WO2023099013A1 - Procédés de traitement de patients atteints d'une lésion cérébrale et procédés d'augmentation de la valeur de l'échelle de résultats de glasgow étendue de patients atteints d'une lésion cérébrale - Google Patents

Procédés de traitement de patients atteints d'une lésion cérébrale et procédés d'augmentation de la valeur de l'échelle de résultats de glasgow étendue de patients atteints d'une lésion cérébrale Download PDF

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WO2023099013A1
WO2023099013A1 PCT/EP2021/084183 EP2021084183W WO2023099013A1 WO 2023099013 A1 WO2023099013 A1 WO 2023099013A1 EP 2021084183 W EP2021084183 W EP 2021084183W WO 2023099013 A1 WO2023099013 A1 WO 2023099013A1
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brain injury
egos
patient
months
compound
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John Stover
Frank Tegtmeier
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Verinos Operations GmbH
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Verinos Operations GmbH
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Priority to EP21830625.6A priority Critical patent/EP4440578A1/fr
Priority to PCT/EP2021/084183 priority patent/WO2023099013A1/fr
Priority to CA3235704A priority patent/CA3235704A1/fr
Priority to AU2021476139A priority patent/AU2021476139A1/en
Priority to TW111146425A priority patent/TW202342049A/zh
Publication of WO2023099013A1 publication Critical patent/WO2023099013A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • the present invention relates to the use of biopterin compounds such as 4-Amino-(6R,S)- 5,6,7,8-tetrahydro-L-biopterin for treatment of patients suffering from brain injury.
  • the invention also relates to the use of such biopterin compounds for increasing the value of the extended Glasgow Outcome Scale (eGOS) of patients suffering from brain injury, thereby improving the condition of the patient.
  • eGOS Glasgow Outcome Scale
  • Traumatic brain injury is a major cause of mortality and long-term disability, with enormous impact on patients and their families (Stocchetti et al, Severe traumatic brain injury: targeted management in the intensive care unit. Lancet Neurol. 2017;16:452-464). In Europe an overall incidence rate of 262 per 100,000 of hospital admitted TBI was reported in a metaanalysis, see Maas et al., Epidemiology of traumatic brain injury in Europe. Acta Neurochir (Wien). 2015 157: 1683-96. The TBI related costs are high and accounted for 33 billion Euros in Europe in 2010. The high costs are owed to mostly to lifetime productivity losses, particularly when young people are affected, see Maas et al, vide supra.
  • TBI TBI pathophysiology
  • - among others - neuroinflammation, brain oedema formation and excitotoxicity Jarrahi et al, Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions. Biomedicines. 2020;8(10):389).
  • Nitric oxide has been discussed as key player in the development of secondary injury after TBI.
  • Nitric oxide synthase has been tested in animal models of TBI with 4-amino-tetrahydrobiopterin (Ronopterin, VAS203) having been shown been shown been shown to be beneficial in animal models of TBI (Terpolilli et al, The novel nitric oxide synthase inhibitor 4-amino-tetrahydro-L-biopterine prevents brain edema formation and intracranial hypertension following traumatic brain injury in mice. J Neurotrauma.
  • the invention provides a method method of treating a human patient suffering from brain injury, wherein the method comprises administering to the patient within a time period of ⁇ 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the invention provides a method of increasing the value of the Extended Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury, thereby improving the condition of the patient, wherein the value of the Extended Glasgow Outcome Scale (eGOS) of the patient reaches eGOS level 7 or eGOS level 8 six months after the occurrence of the brain injury, wherein the method comprises administering to the patient within a time period of ⁇ 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the invention provides a method of increasing the value of the Extended Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury, thereby improving the condition of the patient, wherein the value of the Extended Glasgow Outcome Scale (eGOS) of the patient has increased by 2 or more six months after the occurrence of the brain injury, compared to the eGOS value of the patient determined three months after the occurrence of the traumatic brain injury, wherein the method comprises administering to the patient within a time period of ⁇ 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the invention provides a method of treating a human patient suffering from brain injury, wherein the patient is a female of an age of 40 years or older, and wherein the method comprises (starting) administering to the patient within a time period of > 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the compound having the formula (I) is administered by infusion in a total dose of 17 mg/kg body weight over 48 hours, corresponding to a daily dose of 8.5 mg/kg body weight.
  • the invention provides a method of treating a human patient suffering from brain injury, wherein the patient is of an age of 39 years or younger, and wherein the method comprises (starting) administering to the patient within a time period of > 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the compound having the formula (I) is administered by infusion in a total dose of 20 mg/kg body weight or in a total dose of 30 mg/kg body weight.
  • Fig.l shows the Extended Glasgow Outcome Scale (eGOS) with its levels 1 to 8 as used herein as an outcome measure as brain injury;
  • eGOS Extended Glasgow Outcome Scale
  • Fig. 2 shows a standard questionnaire that is used for determining the eGOS level of a patient.
  • Fig. 3A shows an overview of the Therapy Intensity Level (TIL) treatment with the typical types of interventions used in the treatment of patients with brain injury together with the intensity of the intervention and their respective score
  • Fig. 3B shows an exemplary TIL treatment with an index between 3 and 10 that can be used in the present invention.
