceutically acceptable carriers, diluents, and/or excipients.
• excipient can refer to a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts, and/or to confer a therapeutic enhancement on the active ingredient(s) in the final dosage form. Excipients may facilitate drug absorption, reduce viscosity, or enhance solubility.
• Excipients may also facilitate the handling of the active ingredients, improve in vitro stability, and/or extend GT Docket No.199260-717601 pharmaceutical product shelf life. Excipient selection may vary with the route of administration for drug delivery, the unit dose, as well as the active ingredients comprising the composition.
• a pharmaceutically acceptable excipient can comprise anhydrous calcium phosphate, dihydrate calcium phosphate, hydroxypropyl methylcellulose, croscarmellose sodium, GMO-free croscarmellose sodium, carbomers, magnesium aluminometasilicate, mannitol, povidone (PVP), crospovidone, sorbitol, dimethicone, sodium stearyl fumarate, sodium starch glycollate, hydroxypropylcellulose, native corn starch, modified corn starch, carrageenan, alginates, silicon dioxide, microcrystalline cellulose, carboxymethylcellulose sodium, alginates, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na CMC), carbomers, natural gums, sorbitol, maltitol, glucose syrup, silicones, carbomers, fatty alcohols, alcohols, carbohydrates, petrolatum derivatives, butters, waxes, DMSO Procipient®, esters, fatty acids
• a pharmaceutically acceptable excipient can comprise acacia, acesulfame potassium, acetic acid, glacial, acetone, acetyl tributyl citrate, acetyl triethyl citrate, agar, albumin, alcohol, alginic acid, aliphatic polyesters, alitame, almond oil, alpha tocopherol, aluminum hydroxide adjuvant, aluminum oxide, aluminum phosphate adjuvant, aluminum stearate, ammonia solution, ammonium alginate, ascorbic acid, ascorbyl palmitate, aspartame, attapulgite, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, calcium alginate, calcium carbonate, calcium
• stearic acid pregelatinized, sterilizable maize
• stearyl alcohol sucralose, sucrose, sugar, compressible, sugar, confectioner’s, sugar spheres, sulfobutylether b-cyclodextrin, sulfuric acid, sunflower oil, suppository bases, hard fat, talc, tartaric acid, tetrafluoroethane, thaumatin, thimerosal, thymol, titanium dioxide, tragacanth, trehalose, triacetin, tributyl citrate, triethanolamine, triethyl citrate, vanillin, vegetable oil, hydrogenated, water, wax, anionic emulsifying, wax (e.g.
• a pharmaceutically acceptable excipient can comprise a carbohydrate, an alginate, povidone, a carbomer, a flavor, a natural gum, a silicone, an alcohol, a butter, a wax, a fatty acid, a preservative, a pharmaceutically acceptable salt of any of these, or any combination thereof.
• a pharmaceutically acceptable excipient can comprise a carbohydrate.
• the carbohydrate can comprise lactose, microcrystalline cellulose, cellulose, mannitol, sorbitol, starch, starch glycolate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, a cyclodextrin, maltodextrin, croscarmellose sodium, corn starch, carrageenan, sorbitol, maltitol, glucose, a pharmaceutically acceptable salt of any of these, or any combination thereof.
• the weigh to weight ratio of: a) the pharmaceutically acceptable excipient and b) the active ingredient ranges from about 1:1 to about 10000:1.
• the weight to weight ratio of: a) the pharmaceutically acceptable excipient and b) the active ingredient ranges from about 1:1 to about 20:1, about 1:1 to about 15:1, about 1:1 to about 10:1, about 1:1 to about 5:1, about 1:1 to about 2:1, about 2:1 to about 20:1, about 2:1 to about 15:1, about 2:1 to about 10:1, about 2:1 to about 5:1, about 5:1 to about 20:1, about 5:1 to about 15:1, about 5:1 to about 10:1, about 10:1 to about 15:1, about 10:1 to about 20:1, about 15:1 to about 20:1, about 18:1 to about 25:1, or about 25:1 to about 30:1.
• the weight to weight ratio of: a) the pharmaceutically acceptable excipient and b) the active ingredient may be about: 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, or 30:1
• the weight to weight ratio of: a) the pharmaceutically acceptable excipient and b) the active ingredient ranges from about 1:1 to about 1:10, about 1:1 to about 1:8, about 1:1 to about 1:5, about 1:1 to about 1:2, about 1:2 to about 1:10, about 1:2 to about 1:8, about 1:2 to about 1:5, about 1:5 to about 1:10, about 1:5 to about 1:8, about 1:8 to about 1:10.
• a pharmaceutically acceptable carrier or diluent can comprise water.
• the water can be sterile.
• the water can contain a buffer, a carbohydrate, a salt, a pH adjuster, or any combination of these.
• Simple sugars such as mannitol, sucrose, glucose, or trehalose may be added to inhibit peptide or peptide aggregation, in amounts from 1 to 50 mgs/ml.
• Citrate can be used as a buffer.
• sodium chloride and phosphate salts may or may not be employed. Larger polysaccharides may also be used to enhance stability.
• a carrier may refer to reagents, cells, compounds, materials, compositions, dosage forms, or any combination thereof that can be compatible with agents that can be administered therapeutically.
• a carrier can be suitable for use in contact with a tissue of a subject.
• a carrier may not have a toxicity, an irritation, an allergic response, or any combination thereof.
• a carrier that may be suitable for use can include a liquid, a solid material (e.g., a pill, or a suppository) or any combination thereof.
• a carrier can be designed to resist degradation within the body (non-biodegradable) or they may be designed to degrade within the body (biodegradable).
• a biodegradable material can further be bioresorbable or bioabsorbable.
• a biodegradable material can be degraded and eliminated from the body by conversion into other materials or breakdown and elimination through natural pathways.
• Oral Bioavailability [90]
• the peptides, derivatives thereof, or salts of any of these can be orally bioavailable.
• the pharmaceutical composition is formulated for oral administration.
• the percent oral bioavailability can be at least, at least about, or about: 5%, 10% 20%, 30%, 40%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% after administration.
• a pharmaceutical composition herein can be formulated as a pill, a capsule, a liquid, or a tablet, for oral administration.
• RAP-103 quickly entered the brain by oral, and IV dosing in rodents and non- human primates (Rhesus macaque). The non-human primates showed oral bioavailability of 88%.
• RAP-103 preferentially entered the brain by oral compared to IV dosing (as shown in FIG.1A), a GT Docket No.199260-717601 feature that supports its use in the treatment of a multifactorial neurological disease, a postural instability, or both.
• the peptides, derivatives, salts of any of these can be administered to a subject, who can be a subject in need thereof.
• the subject has a multifactorial neurological disease.
• the subject has a postural instability.
• the subject can be a human, can be a male, or can be a female.
• the subject can be under 18 years of age.
• the subject can be over 18 years of age.
• the subject can be a child, for example a subject from about: 0-18 years of age.
• the subject can be an adult, for example a subject who is equal to, or greater than 18 years of age.
• a subject can be from about 18 to about 75 years of age. In some cases, a subject can be from about 65 to about 75 years of age. In some cases, a subject can be from about 18 to about 64 years of age. In some instances, the subject can range from about 1 year of age to about 120 years of age. In some cases, a subject can be a subject who is equal to, or greater than 65 years of age. In some embodiments, a subject can be from about 1 day to about 10 months old, from about 9 months to about 24 months old, from about 1 year to about 8 years old, from about 5 years to about 25 years old, from about 20 years to about 50 years old, from about 40 years to about 80 years old, or from about 50 years to about 130 years old.
• administer can refer to methods that can be used to enable delivery of compounds, peptides, derivatives thereof, or salts of any of these, or compositions described herein, to the desired site of biological action.
• delivery can include injection, inhalation, catheterization, gastrostomy tube administration, intravenous administration, intraosseous administration, ocular administration, otic administration, topical administration, transdermal administration, local administration, oral administration, rectal administration, nasal administration, intravaginal administration, intracavernous administration, transurethral administration, buccal administration, sublingual administration, or a combination thereof.
• delivery can comprise oral administration, intranasal administration, or intravenous administration.
• the pharmaceutical composition can be administered by: an oral route, an injection route, a sublingual route, a buccal route, a rectal route, a vaginal route, an ocular route, an otic route, a nasal route, an internasal route, an inhalation route, a cutaneous route, a subcutaneous route, an intramuscular route, an intravenous route, a systemic route, a local route, GT Docket No.199260-717601 a transdermal route, or any combination thereof. Delivery can include direct application to the affect tissue or region of the body.
• Delivery can include a parenchymal injection, an intra-thecal injection, an intra-ventricular injection, or an intra-cisternal injection.
• a composition provided herein can be administered by any method.
• a method of administration can be by intraarterial injection, intracerebroventricular injection, intracisternal injection, intramuscular injection, intraorbital injection, intraparenchymal injection, intraperitoneal injection, intraspinal injection, intrathecal injection, intravenous injection, intraventricular injection, stereotactic injection, subcutaneous injection, epidural, or any combination thereof.
• Delivery can include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular or infusion administration).
• delivery can comprise a nanoparticle, a viral vector, a viral-like particle, a liposome, an exosome, an extracellular vesicle, a microrobot, a microneedle, an implant, or a combination thereof.
• delivery can be from a device.
• delivery can be administered by a pump, an infusion pump or a combination thereof.
• delivery can be by an enema, an eye drop, a nasal spray, an ear drop, or any combination thereof.
• delivery can comprise an inhaler, a diffuser, a nebulizer, or a combination thereof.
• Delivery can include topical administration (such as a lotion, a cream, a patch, a gel, a spray, a drip, a liquid formulation, an ointment) to an external surface of a surface, such as a skin.