  • TIL Therapy Intensity Level
  • Fig. 4 shows the distribution of proportion of patients between Placebo and Ronopterin (VAS203)-treated patients reflecting changes in eGOS from 3 to 6 months for all patients and all times to infusion.
  • Fig. 4A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 4B shows the change in eGOS from 3 to 6 months by category
  • Fig. 4C shows the increase of eGOS level by number of patients
  • Fig. 4D shows the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (24 vs.
  • Fig. 4 shows for the Ronopterin-treated group more patients with higher increase in eGOS over time, however the increase is not (statistically) significant (Fig. 4D). In addition, Fig. 4 shows for the Ronopterin-treated group that there are less patients with a decrease in eGOS over time, however this decrease is not (statistically) significant.
  • Fig- 5 shows the distribution of proportion of patients of all ages between Placebo and Ronopterin-treated patients with changes in eGOS from 3 to 6 months, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Fig. 5 shows for the Ronopterin-treated group a significant increase in proportion of patients with increased eGOS
  • Figs.5A to 5D show the results for early infusion ( ⁇ 12 hours), with Fig. 5A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 5B showing the change in eGOS from 3 to 6 months by category, Fig. 5C showing the increase of eGOS level by number of patients and Fig. 5D showing the odds-ratio for the eGOS increase.
  • Figs.5A to 5D show that for early infusion ( ⁇ 12 hours) Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 5A).
  • Figs.5E to 5H show the results for late infusion (>12 hours), with Fig. 5E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 5F showing the change in eGOS from 3 to 6 months by category, Fig. 5G showing the increase of eGOS level by number of patients and Fig. 5H showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 5E). Overall, increase in eGOS by at least 2 levels is encountered more often in Ronopterin- treated patients (15 vs 10), see Fig 5G.
  • Fig- 6 shows the change in eGOS levels from 3 to 6 months, for patients with an age of 18-39 years and at all times to infusion.
  • Fig. 6A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 6B shows the change in eGOS from 3 to 6 months by category
  • Fig. 6C shows the increase of eGOS level by number of patients
  • Fig. 6D shows the odds-ratio for the eGOS increase.
  • Fig. 6 shows that in the Ronopterin-treated group, there are more patients with higher increase in eGOS over time, however this increase is not significant (see Fig. 6D) while in the Ronopterin-treated group, there are less patients with decrease in eGOS over time, however this decrease is not significant.
  • Fig. 7 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for patients aged 18-39 years, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury
  • Figs.7A to 7D show the results for early infusion ( ⁇ 12 hours), with Fig. 7A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 7B showing the change in eGOS from 3 to 6 months by category, Fig. 7C showing the increase of eGOS level by number of patients and Fig. 7D showing the odds-ratio for the eGOS increase.
  • Figs.7A to 7D show that for early infusion ( ⁇ 12 hours) Ronopterin-treated patients show an increase in eGOS levels up to 3 levels (Fig. 7A).
  • Fig. 7C shows that overall, an increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients compared to placed (4 vs 1). The increase in proportion of patients with an increase by at least 1 level is significant compared to Placebo-treated patients, see Fig. 7B and Fig. 7D.
  • Figs.7E to 7H show the results for late infusion (>12 hours), with Fig. 7E showing the change in eGOS from 3 to 6 months by eGOS level, Fig.
  • Fig. 7F showing the change in eGOS from 3 to 6 months by category
  • Fig. 7G showing the increase of eGOS level by number of patients
  • Fig. 7H showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 3 levels (Fig. 7E).
  • Fig. 7E shows an increase in eGOS levels up to 3 levels.
  • Fig. 7E Overall, increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (10 vs 8), see Fig. 7G.
  • Fig. 8 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for patients aged 40-60 years.
  • Fig. 8A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 8B shows the change in eGOS from 3 to 6 months by category
  • Fig. 8C shows the increase of eGOS level by number of patients
  • Fig. 8D shows the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (10 vs. 4), see Fig. 8C.
  • Fig. 8 shows for the Ronopterin-treated group more patients with higher increase in eGOS over time, however the increase is not (statistically) significant (Fig. 8D). In addition, Fig. 8 shows for the Ronopterin-treated group that there are less patients with a decrease in eGOS over time, however this decrease is not (statistically) significant.
  • Fig- 9 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for patients aged 40-60 years, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Figs.9A to 9D show the results for early infusion ( ⁇ 12 hours) with Fig. 9A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 9B showing the change in eGOS from 3 to 6 months by category, Fig. 9C showing the increase of eGOS level by number of patients and Fig. 9D showing the odds-ratio for the eGOS increase.
  • Fig. 9A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 9B showing the change in eGOS from 3 to 6 months by category
  • Fig. 9C showing the increase of eGOS level by number of patients
  • Fig. 9D showing the odds-ratio for the e
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin- treated patients (5 vs. 2), see Fig. 9C.
  • Fig. 9A to Fig. 9D show for patients with an age > 40 years and administration of Ronopterin ⁇ 12 hours a trend to more patients with an increase in their eGOS levels (eGOS responders).
  • Figs.9E to 9H show the results for late infusion (>12 hours), with Fig. 9E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 9F showing the change in eGOS from 3 to 6 months by category, Fig.
  • Fig. 9G showing the increase of eGOS level by number of patients and Fig. 9H showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 9E).
  • Fig. 9E Overall, increase in eGOS by at least 2 levels is encountered more often in Ronopterin- treated patients (5 vs 2), see Fig. 9G.
  • Fig. 10 shows a summary of the Odds Ratios (OR) for increases in eGOS levels from 3 to 6 months for early and late infusion and the age groups 18-39 and 40-60 years ( ⁇ 40 and > 40 years).
  • the odds ratio is a measure of the strength of association with an exposure and an outcome.
  • An OR > 1 means greater odds of association with the exposure and outcome.
  • An OR ⁇ 1 means there is a lower odds of association between the exposure and outcome.
  • an odds ratio of 1 means that there no difference between the odds in both groups, while an odds ratio of >1 means that the odds of the first group are higher and an odds ratio of ⁇ 1 means, that the odds of the first group are lower.
  • an OR > 1.8 is clinically relevant, meaning a compound of interest shows the desired therapeutic efficacy.
  • the odds ratio is 4.398. This means, the chance of recovering from TBI is about 4.4 times higher for the patient population that is treated with Ronopterin than it is for the patient population that receives placebo.
  • Fig. 11 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for male patients.
  • Fig. 11A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 11B shows the change in eGOS from 3 to 6 months by category
  • Fig. 11C shows the increase of eGOS level by number of patients
  • Fig. 11D shows the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (22 vs. 9), see Fig. 11C.
  • Fig. 11C shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for male patients.
  • Fig. 11A shows the change in eGOS from 3 to 6 months by eGOS
  • Fig. 12 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for male patients, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Figs.l2A to 12D show the results for early infusion ( ⁇ 12 hours) with Fig. 12A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 12B showing the change in eGOS from 3 to 6 months by category, Fig. 12C showing the increase of eGOS level by number of patients and Fig. 12D showing the odds-ratio for the eGOS increase.
  • Fig. 12A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 12B showing the change in eGOS from 3 to 6 months by category
  • Fig. 12C showing the increase of eGOS level by number of patients
  • Fig. 12D showing the odds-ratio for the eGOS
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (9 vs 2), see Fig. 12C.
  • Fig. 12A to Fig. 12D show for male patients and administration of Ronopterin ⁇ 12 hours that the increase in proportion of patients with an increase by at least 1 level is significant compared to Placebo-treated patients.
  • Figs.l2E to Fig.l2H show the results for late infusion (>12 hours), with Fig. 12E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 12F showing the change in eGOS from 3 to 6 months by category, Fig.
  • Fig. 12G showing the increase of eGOS level by number of patients and Fig. 12H showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 12E). Overall, increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (13 vs 7), see Fig. 12G.
  • Fig. 13 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for female patients.
  • Fig. 13A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 13B shows the change in eGOS from 3 to 6 months by category
  • FIG. 13C shows the increase of eGOS level by number of patients and Fig. 13D shows the odds-ratio for the eGOS increase.
  • Fig. 11A Ronopterin-treated patients show an increase in eGOS levels up to 2 levels and the overall increase in eGOS by at least 2 levels is encountered less often in Ronopterin-treated patients (2 vs 4), see Fig. 13C.
  • Fig. 13 shows for the Ronopterin-treated group less female patients with higher increase in eGOS over time, however the increase is not (statistically) significant (Fig. 13D).
  • Fig. 14 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for female patients, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury
  • Figs.l4A to 14D show the results for early infusion ( ⁇ 12 hours) with Fig. 14A showing the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 14B showing the change in eGOS from 3 to 6 months by category
  • Fig. 14C showing the increase of eGOS level by number of patients
  • Fig. 14D showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 2 levels and the overall increase in eGOS by at least 2 levels is encountered less often in Ronopterin-treated patients (0 vs 1), see Fig. 14C.
  • Fig. 14A to Fig. 14D show for female patients and administration of Ronopterin ⁇ 12 that there are less female eGOS responders but that there is higher Good Recovery at 3 months.
  • Figs.l4E to Fig.l4H show the results for late infusion (>12 hours), with Fig. 14E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 14F showing the change in eGOS from 3 to 6 months by category, Fig.
  • Fig. 14G showing the increase of eGOS level by number of patients and Fig. 14H showing the odds- ratio for the eGOS increase.
  • Ronopterin-treated female patients show an increase in eGOS levels up to 2 levels (Fig. 14E).
  • Fig. 14E Overall, increase in eGOS by at least 2 levels is encountered less often in Ronopterin-treated patients (2 vs 3), see Fig. 14G.
  • Fig. 15 shows the impact of time to infusion, sex, and age on the proportion of Good Recovery (eGOS value of 7 or 8) in Placebo and Ronopterin-treated patients expressed as Odds Ratio with 95% Confidence Intervals.
  • early infusion ⁇ 12 hours
  • Odds Ratio in favor of Ronopterin in female and male patients
  • Late infusion > 12 hours
  • Odds Ratio in favor of Ronopterin in female patients, mainly in the female patient population with an age > 40 years.
  • Fig.l6A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients
  • Fig.l6B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients
  • Fig. 16C shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in female patients and
  • Fig.l6A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients
  • Fig.l6B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients
  • Fig. 16C
  • 16D shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients.