• a subject can administer the composition in the absence of supervision.
• a subject can administer the composition under the supervision of a medical professional (e.g., a physician, nurse, physician’s assistant, orderly, hospice worker, etc.).
• a medical professional can administer the composition.
• the subject can administer the composition.
• administering can be performed at least about: 1 time per day, 2 times per day, 3 times per day, 4 times per day, 5 times per day, 6 times per day or more than 6 times per day. In some cases, administering can be performed daily, weekly, monthly, or as needed. In some embodiments, administering can be conducted one, twice, three, or four times per day. In some cases, administration can be performed by a subject (e.g., the patient), a health care provider, or both.
• Administration or application of a composition disclosed herein can be performed for a treatment duration of at least about, or equal to: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, GT Docket No.199260-717601 95, 96, 97, 98, 99, 100, 150, 200, 300, 400, 500, 600, 700,
• a treatment duration can be from about 1 to about 30 days, from about 2 to about 30 days, from about 3 to about 30 days, from about 4 to about 30 days, from about 5 to about 30 days, from about 6 to about 30 days, from about 7 to about 30 days, from about 8 to about 30 days, from about 9 to about 30 days, from about 10 to about 30 days, from about 11 to about 30 days, from about 12 to about 30 days, from about 13 to about 30 days, from about 14 to about 30 days, from about 15 to about 30 days, from about 16 to about 30 days, from about 17 to about 30 days, from about 18 to about 30 days, from about 19 to about 30 days, from about 20 to about 30 days, from about 21 to about 30 days, from about 22 to about 30 days, from about 23 to about 30 days, from about 24 to about 30 days, from about 25 to about 30 days, from about 26 to about 30 days, from about 27 to about 30 days, from about 28 to about 30 days, from about 29 to about 30 days, from about 1 to about 90 days, from about 30 day to
• Administration or application of a composition disclosed herein can be performed for a treatment duration of at least about 1 week, at least about 1 month, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, or for life.
• Administration can be performed repeatedly over a lifetime of a subject, such as once a month or once a year for the lifetime of a subject.
• Administration can be performed repeatedly over a substantial portion of a subject’s life, such as once a day, once a week, once a month or once a year for at least about 1 year, 5 years, 10 years, 15 years, 20 years, 25 years, 30 years, or more.
• Administration or application of a composition disclosed herein can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times in a 24- hour period.
• administration or application of a composition disclosed herein can be performed continuously throughout a 24-hour period, for example, when an implant can be used for administration.
• administration or application of composition disclosed herein can be performed at least: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times a week. In some cases, administration or application of composition disclosed herein can be performed at least: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, GT Docket No.199260-717601 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, or more than 90 times a
• a composition can be administered as a single dose or as divided doses.
• the compositions described herein can be administered at a first time point and a second time point.
• a composition can be administered such that a first administration can be administered before the other with a difference in administration time of about: 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year or more.
• administering can be performed for about: 1 day to about 8 days, 1 week to about 5 weeks, 1 month to about 12 months, 1 year to about 3 years, 3 years to about 10 years, 10 years to about 50 years, 25 years to about 100 years, or 50 years to about 130 years.
• the composition can be administered as needed, or for: one day, two days, three days, four days, five days, six days, a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, two years, or chronically.
• the peptide or the derivative thereof or the salt of any of these can be administered in a pharmaceutical composition, which can be in unit dose form.
• the amount of the peptide, or the derivative thereof, or the salt of any of these can be dosed in an amount ranging from about: 0.0001 mg/ kg of body weight of the subject to about 100 g/kg of body weight of the subject; 0.001 mg/kg of body weight of the subject to about 100 g/kg of body weight of the subject; 0.01 mg/kg of body weight of the subject to about 10 g/kg of body weight of the subject; 1 mg/kg of body weight of the subject to about 1 g/kg of body weight of the subject; or 10 mg/kg of body weight of the subject to about 500 mg/kg of body weight of the subject.
• the dosage of a peptide per subject body weight, a derivative thereof, or salt of any of these can be equal to, less than about, or more than about: 0.0001 grams (g) / kilogram (kg), 0.001 g/kg, 0.01 g/kg, 0.1 g/kg, 0.2 g/kg, 0.3 g/kg, 0.4 g/kg, 0.5 g/kg, 0.6 g/kg, 0.7 g/kg, 0.8 g/kg, 0.9 g/kg, 1 g/kg, 2 g/kg, 3 g/kg, 4 g/kg, 5 g/kg, 6 g/kg, 7 g/kg, 8 g/kg, 9 g/kg, 10 g/kg, 15 g/kg, 20 g/kg, 25 g/kg, 30 g/kg, 35 g/kg, 40 g/kg, 45 g/kg, 50 g/kg, 55 g/kg, 60 g/kg, 65
• the amount of a peptide, derivative thereof, or salt of any of these, which can be a pharmaceutically acceptable salt, that is dosed to the patient can range from 0.00001 mg to 1000 g. In some cases, an amount of a peptide, a derivative thereof, or salt of any of these in a GT Docket No.199260-717601 composition can range from about 0.005 mg to about 1000 mg.
• an amount of a peptide, a derivative thereof, or salt of any of these in a composition can be equal to, less than about, or more than about: 0.0001 g, 0.001 g, 0.01 g, 0.1 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g, 45 g, 50 g, 55 g, 60 g, 65 g, 70 g, 75 g, 80 g, 85 g, 90 g, 95 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900 g, or 1000 g.
• an amount of a peptide, a derivative thereof, or salt of any of these in a composition can be equal to, less than about, or more than about: 0.0001 mg, 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg,
• an amount of a peptide, a derivative thereof, or salt of any of these in a composition can be equal to, less than about, or more than about: 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg. In some cases, an amount of a peptide, a derivative thereof, or salt of any of these can range from about: 0.0001 mg to about 1 mg, 0.01 mg to about 1 mg, 0.1 mg to about 1 mg, 1 mg to about 10 mg, 10 mg to about 160 mg, 10 mg to about 100 mg, or 100 mg to about 1000 mg.
• an amount of a peptide, a derivative thereof, or salt of any of these in a composition can range from about: 0.0001 g to about 1 g, 0.01 g to about 1 g, 0.1 g to about 1 g, 1 g to about 10 g, 10 g to about 100 g, or 100 g to about 1000 g.
• a composition such as a pharmaceutical composition may be in the form of a capsule, a tablet, a gummy, an oil, a liquid, a tincture, a lotion, a cream, a balm, a candy, a syrup, a food, a drink, an oil, a suppository, or a liquid for injection.
• a composition can be in the form of an intra venous liquid for injection, an intra muscular liquid for injection, or subcutaneous liquid for injection. Diagnoses [103] In some embodiments, a method can further comprise diagnosing a subject as having the disease. In some cases, a disease can be a multifactorial neurological disease. In some cases, a disease can comprise a postural instability, a gait disturbance, a balance issue, a loss of bladder GT Docket No.199260-717601 control, an urinary incontinence, and any combination thereof. In some embodiments, a diagnosing can comprise employing an in vitro diagnostic. In some embodiments, the in vitro diagnostic can be a companion diagnostic. In some cases, a disease can be a mild cognitive impairment or a mild dementia.
• a diagnosis can comprise a physical examination, a radiological image (e.g., an imaging diagnostic), a neurological examination, a blood, body fluid or tissue test, a hematology exam, clinical chemistry exam, a urinalysis exam, an antibody test, or any combination thereof.
• the diagnostic analyte can be a cytokine, such as a proinflammatory cytokine or a chemokine, or their receptors.
• a diagnosis can comprise a radiological image and the radiological image can comprise: a computed tomography (CT) image, an X-Ray image, a magnetic resonance image (MRI), an ultrasound image, or any combination thereof.
• CT computed tomography
• MRI magnetic resonance image
• Imaging markers of brain inflammation may be used to support diagnoses or response to treatment.
• a diagnosis can comprise detecting the presence of alpha synuclein, amyloid beta (A ⁇ ), tau, or any combination thereof with an in vitro or in vivo assay.
• synapse loss may be diagnosed by SVA2 protein imaging in brain.
• a method may further comprise diagnosing a subject as having the disease.
• a diagnosing may comprise employing an in vitro diagnostic.
• a diagnosing may comprise employing an in vivo diagnostic
• the in vitro diagnostic may be a companion diagnostic.
• kits comprising the pharmaceutical composition contained at least in part in packaging (e.g., a container). Also disclosed herein are methods of making kits comprising a pharmaceutical composition contained at least in part in packaging. In some cases, kits can comprise a container, such as a metal container, a plastic container, a glass container, or any suitable container.
• a kit can comprise a peptide disclosed herein and an additional therapy such as, an aducanumab, a lecanemab, a remternetug, or any combination GT Docket No.199260-717601 thereof.
• a kit can comprise an excipient, a diluent, a carrier or any combination thereof.
• a kit can comprise a peptide disclosed herein in a first container and an additional therapy such as an aducanumab, a lecanemab, a remternetug, or any combination thereof in a second container.
• an aducanumab, a lecanemab, or a remternetug can be the derivative of any of these, the biosimilar of any of these, or the salt of any of these.
• Methods of Treatment [110] Also disclosed herein are methods of treating a disease or condition comprising administering a therapeutically effective amount of a pharmaceutical composition, such as a peptide disclosed herein. In some embodiments, compositions and formulations described herein can be used to treat diseases and conditions disclosed below. [111] In some embodiments, the disease is a multifactorial neurological disease. In some instances, the multifactorial neurological disease is a mixed dementia.