  • Fig.16 at 3 months, male patients show lower proportion of eGOS levels 7 and 8 (Good Recovery) compared to female patients, reflecting more beneficial impact in female patients.
  • male patients show an increase in proportion of eGOS levels 7 and 8 compared to 3 months.
  • Female patients show an increase in Good Recovery from 3 to 6 months.
  • Fig.l7A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients for early infusion ( ⁇ 12 hours)
  • Fig.l7B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients for late infusion (> 12 hours)
  • Fig. 17C shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients for early infusion ( ⁇ 12 hours)
  • Fig.l7A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients for early infusion ( ⁇ 12 hours)
  • Fig.l7B shows the proportion of patients for the 8
  • 17D shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients for late infusion (> 12 hours).
  • early infusion ⁇ 12 hours
  • Late infusion > 12 hours
  • early infusion is associated with an increase in proportion of male patients with Good Recovery (eGOS 7 and 8) which, however, is less pronounced compared to Placebo-treated patients from 3 to 6 months.
  • early infusion is associated with higher proportion of Good Recovery at 6 months in the Ronopterin-treated male patients.
  • Fig.l8A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in female patients for early infusion ( ⁇ 12 hours)
  • Fig.l8B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients for late infusion (> 12 hours)
  • Fig. 18C shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients for early infusion ( ⁇ 12 hours)
  • Fig.l8A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in female patients for early infusion ( ⁇ 12 hours)
  • Fig.l8B shows the proportion of patients for the 8
  • 18D shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients for late infusion (> 12 hours).
  • early infusion ⁇ 12 hours
  • Late infusion > 12 hours
  • early infusion is associated with an increase in proportion of female patients with Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated patients from 3 to 6 months
  • Late infusion is associated with an increase in proportion of female patients with Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated patients from 3 to 6 months
  • early infusion is associated with higher proportion of Good Recovery at 6 months in the Ronopterin-treated female patients.
  • 4-amino-tetrahydrobiopterin also known by its international nonproprietary name (INN) Ronopterin, or as VAS203
  • INN international nonproprietary name
  • VAS203 4-amino-tetrahydrobiopterin
  • the therapeutic efficacy of 4-amino-tetrahydrobiopterin depends on a) the time point at which 4-amino-tetrahydrobiopterin is administered and b) on the patient population that is to be treated.
  • Ronopterin is therapeutically effective with patients of all subpopulations reaching eGOS levels 7 or 8, meaning full neurologic recovery from the brain injury.
  • This therapeutic efficacy of Ronopterin found herein is also reflected by its ability to increase the eGOS level of the patient by 1, 2, 3, or even 4 levels, six months after the occurrence of the brain injury, compared to the eGOS value determined three months after the occurrence of the brain injury.
  • administration of Ronopterin as practiced here will allow patients who, after three months may still be determined to have an eGOS value of 2 or 3 to reach an eGOS value of 7 or 8 six months after occurrence of the traumatic brain injury.
  • the present invention provides for the first time a drug (Ronopterin) that allows patients suffering from brain injury to fully recover from their brain injury, thereby finally providing a long-awaited solution to the unmet medical need to be able to treat, for example, traumatic brain injury.
  • the present invention provides a real breakthrough, far and foremost by allowing patients to fully recover from traumatic brain injury but also in terms of reducing the TBI related high costs described above.
  • it is exemplary referred to the population of female patients at an age of 40 years and older, for which administration of Ronopterin at a time period > 12 hours after occurrence of the traumatic brain injury allows such female patients to reach an eGOS level of 7 or 8 even only three months after occurrence of the traumatic brain injury.
  • the present invention provides the added advantage that patients receiving Ronopterin as described herein only require, while being hospitalized, an accompanying low Therapy Intensity Level (TIL) treatment and not a high Therapy Intensity Level (TIL) treatment which has so far been used in trying to treat patients with traumatic brain injury (see Huijben et al, Use and impact of high intensity treatments in patients with traumatic brain injury across Europe: a CENTER-TBI analysis, Crit Care (2021) pages 25-78).
  • TIL Therapy Intensity Level
  • TIL Treatment Intensity Level
  • the invention provides a method of treating a human patient suffering from brain injury, wherein the method comprises administering to the patient within a time period of ⁇ 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • administering to the patient within a time period of ⁇ 12 hours after the occurrence of the brain injury means that the administration of the compound of formula (I) such as Ronopterin starts within any time in between the time period of ⁇ 12 hours after the occurrence of the brain injury and will continue as long as necessary.
  • the administration can start as early as 3 hours or 4.5 hours after the occurrence of the brain injury (for example, if a patient is hospitalized very shortly after, for example, an accident that leads to the brain injury).
  • the administration may, however, also start within a time period of between 6 to 12 hours after the occurrence of the brain injury, for example, 6, 7, or 10 hours after the occurrence of the brain injury. Regardless of whether the administration starts earlier or later than 6 hours after occurrence of the brain injury, the administration will in any case continue for a suitable time period as specified herein.
  • administering to the patient within a time period of >12 hours after the occurrence of the brain injury means that the administration of the compound of formula (I) such as Ronopterin can start within any time later than 12 hours after the occurrence of the brain injury as long as the administration is considered therapeutically useful. Also in this aspect the administration will continue as long as necessary.
  • the administration can start as early as 12 hours, for example, 12.1 hours after the occurrence of the brain injury (if such an accurate determination of the time that has lapsed since the brain injury can be made) but also only 13, 14, 15, 16, 17, 18, 19 or even 20 hours after the occurrence of the brain injury.
  • the compound having the formula (I) can be administered by any suitable route of administration.
  • the compound of formula (I) is administered by infusion.
  • infusion is used herein its regular meaning to refer to a continuous administration that takes place over a certain period of time.
  • the administration/infusion can be carried over any time that has been found suitable. For example, such an administration may take over a period of about 12 to about 96 hours, a period of about 24 to about 72 hours or over a period of about 24 to about 48 hours.
  • the administration may take place for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 32, 40, 48, 56, 68, 72, 86, or 96 hours.
  • the administration via injection or infusion can also take longer than the time periods given above, if considered advantageous or necessary.
  • the administration time may be extended to over 72 hours.
  • a higher total dosage to be administered may also require a longer infusion time.
  • stop/pause the administration/infusion for a certain period of time for example to avoid unwanted side effects of the compound of formula (I) such as nephrotoxicity. Such a pause may thus prolong an intended administration time of, for example, 48 or 72 hours by several hours.
  • intravenous administration is used herein for the infusion.
  • Intravenous administration is used in its regular term to mean the infusion or injection of a liquid directly into a vein, typically with a syringe and a hollow needle which is pierced through the skin to a sufficient depth for the material to be administered into the body of the subject.
  • the compound of formula (I) such as Ronopterin can be administrated in any dose that is therapeutically effective.
  • the upper limit of the daily dose is usually a dose that is still safe to administer in terms of side effects such as nephrotoxicity.
  • a compound of formula (I) such as Ronopterin is administered at a total dose in the range of 2.5 mg/kg body weight to 30.0 mg/kg body weight.
  • suitable total doses of the compound formula (I) include 2.5, 5.0, 7.5, 8.5, 10.0, 12.5, 15.0, 17.5, 20.0, 22.5, 25.0 or 27.5 mg/kg body weight.
  • the compound of formula (I) may be administered by infusion over 48 hours, corresponding to a daily dose of 8.5 mg/kg body weight.
  • the compound of formula (I) may be administered by infusion over 48 hours, corresponding to a daily dose of 10.0 mg/kg body weight.
  • the compound of formula (I) may be administered by infusion over 72 hours, corresponding (also) to a daily dose of 10.0 mg/kg body weight.
  • administration of a daily dose of 10 .0 mg/kg body weight is in particular suitable for treating a patient suffering from brain injury, wherein the patient is of an age of 39 years or younger, and wherein the method comprises (starting) administering to the patient within a time period of > 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the compound of formula (I) may be administered by infusion over 48 hours, thus in a daily dose of 10.0 mg/kg body weight.
  • the compound of formula (I) may be administered by infusion over 72 hours, and thus also in a daily dose of 10.0 mg/kg body weight.
  • the brain injury can be treated by administration of the compound of formula (I) as described here.
  • the brain injury may for example be traumatic brain injury, non-traumatic brain injury, elevated intracranial pressure, or secondary brain injury.
  • traumatic brain injury occurs when an external force traumatically injures the brain.
  • TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area).
  • a traumatic brain injury can occur as a consequence of a focal impact upon the head, by a sudden acceleration/deceleration within the cranium or by a complex combination of both movement and sudden impact, as well as blast waves, or penetration by a projectile or sharp, or dull object.
  • the Glasgow Coma Scale (GCS), the most commonly used system for classifying TBI severity, grades a person's level of consciousness on a scale of 3- 15 based on verbal, motor, and eye-opening reactions to stimuli.
  • GCS Glasgow Coma Scale
  • cranium when referred to herein is the set of out of the neurocranium (braincase) and the viscerocranium (craniofacial) existing bony and cartilaginous head skeleton of vertebrates. “Intracranial” means within the cranium.
  • traumatic brain injury of any severity can be treated by the administration of the compound of formula (I) as described herein.
  • the patient to be treated may, for example, have been diagnosed with complicated mild, moderate, or severe traumatic brain injury.
  • patient to be treated may have been diagnosed with traumatic brain injury of a Glasgow Coma Score (GCS) > 3.
  • GCS Glasgow Coma Score
  • the patient being assessed of having a Glasgow Coma Score (GCS) > 3 may require intracranial pressure (ICP) monitoring and thus may be taken care of in an intensive care unit (ICU).
  • ICP intracranial pressure
  • ICU intensive care unit
  • the patient does not require ICP monitoring and can, thus, be treated in a normal hospital ward. This may be in particular the case if the patient exhibits a TBI with a GCS of 9 or more, for example, a mild TBI (with a GCS above 13, see above) or a moderate TBI with a GCS of 9-12.
  • a “non-traumatic brain injury” does not involve external mechanical force to acquire a brain injury.
  • causes for non-traumatic brain injury may include lack of oxygen, glucose, or blood.
  • Infections can cause encephalitis (brain swelling), meningitis (meningeal swelling), or cell toxicity as e.g. caused by fulminant hepatic failure, as can tumours or poisons.