• a mixed dementia can comprise a disease with two or more pathogenic proteins, for example alpha synuclein, tau, and/or amyloid beta.
• the multifactorial neurological disease is a Lewy Body variant of Alzheimer’s Disease (LBVAD), an Alzheimer’s Disease related dementia (ADRD), a vascular dementia, or any combination thereof.
• a vascular dementia can comprise a subcortical vascular dementia, a stroke-related dementia, a multi-infarct dementia, a mixed dementia, or any combination thereof.
• a multifactorial neurological disease can comprise a vascular disease, an alpha synuclein deposition in the brain, a tau deposition in the brain, an amyloid beta (A ⁇ ) deposition in the brain, or any combination thereof.
• a vascular disease can comprise a reduced blood supply in the brain as compared to a subject without the vascular disease.
• a vascular dementia can comprise a reduced blood supply in the brain as compared to a subject without the vascular dementia.
• the blood supply can be measured by an imaging technique.
• a composition herein can be used to treat multi-infarct dementia (MID).
• MID can comprise vascular cognitive impairment.
• multi-infarct dementia can occur after repeated small, often "silent,” blockages affect blood flow to a certain part of the brain.
• the changes that occur after each blockage may not be apparent, but over time, the combined effect starts to cause symptoms of impairment.
• MID typically affects people between the ages of 60 and 75 with high blood pressure, diabetes, and smoking common risk factors.
• amyloid beta can be present in brains of MID patients and may GT Docket No.199260-717601 exacerbate the vascular pathology.
• symptoms of multi-infarct dementia may begin suddenly and include confusion or problems with short-term memory, wandering or getting lost in familiar places, walking with rapid, shuffling steps, loss of bladder or bowel control, laughing or crying at inappropriate times, difficulty following instructions, and issues counting money and making monetary transactions.
• the symptoms and/or pathology of multi-infarct dementia may differ from other dementias.
• Alzheimer’s disease is characterized by memory loss
• Lewy body dementia is characterized by visual hallucinations and Parkinson’s disease-like symptoms.
• compositions and formulations can be used to treat a tauopathy.
• a tauopathy can comprise a primary tauopathy.
• a tauopathy can comprise a secondary tauopathy.
• compositions and formulations can be used to treat a progressive supranuclear palsy, a frontotemporal lobar degeneration, a chronic traumatic encephalopathy.
• compositions and formulations can be used to treat a parkinsonism.
• a parkinsonism can be a constellation of signs and symptoms that are characteristically observed in Parkinson’s disease, but that are not due to Parkinson’s disease.
• Parkinsonism is a primary type of hypokinetic movement disorder, manifesting as a rigidity, a tremor, a bradykinesia, or any combination thereof.
• compositions and formulations can be used to treat a mild cognitive impairment and/or a mild dementia.
• a mild cognitive impairment and/or mild dementia can comprise an Alzheimer’s disease, a mixed dementia, a vascular dementia, a disease with an amyloid beta or any combination thereof.
• the mild cognitive impairment or the mild dementia comprises deposition in a brain of: an alpha synuclein, a tau, an amyloid beta, or any combination thereof.
• composition and formulations can be used to a treat young onset dementia, an early onset dementia, an atypical Alzheimer’s Disease, a frontal variant AD (fvAD), a posterior cortical atrophy (PCA), a Benson’s syndrome, a cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts, a corticobasal syndrome, a normal pressure hydrocephalus, a primary progressive aphasia, a progressive supranuclear palsy, a Wernicke-Korsakoff syndrome, an Argyrophilic grain disease, a Richardson’s syndrome, or any combination thereof.
• composition and formulations can be used to treat Pick's disease, Huntington’s disease, leukoencephalopathy, chronic traumatic encephalopathy dementia, a cognitive decline related to diabetes, an amyotrophic lateral sclerosis, or any combination thereof.
• compositions and formulations can be used to treat a liver disease such as GT Docket No.199260-717601 cirrhosis.
• compositions and formulations herein can be used to treat a dementia resulting from a cirrhosis.
• a cirrhosis can comprise a hepatitis, an alcohol abuse, a nonalcoholic fatty liver disease or any combination thereof.
• a cirrhosis can comprise a stage I, a stage II, a stage III, or a stage IV cirrhosis.
• a cirrhosis can be hepatitis C cirrhosis, hepatitis B cirrhosis, an alcohol-related liver disease, non-alcoholic fatty liver disease, or any combination thereof.
• compositions and formulations herein can be used to treat a cirrhosis and a dementia.
• compositions and formulations can be used to treat an Alzheimer’s Disease related dementia (ADRD), an Alzheimer’s Disease, a Parkinson’s disease, a multiple- etiology dementia, a mixed-etiology dementia, a mixed dementia, a dementia-multifactorial, a corticobasal degeneration (CBD), a cortical atrophy (e.g., brain atrophy), a posterior-cortical- atrophy, a multiple system atrophy (MSA), a frontotemporal degeneration, a frontotemporal dementia, a vascular dementia, a Parkinson's disease dementia, a dementia with Lewy Bodies (e.g., Lewy Body Dementia), an HIV-associated neurocognitive disorder (HAND), a long COVID (e.g., post-COVID), an alcohol-related dementia, Creutzfeldt-Jakob disease, a prion dementia, a Down syndrome, or any combination thereof.
• ADRD Alzheimer’s Disease related dementia
• ADRD Alzheimer
• compositions and formulations can be used to treat a transmissible spongiform encephalopathy, like a Creutzfeldt-Jakob disease.
• a transmissible spongiform encephalopathy can comprise a prion disease.
• a transmissible spongiform encephalopathy can comprise a variant Creutzfeldt-Jakob disease (vCJD), a bovine spongiform encephalopathy, a Gerstmann-Straussler-Scheinker syndrome, a fatal familial insomnia, a kuru, or any combination thereof.
• compositions and formulations can be used to treat vascular contributions to cognitive impairment and dementia (VCID).
• a long COVID can comprise a difficulty thinking, a difficulty concentrating, a brain fog, or any combination thereof.
• compositions and formulations can be used to treat a macular degeneration.
• a macular degeneration can comprise an age-related macular degeneration.
• a macular degeneration can comprise a dry macular degeneration.
• a macular degeneration can comprise a wet macular degeneration.
• compositions and formulations can be used to treat a post-traumatic stress disorder (PTSD), a depression, or both.
• PTSD post-traumatic stress disorder
• a depression can comprise a major depressive disorder, a persistent depressive disorder, a disruptive mood dysregulation disorder, a premenstrual dysphoric disorder, a depressive disorder due to hypothyroidism or due to Parkinson’s disease, or any combination thereof.
• compositions and formulations can be used to treat a PrP C -NOX-dependent pathway related GT Docket No.199260-717601 disease, an excitotoxic glutamate related disease, or any combination thereof.
• compositions and formulations can be used to treat NOX-dependent pathway related disease, or a PrP C dependent pathway disease.
• composition herein can be used to treat GPCR mGluR5, PirB, or any combination thereof related diseases.
• compositions and formulations can be used to treat a dementia with Lewy bodies and amyloid beta (A ⁇ ). In some embodiments, compositions and formulations can be used to treat a dementia with alpha-synuclein and amyloid beta (A ⁇ ). In some embodiments, compositions and formulations can be used to treat an idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD). In some embodiments, compositions and formulations can be used to treat a REM sleep behavior disorder. In some embodiments, compositions and formulations can be used to treat a disease caused by elevated IL-6. In some cases, a disease caused by elevated IL-6 can comprise a multifactorial neurological disease.
• compositions and formulations can be used to treat a hallucination, a sleep disorder cognitive decline, a sleep disorder, an ataxia, a gait disturbance, a postural instability, a balance issue, a tremor, a loss of bladder control, an urinary incontinence, an eye movement disorder, or any combination thereof.
• the disease is postural instability.
• an hallucination can comprise a visual hallucination, an auditory hallucination, an olfactory hallucination, a tactile hallucination, a gustatory hallucination, a general somatic hallucination, or any combination thereof.
• a sleep disorder can comprise a rapid eye movement sleep behavioral disorder, an apnea, a longer time in bed, habitual napping, or any combination thereof.
• a balance issue can comprise a benign paroxysmal positional vertigo, a vertigo, a labyrinthitis, a Méley’s Disease, a vestibular neuronitis, a perilymph fistula, a Mal de Debarquement Syndrome, or any combination thereof.
• a tremor can comprise a postural tremor, a kinetic tremor, an intention tremor, a task-specific tremor, an isometric tremor, an essential tremor, a dystonic tremor, a cerebellar tremor, a psychogenic tremor, a physiologic tremor, an enhanced physiologic tremor, a parkinsonian tremor, an orthostatic tremor, or any combination thereof.
• a urinary incontinence can comprise a stress incontinence, an urge incontinence, an overflow incontinence, a functional incontinence, a mixed incontinence, or any combination thereof.
• a loss of bladder control and comprise an overactive bladder.
• an eye movement disorder can comprise a strabismus, a nystagmus, an amblyopia, an esotropia, an exotropia, a hypertropia, or any combination thereof.
• an ataxia can comprise a Friedreich's ataxia, an ataxia- telangiectasia, a spinocerebellar ataxia, an episodic ataxia, an acquired ataxia, an idiopathic late- GT Docket No.199260-717601 onset cerebellar ataxia, a degenerative ataxia, a hereditary ataxia, or any combination thereof.
• a gait disturbance can comprise a propulsive gait, a scissor gait, a spastic gait, a steppage gait, a waddling gait, or any combination thereof.
• the postural instability can be from a neurological disease such as Parkinson’s disease. In some instances, the postural instability is not from Parkinson’s disease.