  • encephalitis brain swelling
  • meningitis meningitis
  • cell toxicity e.g. caused by fulminant hepatic failure
  • tumours or poisons can occur through stroke, heart attack, near-drowning, strangulation or a diabetic coma, poisoning or other chemical causes such as alcohol abuse or drug overdose, infections or tumours and degenerative conditions such as Alzheimer’s disease and Parkinson’s disease.
  • non-traumatic brain injury that can be treated with the invention as described here, may be ischemic/ hypoxic/hemorrhagic brain injury (e g. stroke), post-resuscitation (after e.g. cardiac arrest), subarachnoid haemorrhage, anticoagulation-induced haemorrhage or non- traumatic brain injury that is caused by inflammation and infection.
  • meningitis which is an acute inflammation of the membranes covering the brain and spinal cord, known collectively as the meninges.
  • the inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs.
  • Encephalitis is another example of an infection that can be treated with the compound of formula (I) as described herein.
  • the inflammation may be Systemic Inflammatory Response Syndrome (SIRS).
  • Secondary injury refers to a variety of events that take place in the minutes and days following the injury. These processes, which include alterations in cerebral blood flow and the pressure within the skull, contribute substantially to the damage from the initial injury. Secondary injury events may include local changes for example damage to the blood-brain barrier, release of factors that cause inflammation, free radical overload, excessive release of the neurotransmitter glutamate (excitotoxicity), influx of calcium and sodium ions into neurons, and dysfunction of mitochondria. Injured axons in the brain's white matter may separate from their cell bodies as a result of secondary injury, potentially killing those neurons.
  • a secondary brain injury that can treated as described herein may comprise a condition selected from the group consisting of edema formation from local or global hypoxia, ischemia, inflammation with and without infection, acute and chronic neuroinflammation after traumatic brain injury and neoplasms with both benign neoplasms and malignant neoplasms being treatable.
  • intracranial pressure may elevate due to swelling or a mass effect from a lesion, such as a haemorrhage.
  • cerebral perfusion pressure the pressure of blood flow in the brain
  • ischemia results.
  • ICP intracranial pressure
  • CSF cerebrospinal fluid
  • ICP is measured in millimeters of mercury (mmHg) and, at rest, is normally 7-15 mmHg for a supine adult. Changes in ICP are attributed to volume changes in one or more of the compartments contained in the cranium.
  • An “elevated pressure in the cranium” or “elevated intracranial pressure” means an increased pressure in the cranium of a subject in comparison to a normal, healthy subject. As the ICP is normally between 7-15 mm Hg; thus at 20-25 mm Hg, the upper limit of normal, is already considered an elevated ICP and a treatment to reduce this pressure may be needed.
  • an elevated ICP can be considered any pressure higher that 20 mm Hg in the cranium of a supine subject, preferably a pressure is higher than 25 mm Hg, higher than 26 mm Hg, higher than 27 mm Hg, higher than 28 mm Hg, higher than 29 mm Hg, higher than 30 mm Hg, higher than 31 mm Hg, higher than 32 mm Hg, higher than 33 mm Hg, higher than 34 mm Hg or higher than 35 mm Hg.
  • the age and the sex of the patient has to be considered for the treatment.
  • the patient may be up to 39 years old.
  • the patent may be 40 years or older. If the patient is 39 years or younger, the patient may either be a child of an age between 1 year to 10 years, or a teenager or adolescent of an age of 11 to 17 or an adult that has an age in the range of 18 to 39 years. If the patient is 40 years of age or older, the patient can have any age above for 40 years. Such a patient may have an age in the range of 40 to 90 years, 40 to 80 years, 40 to 70 years or 40 to 65 years or 40 to 60 years.
  • the patient may thus have an age of 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 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 or 90 years.
  • the therapeutic methods and uses of a compound of formula (I) as described herein comprise an improvement of the physiological condition of the patients suffering from brain injury such as traumatic or non-traumatic brain injury.
  • the condition of the patient (as a result and a measure of the efficacy of the treatment, i.e. typically reduction of the severity of the brain injury) can be expressed by the Extended Glasgow Outcome Scale (eGOS).
  • eGOS Extended Glasgow Outcome Scale
  • GOS Extended Glasgow Outcome Scale
  • GOSE Extended Glasgow Outcome Scale
  • the original GOS and the subsequently developed extended eGOS are recommended by several national public health bodies including the National Institute of Health (NIH) in the U.S. as the outcome measure for major trauma and head injury, respectively.
  • NASH National Institute of Health
  • the suitability of the GOS and eGOS is inter alia based on its simplicity, short administration time, reliability and validity, stability, flexibility of administration (face-to-face, over the telephone and by post), cost-free availability and ease of access.
  • eGOS levels/value as used herein refer to the Level as in given in Table and as also provided by Fig. 1.
  • an eGOS level of 7 indicates lower good recovery of a patient, wherein the patient is able to resume normal life with some disabling due to neurological and/or psychological deficits
  • the eGOS level of 8 refers to upper good recovery, with the patient having fully returned to normal life.
  • the eGOS level/value of a patient can be determined by the respective standard questionnaire that is shown in Fig. 2 and that is available, for example, at https ://www. sralab . org/rehabilitation- measures/glasgow-outcome-scale-extended.