• compositions and formulations can be used to treat a spastic paraparesis, a spasticity, or any combination thereof.
• compositions and formulations can be used to treat a behavior change such as inappropriate social behavior, a loss of empathy, a lack of judgement, loss of inhibition, lack of interest, an apathy, a compulsive behavior, a decline in personal hygiene, a change in an eating habit (e.g., over eating sweets and/or carbohydrates), eating objects, or any combination thereof.
• compositions and formulations can be used to treat speech and language problems such as increasing trouble understanding written or spoken language, trouble naming things, hesitant speech, mistakes in sentence building or any combination thereof.
• compositions and formulations can be used to treat movement conditions such as tremors (as described above), rigidity, muscle spasms, muscle twitches, poor coordination, trouble swallowing, muscle weakness, inappropriate laughing, inappropriate crying, falls, trouble walking, or any combination thereof.
• compositions and formulations can be used to treat an emotional instability, a depression, an anxiety, a panic attack, a suicidal ideation, or any combination thereof.
• an emotional instability can comprise a range of emotions such as rage, grief, shame, panic, terror, emptiness, loneliness, or any combination thereof.
• emotional instability can comprise an emotionally unstable personality disorder.
• a depression can comprise a major depressive disorder, a bipolar depression, a perinatal depression, a postpartum depression, a persistent depressive disorder, a premenstrual dysphoric disorder, a psychotic depression, a seasonal affective disorder, atypical depression, or any combination thereof.
• an anxiety can comprise a generalized anxiety disorder, a obsessive- compulsive disorder, a panic disorder, a post-traumatic stress disorder, a social phobia, an agoraphobia, a phobia, a social anxiety disorder, a specific phobia, or any combination thereof.
• a panic attack can comprise an expected panic attack, or an unexpected panic attack.
• suicidal ideation can comprise an active suicidal ideation or a passive suicidal ideation.
• a peptide herein can be used to treat a side effect from an aducanumab, a lecanemab, GT Docket No.199260-717601 a remternetug, a derivative of any of these, a biosimilar of any of these, or a salt of any of these.
• a side effect can comprise a brain bleeding, a brain swelling, a small brain bleeding, a headache, falls, a diarrhea, an Amyloid-related imaging abnormalities (ARIA)-edema (ARIA- E), an ARIA-hemosiderin deposition (ARIA-H) microhemorrhage, an ARIA-H superficial siderosis, dizziness, a confusion, a delirium, an altered mental status, a disorientation, a hypersensitivity, an angioedema, a urticaria, an immunogenicity, feeling flushed, a chill(s), a fever, a rash, changes in blood pressure, a vision change, a joint pain, a nausea, a vomiting, a shortness of breath, a rash, a body ache, or any combination thereof
• Co-Therapies [121]
• a method may further comprise administering a second therapy to the subject.
• a pharmaceutical composition can further comprise a second therapy.
• a second therapy may comprise a carbidopa-levodopa, a carbidopa, a levodopa, a dopamine agonist, a pramipexole, a rotigotine, an apomorphine, an MAO-B inhibitor, a selegiline, a rasagiline, a safinamide, a catechol O-methyltransferase (COMT) inhibitor, an entacapone, a opicapone, an anticholinergic, a benztropine, a trihexyphenidyl, an amantadine, an adenosine receptor antagonist, an istradefylline, a pimavanserin, a derivative of any of these, a salt of any of these, or any combination thereof.
• a second therapy may comprise a carbidopa-levodopa, a carbidopa
• a second therapy can comprise a deep brain simulation or a surgery.
• a method herein can comprise treating a disease herein in a subject in need thereof.
• the method can comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease.
• the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these or DAPTA or a salt thereof; and II) a lecanemab
• a method herein can comprise treating a disease herein in a subject in need thereof.
• the method can comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease.
• the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt GT Docket No.199260-717601 thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or
• a method herein can comprise treating a disease herein in a subject in need thereof.
• the method can comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease.
• the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-
• a method herein can comprise treating a disease herein in a subject in need thereof.
• the method can comprise administering administering to the subject a therapeutically effective amount of: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-
• a second therapy can comprise a cholinesterase inhibitor.
• a cholinesterase inhibitor can comprise a galantamine, a rivastigmine, a donepezil, a salt of GT Docket No.199260-717601 any of these, or any combination thereof.
• a second therapy can comprise aducanumab, a derivative thereof, a biosimilar thereof, or a salt thereof.
• a second therapy can comprise an N-methyl D-aspartate antagonist, or a salt thereof.
• a N- methyl D-aspartate antagonist can comprise a memantine, or a salt thereof.
• a second therapy can comprise lecanemab, a derivative thereof, a biosimilar thereof, or a salt thereof.
• a second therapy can comprise a donepezil and a memantine, or a salt thereof of any of these.
• a second therapy can comprise a remternetug, a derivative thereof, a biosimilar thereof, or a salt thereof.
• a second therapy can comprise a tetrabenazine, a deutetrabenazine, a salt of any of these, or any combination thereof.
• a second therapy can comprise an antipsychotic drug.
• an antipsychotic drug can comprise a haloperidol, a fluphenazine, an olanzapine, an aripiprazole, a salt of any of these, or any combination thereof.
• a second therapy can comprise an amantadine, a levetiracetam, a clonazepam, a salt of any of these, or any combination thereof.
• a second therapy can comprise an antidepressant.
• an antidepressant can comprise a citalopram, an escitalopram, a fluoxetine, a sertraline, a salt of any of these, or any combination thereof.
• a second therapy can comprise an antipsychotic.
• an antipsychotic can comprise a quetiapine, an olanzapine, a salt of any of these, or any combination thereof.
• a second therapy can comprise a divalproex , a carbamazepine, a lamotrigine, a salt of any of these, or any combination thereof.
• a second therapy can comprise maraviroc, plerixafor (AMD3100), a salt of any of these, or any combination thereof.
• a composition described herein for use in the treatment of a disease can comprise maraviroc, plerixafor (AMD3100), a salt of any of these, or any combination thereof.
• a second therapy can comprise a high blood pressure medication, a high cholesterol medication, an anticoagulant medication, or a diabetes medication.
• a second therapy can comprise an aspirin, a clopidogrel, a niacin, or any combination thereof.
• a high cholesterol medication can comprise a bile acid sequestrant, a cholesterol absorption inhibitor, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, a adenosine triphosphate-citrate lyase (ACL) inhibitor, a medication to treat familial hypercholesterolemia, a salt of any of these, or any combination thereof.
• a high cholesterol medication can comprise a statin, or a salt thereof.
• a statin can comprise an atorvastatin, a fluvastatin, a lovastatin, a pravastatin, a pitavastatin, a rosuvastatin, a simvastatin, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise GT Docket No.199260-717601 a diuretic.
• a diuretic can comprise a hlorthalidone, a chlorothiazide, a hydrochlorothiazide, an indapamide, a metolazone, an amiloride, a spironolactone, a triamterene, a bumetanide, a furosemide, a torsemide, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise a beta blocker.
• a beta blocker can comprise an acebutolol, a atenolol, a betaxolol, a bisoprolol, a bisoprolol/hydrochlorothiazide, a metoprolol, a metoprolol tartrate or succinate, a nadolol, a pindolol, a propranolol, a solotol, a timolol, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise an angiotensin converting enzyme (ACE) inhibitors.
• ACE angiotensin converting enzyme
• an ACE inhibitor can comprise a benazepril, a captopril, an enalapril, afosinopril, a lisinopril, a moexipril, a perindopril, a quinapril, a ramipril, a trandolapril, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise an angiotensin II receptor blocker.
• an angiotensin II receptor blocker can comprise a candesartan, an eprosartan, an irbesartan, a losartan, a telmisartan, a valsartan, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise a calcium channel blocker.
• a calcium channel blocker can comprise amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise an alpha-blocker or an alpha-beta-blocker.
• an alpha-blocker or an alpha- beta-blocker can comprise a doxazosin, a prazosin, a terazosin, a carvedilol, a labetalol, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise a vasodilator such as a hydralazine, a minoxidil, a salt of any of these, or any combination thereof.
• a high blood pressure medication can comprise an aliskiren, an eplerenone, a spironolactone, a methyldopa, a clonidine, a guanfacine, a salt of any of these, or any combination thereof.
• an anticoagulant medication can comprise a warfarin, a rivaroxaban, a dabigatran, an apixaban, an edoxaban, an enoxaparin, a fondaparinux, a salt of any of these, or any combination thereof.
• an diabetes medication can comprise an insulin, a tolbutamide, a glimepiride, a glipizide, a glyburide, a repaglinide, a nateglinide, a metformin, an acarbose, a pioglitazone, a rosiglitazone, an exenatide, a liraglutide, an albiglutide, a dulaglutide, an alogliptin, a sitagliptin, a saxagliptin, a linagliptin, a canagliflozin, a dapagliflozin, an empagliflozin, a salt of any of these, or any combination thereof.
• an insulin can comprise a rapid-acting insulin, a short-acting insulin, an intermediate-actin insulin, a mixed insulin, or a long-acting insulin.
• a second therapy can comprise a psychotherapy, a speech therapy, a physical therapy, an occupational therapy, or any combination thereof.
• a method can comprise administering 1, 2, 3, 4, 5, 6, or more than 6 additional therapies.
• any second therapy disclosed herein can be used as an additional therapy.
• a second therapy or additional therapy can be administered concurrently or consecutively with a peptide disclosed herein.
• lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these can be administered concurrently or consecutively to a peptide of the disclosure herein.
• the lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these is included in a pharmaceutical composition with a peptide of the disclosure.
• the lecanemab, a derivative thereof, a biosimilar thereof, or a salt of any of these is included in a separate pharmaceutical composition from a peptide of the disclosure.
• aducanumab, a derivative thereof, a biosimilar thereof, or a salt of any of these can be administered concurrently or consecutively to a peptide of the disclosure herein.
• the aducanumab, a derivative thereof, a biosimilar thereof, or a salt of any of these is included in a pharmaceutical composition with a peptide of the disclosure. In some cases, the aducanumab, a derivative thereof, a biosimilar thereof, or a salt of any of these is included in a separate pharmaceutical composition from a peptide of the disclosure. In another example, remternetug, a derivative thereof, a biosimilar thereof, or a salt of any of these can be administered concurrently or consecutively to a peptide of the disclosure herein.
• the remternetug, a derivative thereof, a biosimilar thereof, or a salt of any of these is included in a pharmaceutical composition with a peptide of the disclosure. In some cases, the remternetug, a derivative thereof, a biosimilar thereof, or a salt of any of these is included in a separate pharmaceutical composition from a peptide of the disclosure.
• the second therapy or additional may be administered as needed, or for: one day, two days, three days, four days, five days, six days, a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, or chronically.
• the second therapy or additional therapy may be administered so that the active ingredient or the pharmaceutically acceptable salt thereof in the unit dose ranges from about: 500 ⁇ g (micrograms) to about 1000 mg, 10 ⁇ g to about 50 ⁇ g, 40 ⁇ g to about 90 ⁇ g, 80 ⁇ g to about 120 ⁇ g, 100 ⁇ g to about 150 ⁇ g, 140 ⁇ g to about 190 ⁇ g, 150 ⁇ g to about 220 ⁇ g, 200 ⁇ g to about 250 ⁇ g, 240 ⁇ g to about 300 ⁇ g, 290 ⁇ g to about 350 ⁇ g, 340 ⁇ g to about 410 ⁇ g, 400 ⁇ g to about 450 ⁇ g, 440 ⁇ g to about 500 ⁇ g, 500 ⁇ g to about 700 ⁇ g, 600 ⁇ g to about 900 ⁇ g, 800 ⁇ g to about GT Docket No.199260-717601 1 mg, 1 mg to about 5 mg, 1 mg to about 10 mg, 5 mg to about 15 mg,
• the unit dose range may be equal to, less than about, or more than about: 10 ⁇ g, 25 ⁇ g, 50 ⁇ g, 75 ⁇ g, 100 ⁇ g, 150 ⁇ g, 200 ⁇ g, 220 ⁇ g, 250 ⁇ g, 300 ⁇ g, 350 ⁇ g, 400 ⁇ g, 450 ⁇ g, 500 ⁇ g, 550 ⁇ g, 600 ⁇ g, 650 ⁇ g, 700 ⁇ g, 750 ⁇ g, 800 ⁇ g, 850 ⁇ g, 900 ⁇ g, 950 ⁇ g, 1000 ⁇ g, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg ,14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg.
• the unit dose range may be less than about: 10 ⁇ g, 25 ⁇ g, 50 ⁇ g, 75 ⁇ g, 100 ⁇ g, 150 ⁇ g, 200 ⁇ g, 220 ⁇ g, 250 ⁇ g, 300 ⁇ g, 350 ⁇ g, 400 ⁇ g, 450 ⁇ g, 500 ⁇ g, 550 ⁇ g, 600 ⁇ g, 650 ⁇ g, 700 ⁇ g, 750 ⁇ g, 800 ⁇ g, 850 ⁇ g, 900 ⁇ g, 950 ⁇ g, 1000 ⁇ g, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg.
• the second therapy or additional therapy may be administered so that the active ingredient or the pharmaceutically acceptable salt thereof in the unit dose ranges from about: 0.0001 mg/kg of body weight of the subject to about 1000 g/kg of body weight of the subject; 0.001 mg/kg of body weight of the subject to about 100 g/kg of body weight of the subject; 0.01 mg/kg of body weight of the subject to about 10 g/kg of body weight of the subject; 1 mg/kg of body weight of the subject to about 1 g/kg of body weight of the subject; or 10 mg/kg of body weight of the subject to about 500 mg/kg of body weight of the subject.
• the dosage of a second therapy or additional therapy per subject body weight can be equal to, less than about, or more than about: 0.0001 grams (g) / kilogram (kg), 0.001 g/kg, 0.01 g/kg, 0.1 g/kg, 0.2 g/kg, 0.3 g/kg, 0.4 g/kg, 0.5 g/kg, 0.6 g/kg, 0.7 g/kg, 0.8 g/kg, 0.9 g/kg, 1 g/kg, 2 g/kg, 3 g/kg, 4 g/kg, 5 g/kg, 6 g/kg, 7 g/kg, 8 g/kg, 9 g/kg, 10 g/kg, 15 g/kg, 20 g/kg, 25 g/kg, 30 g/kg, 35 g/kg, 40 g/kg, 45 g/kg, 50 g/kg, 55 g/kg, 60 g/kg, 65 g/kg, 70 g/kg
• Embodiments A number of methods, compositions and kits are disclosed herein. Specific exemplary embodiments of these methods, compositions and kits are disclosed below. The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these GT Docket No.199260-717601 numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed. [135] Embodiment 1.
• a method of treating a multifactorial neurological disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the multifactorial neurological disease, wherein the pharmaceutical composition comprises:a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D--S
• Embodiment 2 The method of embodiment 1, wherein the peptide, the derivative thereof, or the salt thereof comprises at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Ty
• Embodiment 3 The method of embodiment 1 or embodiment 2, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr or a salt thereof.
• Embodiment 4. The method of any one of embodiments 1-3, comprising the derivative of I, wherein I is esterified, glycosylated, or amidated at the C terminus.
• Embodiment 5. The method of any one of embodiments 1-4, wherein the multifactorial neurological disease is the vascular dementia.
• Embodiment 6. The method of any one of embodiments 1-4, wherein the multifactorial neurological disease is the ADRD.
• Embodiment 8 The method of embodiment 5, wherein the vascular dementia comprises a subcortical vascular dementia, a stroke-related dementia, a multi-infarct dementia, a mixed dementia, or any combination thereof.
• Embodiment 9 The method of any one of embodiments 1-8, wherein the pharmaceutical composition is in unit dose form.
• Embodiment 10 The method of any one of embodiments 1-9, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.
• the multifactorial neurological disease comprises a vascular disease, an alpha synuclein deposition in the brain, a tau deposition in the brain, an amyloid beta (A ⁇ ) deposition in the brain, or any combination thereof.
• Embodiment 12 The method of any one of embodiment 11, wherein the a vascular disease comprises reduced blood supply in the brain.
• Embodiment 13 The method of any one of embodiments 1-12, wherein the administering is daily, weekly, or monthly.
• Embodiment 14 The method of any one of embodiments 1-13, wherein administering is once, twice, three, or four times per day.
• Embodiment 16 The method of any one of embodiments 1-15, wherein pharmaceutical composition comprises the peptide, the derivative thereof, or the salt thereof in an amount of from about 0.005 mg to about 1000 mg. [151] Embodiment 17.
• Embodiment 18 The method of any one of embodiments 1-17, wherein the pharmaceutical composition is formulated for oral administration.
• Embodiment 19 The method of embodiment 18, wherein the pharmaceutical composition is in a form of a pill or a liquid.
• Embodiment 20 The method of any one of embodiments 1-19, wherein a second therapy is administered concurrently or consecutively.
• Embodiment 21 The method of embodiment 20, wherein the second therapy comprises a carbidopa, a levodopa, a cholinesterase inhibitor, a N-methyl D-aspartate antagonist, a catechol O- methyltransferase (COMT) inhibitor, a MAO-B inhibitor, an aducanumab, a lecanemab, a remternetug, a high blood pressure medication, a high cholesterol medication, an anticoagulant medication, a diabetes medication, a salt of any of these, or any combination thereof.
• the second therapy comprises a carbidopa, a levodopa, a cholinesterase inhibitor, a N-methyl D-aspartate antagonist, a catechol O- methyltransferase (COMT) inhibitor, a MAO-B inhibitor, an aducanumab
• Embodiment 22 The method of any one of embodiments 20-21, wherein the pharmaceutical composition further comprises the second therapy.
• Embodiment 23 The method of any one of embodiments 1-22, wherein the subject was diagnosed with the multifactorial neurological disease prior to the administration.
• Embodiment 24 The method embodiment 23, wherein the diagnoses comprise an in vitro test, a physical exam, an imaging diagnostic or a combination thereof.
• Embodiment 25 The method of any one of embodiments 1-24, wherein the subject is a mammal.
• Embodiment 26 The method of embodiment 25, wherein the mammal is a human.
• Embodiment 27 The method of embodiment 25, wherein the mammal is a human.
• a method of treating a disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease, wherein the pharmaceutical composition comprises: a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D- Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D- Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D- Ser, D
• Embodiment 28 The method of embodiment 27, wherein the peptide, the derivative thereof, or the salt thereof comprises at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, GT Docket No.199260-717601 D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or
• Embodiment 29 The method of embodiment 27 or embodiment 28, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr or a salt thereof.
• Embodiment 30 The method of any one of embodiments 27-29, comprising the derivative of I, wherein I is esterified, glycosylated, or amidated at the C terminus.
• Embodiment 31 The method of any one of embodiments 27-30, wherein the disease is the postural instability.
• Embodiment 32 The method of any one of embodiments 27-30, wherein the disease is the gait disturbance.
• Embodiment 33 The method of any one of embodiments 27-30, wherein the disease is the gait disturbance.
• Embodiment 34 The method of any one of embodiments 27-30, wherein the disease is the balance issue.