  • the eGOS value as an “outcome score” is assessed not immediately after the occurrence of the brain injury but after a certain period of time “post-injury” such a 3 months, 6 months, or 12 months after the occurrence of the brain injury.
  • post-injury such a 3 months, 6 months, or 12 months after the occurrence of the brain injury.
  • assessment of the eGOS 3 months, 6 months, and 12 months post injury are the standard approach for assessing brain injury such as traumatic brain injury.
  • “3 months eGOS values” and “6 months eGOS values” have been used herein. It is of course also possible to use eGOS values determined at a different point to time.
  • the assessment of the eGOS value may not be taken at exactly the day that is 3 or 6 months after the brain injury but that day can deviate by a couple of days. For example, if the traumatic brain injury occurred on 1 February, the 3 months eGOS value does not necessarily have to be determined on 1 May but can also be determined in late April or early May, for example on 29 April or 5 May.
  • the neurological condition of a patient that has suffered from brain injury can also be assessed/evaluated herein by other commonly used outcome scores such as the Disability Rating Scale (DRS) or the Functional Independence Measure (FIM).
  • DRS Disability Rating Scale
  • FIM Functional Independence Measure
  • a difference in the eGOS value of +1 means herein that the eGOS value at 6 month is 1 level higher than the eGOS value at 3 months, for example, since the patient has improved from eGOS level 4 to eGOS level 5 within the respective 3 months period.
  • administration of the compound of formula (I) increases the value of the Extended Glasgow Outcome Scale (eGos) of the patient by at least 1 or at least 2 eGOS levels when assessed six months after the occurrence of the brain injury such as traumatic brain injury and when compared to the eGOS level of the patient 3 months after the occurrence of the trauma.
  • eGos Extended Glasgow Outcome Scale
  • the eGOS level of a patient can increase, for example, increase from 2 after three months to eGOS level 4, 5, 6, 7 or even 8 six months after the brain injury.
  • the eGOS level of a patient can increase, for example, increase from 3 after three months to eGOS level 5, 6, 7 or 8 six months after the brain injury.
  • the patient in one embodiment of the invention in which the compound of formula (I) is administered within time period of ⁇ 12 hours after the occurrence of the traumatic brain injury, the patient is a male patient having an age of 39 years or below. Such a male patient may reach eGOS level 7 or eGOS level 8 six months after the traumatic brain injury.
  • the value of the Extended Glasgow Outcome Scale (eGos) of the patient increases by at least 1 level, or at least 2 level, including by 3, 4 or 5 levels, when assessed six months after the occurrence of the traumatic brain injury, compared to the eGOS value of the patient determined three months after the traumatic brain injury,
  • the patient is a male patient having an age of 40 years or higher.
  • Such a male patient may reach eGOS level 7 or eGOS level 8 six months after the traumatic brain injury.
  • the value of the Extended Glasgow Outcome Scale (eGos) of the patient increases by at least 1 level, or at least 2 levels, including by 3, 4 and 5 levels, when assessed six months after the occurrence of the traumatic brain injury, compared to the eGOS value of the patient determined three months after the traumatic brain injury.
  • the patient is a female patient having an age of 39 years or below.
  • a female patient may reach eGOS level 7 or eGOS level 8 already three months after, but at least six months after occurrence of the traumatic brain injury.
  • the value of the Extended Glasgow Outcome Scale (eGOS) of the patient increases by at least 1 level or at least 2 levels, including 3, 4 and 5 levels, when assessed six months after the occurrence of the traumatic brain injury, compared to the eGOS value of the patient determined three months after the traumatic brain injury.
  • the patient is a female patient having an age of 40 years or older, for example, an age in the range of 40 to 60 years, or an age of 40 to 70 years, or an age in the range of 40 to 80 years or an age in the range of 40 to 90 years.
  • an administration of the compound of formula (I) results in the female patient reaching eGOS level 7 or eGOS level 8 either already three months or at least six months after the traumatic brain injury.
  • the value of the Extended Glasgow Outcome Scale (eGOS) of the patient increases by at least 1 level or at least 2 levels, including 3, 4 and 5 levels, when assessed six months after the occurrence of the traumatic brain injury, compared to the eGOS value of the patient determined three months after the traumatic brain injury.
  • the treatment comprises providing within a period of 14 days after occurrence of the traumatic brain injury the patient with (only) a low Therapy Intensity Level (TIL) treatment.
  • the low Therapy Intensity Level (TIL) treatment may have a therapy index level of only between 3 and 10.
  • TIL treatment is used herein in its regular meaning (cf. in this respect, for example, Huijben et al, Crit Care (2021, vide supra) and as illustrated by Fig. 3A which shows an overview of the Therapy Intensity Level (TIL) treatment with the typical types of interventions used in the treatment of patients with brain injury together with the intensity of the intervention and their respective score.
  • Fig. 3B shows options for exemplary low TIL treatments that can be used herein and which yield an index between 3 and 10.
  • a low TIL treatment used here may only comprise as interventions “Head elevation”, “Sedation” and “Increased oxygenation“ which together have a low TIL score of only 3.