• Embodiment 35 The method of any one of embodiments 27-30, wherein the disease is the urinary incontinence.
• Embodiment 36 The method of any one of embodiments 27-35, wherein the pharmaceutical composition is in unit dose form.
• Embodiment 37 The method of any one of embodiments 27-36, wherein the pharmaceutical composition further comprises an excipient, a diluent, a carrier, or a combination thereof.
• Embodiment 38 Embodiment 38.
• a method of treating a disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease, wherein the pharmaceutical composition comprises: a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises: i) [D-Ala1]-Ser-Thr-Thr-Thr- Asn-Tyr-Thr-NH2 or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers and the N-terminal amino acid is an amide; ii) [D- Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof, and wherein the disease is selected from the group consisting of: a postural instability, a gait disturbance, a balance issue, a post-
• Embodiment 39 A method of treating a mild cognitive impairment or a mild dementia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the mild cognitive impairment or the mild dementia, wherein the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D- Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D- Trp, or
• Embodiment 40 The method of embodiment 39, wherein the peptide, the derivative thereof, or the salt thereof comprises at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Thr, D
• Embodiment 41 The method of embodiment 39 or embodiment 40, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr or a salt thereof.
• Embodiment 42 The method of any one of embodiments 39-41, comprising the derivative of I, wherein I is esterified, glycosylated, or amidated at the C terminus.
• Embodiment 43 The method of any one of embodiments 39-42, wherein the mild cognitive impairment or the mild dementia is a disease with an amyloid beta (A ⁇ ).
• Embodiment 44 The method of any one of embodiments 39-42, wherein the mild cognitive impairment or the mild dementia is a disease with an amyloid beta (A ⁇ ).
• Embodiment 45 The method of any one of embodiments 39-42, wherein the mild cognitive impairment or the mild dementia is a mixed dementia.
• Embodiment 46 The method of any one of embodiments 39-42, wherein the mild cognitive impairment or the mild dementia is a vascular dementia.
• Embodiment 47 The method of any one of embodiments 39-46, wherein the pharmaceutical composition is in unit dose form. GT Docket No.199260-717601 [182] Embodiment 48.
• Embodiment 49 The method of any one of embodiments 39-48, wherein the mild cognitive impairment or the mild dementia comprises deposition in a brain of: an alpha synuclein, a tau, or both.
• Embodiment 50 The method of any one of embodiments 39-49, wherein the administering is daily, weekly, or monthly.
• Embodiment 51 The method of any one of embodiments 39-50, wherein administering is once, twice, three, or four times per day.
• Embodiment 52 The method of any one of embodiments 39-50, wherein administering is once, twice, three, or four times per day.
• Embodiment 53 The method of any one of embodiments 39-52, wherein pharmaceutical composition comprises the peptide, the derivative thereof, or the salt thereof in an amount of from about 0.005 mg to about 1000 mg.
• Embodiment 54 The method of any one of embodiments 39-52, wherein pharmaceutical composition comprises the peptide, the derivative thereof, or the salt thereof in an amount of from about 0.005 mg to about 1000 mg.
• Embodiment 55 The method of any one of embodiments 39-54, wherein the pharmaceutical composition is formulated for oral administration or for intravenous administration.
• Embodiment 56 The method of any one of embodiments 39-54, wherein the pharmaceutical composition is formulated for oral administration or for intravenous administration.
• Embodiment 55 wherein the pharmaceutical composition is in a form of a pill or a liquid.
• Embodiment 57 The method of any one of embodiments 39-56, wherein the pharmaceutical composition is in a form of a liquid.
• Embodiment 58 The method of any one of embodiments 39-57, wherein the subject was diagnosed with the mild cognitive impairment or the mild dementia prior to the administration.
• Embodiment 59 The method embodiment 58, wherein the diagnoses comprise an in vitro test, a physical exam, an imaging diagnostic or a combination thereof. GT Docket No.199260-717601 [194] Embodiment 60. The method of any one of embodiments 39-59, wherein the subject is a mammal.
• Embodiment 61 The method of embodiment 60, wherein the mammal is a human.
• Embodiment 62 A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition to treat the disease, wherein the pharmaceutical composition comprises: a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises: i) [D-Ala1]-Ser-Thr-Thr-Thr- Asn-Tyr-Thr-NH2 or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers and the N-terminal amino acid is an amide; ii) [D- Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination
• Embodiment 63 A pharmaceutical composition, wherein the pharmaceutical composition comprises: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G- H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D- Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg, or Gly, or a derivative of any of these; and II) a lecanem
• Embodiment 64 The pharmaceutical composition of embodiment 63, wherein the peptide, the derivative thereof, or the salt thereof comprises at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: [199] A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D- Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these;
• Embodiment 65 The pharmaceutical composition of embodiment 63 or embodiment 64, wherein the peptide or the salt thereof is D-Thr, D-Thr, D-Asn, D-Tyr, and D-Thr or a salt thereof. GT Docket No.199260-717601 [201] Embodiment 66. The pharmaceutical composition of any one of embodiments 63-65, comprising the derivative of I, wherein I is esterified, glycosylated, or amidated at the C terminus. [202] Embodiment 67. The pharmaceutical composition of any one of embodiments 63-66, wherein the pharmaceutical composition further comprises an: excipient, a diluent, a carrier, or a combination thereof. [203] Embodiment 68.
• the pharmaceutical composition of any one of embodiments 63-67 comprising the pharmaceutical composition, which comprises the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these.
• Embodiment 69 The pharmaceutical composition of any one of embodiments 63-67, comprising the pharmaceutical composition, which comprises the aducanumab, the derivative thereof, the biosimilar thereof, or the salt of any of these.
• Embodiment 70 The pharmaceutical composition of any one of embodiments 63-67, comprising the pharmaceutical composition, which comprises the remternetug, the derivative thereof, the biosimilar thereof, or the salt of any of these.
• Embodiment 71 Embodiment 71.
• Embodiment 72 The pharmaceutical composition of any one of embodiments 63-71, wherein the pharmaceutical composition comprises the peptide, the derivative thereof, or the salt thereof in an amount of from about 0.005 mg to about 1000 mg.
• Embodiment 73 The pharmaceutical composition of any one of embodiments 63-72, wherein the pharmaceutical composition comprises the lecanemab, the aducanumab, the remternetug, the derivative thereof, the biosimilar thereof, or the salt of any of these in an amount of from about 1 mg to about 500 mg.
• Embodiment 74 Embodiment 74.
• Embodiment 75 The pharmaceutical composition of any one of embodiments 63-74, wherein the pharmaceutical composition is formulated for intravenous delivery or for oral delivery.
• Embodiment 76 The pharmaceutical composition of any one of embodiments 63-75, wherein pharmaceutical composition is in a form of a pill or a liquid. GT Docket No.199260-717601 [212] Embodiment 77.
• a pharmaceutical composition wherein the pharmaceutical composition comprises: a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises: i) [D- Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH 2 or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers and the N-terminal amino acid is an amide; ii) [D-Ala1]-Ser-Thr-Thr-Thr-Asn-Tyr-Thr or a derivative thereof, in which the first amino acid is a D stereoisomer and the remaining amino acids are L stereoisomers; or iii) or any combination thereof; and a lecanemab, an aducanumab, a remternetug, a derivative of any of these, a biosimilar of any of these, or a salt of any of these and optionally, an excipient, a diluent, a
• Embodiment 78 A kit comprising the pharmaceutical composition of anyone of embodiments 63-77 and a container.
• Embodiment 79. A kit comprising: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-S
• Embodiment 80 A method of treating a dementia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of: I) a peptide, a derivative thereof, or a salt thereof, wherein the peptide comprises at least five contiguous amino acids or derivatives thereof comprising the general formula: E-F-G-H-I, wherein: E is D-Ser, D- Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D- Lys, or D-Trp, or a derivative of any of these; H is D-Tyr, or a derivative thereof; and I is D-Thr, D-Ser, D-Arg
• Embodiment 81 The method of embodiment 80, wherein the peptide, the derivative thereof, or the salt thereof comprises at least eight contiguous amino acids or derivatives thereof, comprising the general formula A-B-C-E-F-G-H-I, and wherein: A is D-Ala, or a derivative thereof; B is D-Ser, or D-Thr, or a derivative of any of these; C is D-Ser, or D-Thr, or a derivative GT Docket No.199260-717601 of any of these; E is D-Ser, D-Thr, D-Asn, D-Glu, D-Arg, D-Ile, or D-Leu, or a derivative of any of these; F is D-Ser, D-Thr, D-Asp, or D-Asn, or a derivative of any of these; G is D-Thr, D-Ser, D-Asn, D-Arg, D-Gln, D-Lys, or D-Trp, or
• Embodiment 82 The method of embodiment 80 or 81, wherein the peptide, the derivative thereof, or the salt thereof is in unit dose form.
• Embodiment 83 The method of any one of embodiments 80-82, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these is in unit dose form.
• Embodiment 84 The method of any one of embodiments 80-82, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these is in unit dose form.
• Embodiment 85 The method of any one of embodiments 80-84, wherein the pharmaceutical composition is formulated for intravenous administration or for oral administration.
• Embodiment 86 The method of any one of embodiments 80-84, wherein the pharmaceutical composition is formulated for intravenous administration or for oral administration.
• Embodiment 87 The method of any one of embodiments 80-86, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these is administered concurrently or consecutively to the peptide, the derivative thereof, or the salt thereof.
• Embodiment 88 Embodiment 88.
• Embodiment 90 The method of any one of embodiments 80-87, wherein the peptide, the derivative thereof, or the salt thereof is in an amount of from about 0.005 mg to about 1000 mg.
• Embodiment 89 The method of any one of embodiments 80-88, wherein the lecanemab, the derivative thereof, the biosimilar thereof, or the salt of any of these is in an amount of from about 1 mg to about 500 mg.
• Embodiment 90 Embodiment 90.
• Embodiment 92 The method of any one of embodiments 80-91, wherein the administering of the peptide, the derivative thereof, or the salt thereof is daily, weekly, or monthly.
• Embodiment 93 The method of any one of embodiments 80-91, wherein the administering of the peptide, the derivative thereof, or the salt thereof is daily, weekly, or monthly.
• Example 1 [230] The synthetic process used for manufacture of RAP-103 Acetate Salt involves the following steps which follow the Merrifield FMOC synthesis method SPPS (Solid phase Peptide Synthesis), using the common commercially available coupling reagents, resins, and deblocking reagents: [231] Step 1: peptide synthesis: solid phase peptide synthesis (SPPS) of the protected peptide [232] Step 2: cleavage and deprotection: trifluoroacetic acid (TFA) cleavage of the protecting groups from the peptide and cleavage of the peptide from the resin [233] Step 3: purification and in-process lyophilization: peptide purification and in-process lyophilization of the peptide [234] Step 4: ion exchange (salt exchange) and final lyophilization: ion exchange (salt exchange) from TFA to acetate salt and Final lyophilization.
• SPPS Solid phase Peptide Synthesis
• FIG. 2 A schematic of a synthesis method for RAP-103 is shown in FIG. 2 and comprises the following steps: 2-chlorotrityl chloride resin SPPS, cleavage and deprotection, purifications and in-process lyophilization, ion exchange (salt exchange) and final lyophilization.
• the following components are equipment and components were used for synthesis.
• Reaction vessel [236] The synthesis was carried out at room temperature in a custom-designed glass vessel, with the bottom part comprising a fritted disk of coarse porosity. The size of the reactor is dependent GT Docket No.199260-717601 on the amount of polymer to be used for the synthesis.
• the reactor was designed to assist in the addition of amino acid derivatives, solvents and reagents, as required.
• the reaction vessel was equipped with a mechanical stirrer to allow for efficient mixing of the peptide-resin. No components of the equipment or utensils utilized for the synthesis process were composed of materials that can cause adulteration of the product.
• Solid phase support 2-Chlorotrityl chloride resin was used for the synthesis.
• the base labile protecting group was used to block the ⁇ -amino group during the coupling reaction and was removed in the deblocking step, to allow the introduction of the next amino acid in the sequence.
• Fmoc (9-Fluorenylmethyloxycarbonyl) was used as the base labile ⁇ -amino protecting group.
• the acid labile protecting group was used to protect the side- chain reactive functional groups of the amino acids during synthesis and must be resistant to the deblocking mixture (20% piperidine in DMF). Following the peptide synthesis, these protecting groups were removed by strong acid (aqueous trifluoroacetic acid with scavengers).
• the acid- labile protecting groups for this process are t-butyl (tBu), trityl (Trt).
• tBu t-butyl
• Trt trityl
• the following amino acids were used in the synthesis of RAP-103 Acetate Salt: Fmoc-D- Tyr(tBu)-OH, Fmoc-D-Asn(Trt)-OH, and Fmoc-D-Thr(tBu)-OH.
• Step 1 Peptide Synthesis: [240] Resin Loading- 2-Chlorotrityl chloride (CTC) resin was activated with Acetyl chloride (AcCl) and then treated with Fmoc-D-Thr(tBu)-OH and Diisopropylethylamine (DIPEA) followed by a solution mixture of Dichloromethane (DCM), Methanol (MeOH) and Diisopropylethylamine (DIPEA).
• CTC 2-Chlorotrityl chloride
• AcCl Acetyl chloride
• DIPEA Diisopropylethylamine
• Fmoc Deprotection [242] During the deprotection step, the base-labile temporary protecting group (Fmoc) was cleaved from the ⁇ amino function of the N-terminal amino acid on the growing peptide chain by treating the resin twice with a solution of 20 % piperidine in dimethylformamide (DMF). Two deprotection treatments were performed, the 1st deprotection stir time was approximately 10 minutes, and the 2nd deprotection stir time was approximately 30 minutes. Wash cycle: GT Docket No.199260-717601 [243] The wash steps were performed to eliminate excess reagents used in the preceding step.
• Fmoc Deprotection [242] During the deprotection step, the base-labile temporary protecting group (Fmoc) was cleaved from the ⁇ amino function of the N-terminal amino acid on the growing peptide chain by treating the resin twice with a solution of 20 % piperidine in dimethylformamide (DMF). Two deprotect
• the solvents selected for each step were carefully chosen to ensure that there is no risk of introducing an undesirable side reaction while eliminating the excess of reagents as efficiently as possible.
• the duration of each wash step was timed to allow for thorough contact of the peptide-resin with the solvent and to provide ample time for extraction of the reagents.
• DMF was used after deblocking as well as after coupling because it has excellent solubilizing and swelling properties for all reagents used in the coupling step.
• isopropanol (IPA) was utilized after coupling reaction because it shrinks the resin, which also aids in removal of excess solvents and reagents.
• Activation and coupling [244] During the activation and coupling steps, the deprotected ⁇ -amino group is acylated by the next activated amino acid in the sequence.
• the reagents used to accomplish acylation were carefully selected to create optimal reaction conditions and easy elimination of the excess reagents at the end of the coupling reaction.
• Activation of Fmoc-Tyr(tBu)-OH was performed by dissolving the protected amino acid with coupling reagents 1-H-Benzotriazolium,1-[bis(dimethylamino)methylene]-5-chloro- tetrafluoroborate(1-),3-oxide (TCTU) and diisopropylethylamine (DIPEA) in DMF.
• the solution of activated amino acid was then added to the peptide-resin.
• the mixture was stirred at room temperature for 20 minutes and then DIPEA in DMF was added in it. The mixture was allowed to react for approximately 160 minutes.
• Activation of the remaining amino acid derivatives was performed by dissolving the protected amino acid with coupling reagents Oxima (Oxymapure) in DMF and 1,3- Diisopropylcarbodiimide (DIC). The solution of activated amino acid was then added to the peptide-resin. The suspension was stirred at room temperature for 20 minutes, after which a second aliquot of DIC was added to the reaction mixture. The mixture was stirred and allowed to react for approximately 160 minutes. Recoupling and acetylation: [247] After a minimal reaction time of one hour, the presence of remaining unreacted amino groups was monitored using the qualitative TNBS (trinitrobenzenesulfonic acid) test or the Ninhydrin test.
• TNBS trinitrobenzenesulfonic acid
• the TNBS test is performed adding a few drops of trinitrobenzenesulfonic acid to the peptide-resin in a test tube sample and allowing the two to react for three minutes. The presence of free amino groups causes a colored reaction; orange-colored beads indicate incomplete coupling and the presence of unreacted amine.
• a few drops of the Ninhydrin GT Docket No.199260-717601 reagents were added to a sample of the peptide-resin in a small test tube. Blue-stained resin beads indicate the presence of unreacted amine.
• Step 2 Cleavage and Deprotection: [251] During the cleavage operation, the peptide was detached from the resin with concomitant cleavage of the side chain protecting groups. This was accomplished by the treatment of the peptide-resin with trifluoroacetic acid (TFA) in the presence of scavengers and Trifluoroethanol (TFE) in TFA and Dichloromethane (DCM).
• TFA trifluoroacetic acid
• TFE Trifluoroethanol
• DCM Dichloromethane
• the peptide was precipitated using cooled isopropyl ether (IPE), and filtered using a Buchner funnel with filter paper. The precipitated peptide was washed with IPE and dried in a vacuum oven at room temperature. After drying was completed, the crude peptide was weighed and recorded.
• Step 3 Purification and In-process Lyophilization: [252] The purification is performed by preparative Reversed Phase High Performance Chromatography (RP-HPLC).
• the purification equipment was based on the principle of compression in which the chromatographic support is packed in a compression module. A constant pressure was applied to the column. Different column sizes are available and the choice of which to use is based on the amount of material to be processed. The solvents were delivered through pumps and the necessary gradients are created manually or with an automatic gradient maker. Nature of support: GT Docket No.199260-717601 [254]
• the purification of crude peptide was accomplished by preparative HPLC using reversed phase material as the support.
• the reversed phase material consists of a silica gel coated with aliphatic chains; the free remaining silanol groups have been end-capped to avoid undesirable ionic interaction/binding between the mixture to be purified and the support.
• a typical purification run consists of three steps: equilibration Luna C18 column, loading and elution of the product, and washing of the column to prepare it for the next run. Equilibration of the column was accomplished by washing it with aqueous TFA solution. The crude peptide was dissolved in an aqueous TFA solution, filtered and then was loaded onto the column. Product elution was achieved using a gradient of aqueous TFA and acetonitrile (CH3CN) buffer solutions.
• CH3CN acetonitrile
• Step 4 ion-exchange (Salt exchange) and final lyophilization: [258] ion-exchange (salt exchange): [259]
• the Ion-exchange also referred to as the salt exchange stage, converts the peptide into the required salt form (acetate salt).
• the preparation of ion-exchange resin (AMBERLITE IRN 78) was accomplished by washing the resin sequentially with methanol (MeOH), USP Water, 2N sodium hydroxide (NaOH), USP water, acetic acid (AcOH – 20% in USP water) and USP water until neutrality.
• the peptide from in-process lyophilization step was dissolved in USP water and loaded onto already prepared Ion-exchange resin.
• Plasma samples were collected into K2EDTA MAP tubes, placed on wet ice, and processed to plasma (in a centrifuge set to maintain 2000 g, at 4°C for 15 minutes) within 60 minutes of collection and were stored in a freezer set to maintain -80°C until analysis. Samples were analyzed by using a qualified high performance liquid chromatography (HPLC) with mass spectrometric (MS/MS) detection to determine the concentrations of RAP-103. Giving dosage forms to animals shows that RAP-103 quickly entered the brain (rats and guinea pigs) by IV or oral gavage dosing and persisted at therapeutic levels for at least 24 hrs as shown in FIG.1A. RAP-103 preferentially enters the brain compared to plasma levels.
• HPLC high performance liquid chromatography
• MS/MS mass spectrometric
• Example 4 GT Docket No.199260-717601 [263] A subject is diagnosed with an advanced mixed dementia. A peptide described herein (R- 103) is administered by a capsule to the subject. The capsules contain excipients to enhance stability, dissolution, and absorption. Enteric coatings are applied to control delivery and maintain therapeutic levels. The subject has an increased memory retention after administration of the peptide as compared to their memory retention prior to administration as determined by a cognitive assessment.
• Example 5 [264] A 59 year old female subject was diagnosed with a human retroviral neurocognitive disorder. The patient also suffered from a 9 year history of progressive spastic paraparesis, and incontinence.
• a peptide multi-chemokine receptor antagonist of the present disclosure (DAPTA) was administered at a dose of about 6 mg per day for 10 weeks. After two weeks administration the female subject had improvement in her urinary incontinence and walking which continued to the end of week 10. Initially it took 65 seconds to walk 10 meters, at the end of 10 weeks it took 15. Four weeks after treatment stopped stiffness and difficulty walking returned. The administration of a peptide of the present disclosure surprisingly and unexpectedly improved spasticity and urinary incontinence.
• Example 6 [265] A subject is diagnosed with mild cognitive impairment. A peptide described herein (e.g., R- 103) and lecanemab are administered to the subject to treat the cognitive impairment.
• the subject has increased memory retention after administration of the peptide and lecanemab as compared to their memory retention prior to administration as determined by a cognitive assessment. Further the peptide reduces side effects of lecanemab. For example, R-103 reduces the side effect of brain bleeding and/or brain swelling associated with lecanemab.
• Example 7 [266] A subject is diagnosed with a dementia. A peptide described herein (e.g., R-103) and aducanumab are administered to the subject to treat the dementia. The subject has increased memory retention after administration of the peptide and aducanumab as compared to their memory retention prior to administration as determined by a cognitive assessment. Further the peptide reduces side effects of aducanumab.
• R-103 reduces the side effect of brain bleeding and/or brain swelling associated with aducanumab.
• GT Docket No.199260-717601 Example 8: [267]
• a subject is diagnosed with an Alzheimer’s disease.
• a peptide described herein (e.g., R- 103) and remternetug are administered to the subject to treat the Alzheimer’s disease.
• the subject has an increased memory retention after administration of the peptide and remternetug as compared to their memory retention prior to administration as determined by a cognitive assessment.
• the peptide reduces side effects of remternetug.
• R-103 reduces the side effect of brain bleeding and/or brain swelling associated with remternetug.
• Example 9 [268] Rodent hippocampal neuronal cultures and human neurons derived from WTC-11 iPSCs had active glutamatergic synapses. Cultures of both rodent and human neurons were grown to maturity in 24-well glass bottom plates in glial conditioned media and were used to assess the ability of RAP-103 to protect against the loss of spines and synapses caused by prolonged (5 day) A ⁇ d/t treatment. MAP2 immunolabeled dendrites with associated PSD95 stained postsynaptic densities are shown as an overlay of mouse neurons in FIG. 3B.
• PSD95 puncta are within dendrites (see FIG 3A-3B) but many dendrites are weakly immunolabeled for MAP2 and disappeared on the images because of the increased transparency required for construction of these overlays.
• Spine projections contained MAP2 and most had an associated PSD95 label but a few PSD95 puncta appeared along dendrites without the underlying MAP2 immunolabel.
• Cultures treated with A ⁇ d/t for 5 days in which PSD95 puncta were normalized to MAP2 area showed a significant decrease in spines that did not occur in the presence of RAP-103 as shown in FIG.3D. The results show RAP-103 inhibits A ⁇ d/t-induced dendritic spine and synapse loss in neuronal cultures.
• FIG.4A shows day 55 human neurons immunolabeled for VGLUT and PSD95 with the magnified boxed region shown in inset.
• FIG. 4B shows treatment with A ⁇ d/t and RAP-103 increased synapse number per field and was comparable to the control. In contrast, treatment with A ⁇ d/t alone decreased synapse number per field.
• RAP-103 was able to cause disassembly of rods faster and at 1/500 th the concentration of AMD3100.
• FIG.5A-5B shows rod formation was reversed during RAP-103 treatment.
• Example 11 [271] To test for prevention of memory impairment, RAP-103 was administered in an alpha synuclein animal model (Thy1-aSyn mice). Thy1-aSyn mice (which overexpress human ⁇ - synuclein under the Thy1 promoter) were tested for memory impairment by the Morris Water Maze Testing Assay (as seen in FIGS. 6A-6D) against healthy control mice. Both types of mice were treated with RAP-103 or a vehicle control.
• FIG.6B shows the total distance in target (%) of the RAP-103 treated Thy1-aSyn mice was comparable to control mice (WT and WT treated with R103). In contrast, the Thy1-aSyn mice vehicle control treated mice had a significantly reduced distance in target. Similar results were seen for time in target and target crossings (FIG.6C-6D). The results show RAP-103 treated Thy1-aSyn mice were able to maintain there ability to remember the location of the platform as compared to vehicle treated Thy1-aSyn mice. The data suggests RAP-103 can be used to increase memory in diseases with alpha synuclein.
• Example 12 [272] To determine if the rod inhibition by the RAP-peptides could be acting downstream of receptors by directly targeting cofilin-actin interactions, the ability of RAP-310 to inhibit rods induced by excitotoxic concentrations of glutamate via the AMPA receptor was tested. The RAP peptide fully inhibited the A ⁇ d/t induced rods but had no inhibition of those induced by glutamate as shown in FIG.7A. To determine if RAP-103 inhibited rods in human neurons that are induced by other ligands with well characterized receptors, rods were induced with the cytokine interleukin 6 (IL-6) as shown in FIG.7B.
• IL-6 cytokine interleukin 6
• Example 14 [274] RAP-103 and RAP-310 were tested to determine the concentrations at which RAP-103 and RAP-310 inhibited formation of A ⁇ d/t-induced rods.
• Rodent and human neurons were dosed with A ⁇ d/t along with RAP-103 as shown in FIGS. 9A-9D.
• Rod quantification in DIV 6 mouse hippocampal neurons is shown in FIG. 9A and FIG. 9B.
• Rod quantification in Day 55 human neurons is shown in FIG. 9C and FIG. 9D.
• the cells were treated 24 hr with A ⁇ d/t along with RAP-103 (FIG.9A and FIG.9C) or RAP-310 (FIG.9B and FIG.9D) at concentrations shown.
• FIG.9A shows RAP-103 inhibited rods in mouse hippocampal neurons at a dose of about 1 pM.
• FIG. 9B shows RAP-310 inhibited rods in mouse hippocampal neurons at a dose of about 0.33 pm to about 1 pM.
• FIG.9C shows RAP-103 inhibited rods in human neurons at a dose of about 0.1 pM.
• FIG. 9D shows RAP-310 inhibited rods in human neurons at a dose of about 0.1 pM. Both RAP peptides had nearly similar rod-inhibiting activity and were about 10-fold more effective in blocking rod formation in human neurons than in mouse neurons.
• FIG. 10A shows rod formation induced by adenoviral-mediated overexpression of PrPC in rat hippocampal neurons GT Docket No.199260-717601 infected on DIV 2 with 100 moi AdPrPC and treated with RAP-103 [50 pM] at the same time (4 day) or on DIV 5 (1 day), fixed and immunolabeled on DIV 6, was prevented (4 day) or reversed (1 day) by RAP-103 treatment.
• FIG. 10A shows rod formation induced by adenoviral-mediated overexpression of PrPC in rat hippocampal neurons GT Docket No.199260-717601 infected on DIV 2 with 100 moi AdPrPC and treated with RAP-103 [50 pM] at the same time (4 day) or on DIV 5 (1 day), fixed and immunolabeled on DIV 6, was prevented (4 day) or reversed (1 day) by RAP-103 treatment.
• RAP-103 shows rods induced in human neurons treated on Day 54 with 500 pM dual tropic gp120 and fixed on Day 55 are inhibited from forming by RAP-103 [10 pM]. These results show RAP-103 can prevent and/or reverse rod formation by different initiators.
• RAP-103 reduced the increase in TNF ⁇ release of combined A ⁇ and ⁇ -Syn by about 70%, to levels less than A ⁇ alone. RAP-103 by itself did not induce TNF ⁇ release. Thus, RAP- 103 was surprisingly effective at reducing TNF ⁇ release by the combination of A ⁇ and ⁇ -Syn, used here as a model of mixed-dementias in humans. Activation of TNF ⁇ release was specific for PFF of A ⁇ and ⁇ -Syn and did not occur with the co-stimulator ⁇ IFN. This example shows ⁇ -Syn synergistically enhances A ⁇ fibril mediated TNF ⁇ release, a mediator of neuron damage and synapse loss that would then cause enhanced pathological effects in people.
• RAP- 103 blocks TNF ⁇ release driven by combined A ⁇ and ⁇ -Syn fibrils, an effect which would treat a multifactorial neurological disease.

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