  • this treatment may comprise as interventions “Head elevation”, “Sedation”, “Increased oxygenation “, Cooling” and “Osmotherapy” which together have a low TIL score of only 6
  • interventions “Head elevation”, “Sedation”, “Increased oxygenation “, Cooling” and “Osmotherapy” which together have a low TIL score of only 6
  • TIL Therapy Intensity Level
  • the compound is typically 4-Amino-(6R,S)-5,6,7,8- tetrahydro-L-biopterin having the formula (la):
  • the compound (la) may be a diastereomeric mixture that comprises more (6R)-4-Amino-5,6,7,8-tetrahydro-L-biopterin than (6S)-4-Amino-5, 6, 7, 8-tetrahydro-L- biopterin.
  • any suitable pharmaceutical composition containing 4-Amino-5,6,7,8-tetrahydro-L-biopterin can be used.
  • suitable formulations are described in International Patent Application WO 2004/084906, or the corresponding US patent 8,222,828 as well as in European Patent 2 926 805, US patent 10,016,431 or International Patent Application WO 2015/150294.
  • infusion of the compound of formula (I) such as Ronopterin can be carried out with a reconstituted solid composition of the compound of formula (I), wherein a unit dosage of the solid composition contains, as described in US patent 10,016,431 or WO 2015/150294, 650 ⁇ 60 mg of the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 140 ⁇ 30 mg of water of crystallization, 70 ⁇ 7 mg Na2HPO4 • 2 H2O, 16.5 ⁇ 2 mg NaH2PO4 ⁇ 2 H2O, and 350 ⁇ 30 mg NaCl.
  • a unit dosage of the solid composition may contain 650 ⁇ 60 mg of the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin, 60 ⁇ 50 mg of water of crystallization, 70 ⁇ 7 mg Na2HPO4 • 2 H2O, 12 ⁇ 2.5 mg NaH2PO4 • 2 H2O, and 350 ⁇ 30 mg NaCl.
  • the reconstitution then comprises providing a vial containing 1g of the unit dosage and adding 50 ml water to 1g of the unit dosage to yield a ready-to-use infusion solution with a concentration of Ronopterin of 20 mg/mL.
  • Such an infusion solution can then be administered (infused) to a patient (population) as described here, for a suitable period of time (such as 12 to 96 hours) starting with the administration either within a time period of ⁇ 12 hours or within a time period of > 12 hours.
  • a further aspect of the invention is directed to a method of treating a human patient suffering from brain injury, wherein the patient is a female of an age of 40 years or older, and wherein the method comprises (starting) administering to the patient within a time period of > 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • a third aspect of the present invention relates to a method of increasing the value of the Extended Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury, thereby improving the condition of the patient, wherein the value of the Extended Glasgow Outcome Scale (eGOS) of the patient reaches eGOS level 7 or eGOS level 8 six months after the occurrence of the brain injury, wherein the method comprises (starting) administering to the patient within a time period of ⁇ 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the eGOS value of the patient when assessed six months after the occurrence of the traumatic brain injury can have increased by 1, 2, 3, 4, 5, or 6 eGOS levels compared to the eGOS value of the patient determined three months after the occurrence of the traumatic brain injury.
  • a fourth aspect of the present invention relates to a method of increasing the value of the Extended Glasgow Outcome Scale (eGOS) of a human patient suffering from brain injury, thereby improving the condition of the patient, wherein the value of the Extended Glasgow Outcome Scale (eGOS) of the patient has increased by 2 or more six months after the occurrence of the brain injury and compared to the eGOS value determined three months after the occurrence of the brain injury.
  • This method comprises (starting) administering to the patient within a time period of ⁇ 12 hours after the occurrence of the brain injury a therapeutically effective amount of a compound having the formula (I):
  • the value of the Extended Glasgow Outcome Scale (eGOS) of the patient can have increased by 1, 2, 3, 4, 5, or 6 level six months after the occurrence of the brain injury, when compared to the eGOS value determined three months after the occurrence of the brain injury. Also in this method administering a compound of formula (I) results in the value of the Extended Glasgow Outcome Scale (eGOS) of the patient reaching eGOS level 7 or eGOS level 8 six months after the occurrence of the brain injury.
  • Example 1 Manufacturing of Ronopterin Ronopterin (VAS203) is prepared in a multistep synthesis starting from commercially available L-biopterin as described in Example 1 of, for instance, US patent 10,016,431 or WO 2015/150294.
  • Example 2 Manufacturing of solid Ronopterin containing composition (Drug Product)
  • Ronopterin (VAS203) is supplied as a sterile, white to pale red or brown lyophilised powder filled in 50 mL glass vials under nitrogen as a protective atmosphere.
  • Each vial contains 650 ⁇ 60 mg of the free base of 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin and 140 ⁇ 30 mg of water of crystallisation. Additionally, the vials contain 350 ⁇ 30 mg sodium chloride (NaCl), 70 ⁇ 7 mg disodium hydrogen phosphate dihydrate (Na 2 HPC>4 2 H 2 O), and 16.5 ⁇ 2 mg sodium dihydrogen phosphate dihydrate (NaH 2 PC>4 2 H 2 O).
  • the limits of tolerance of the drug product composition are relatively high ( ⁇ 10 %).
  • the reason for this is the variation of the hydrochloride content of Ronopterin.
  • the hydrochloride content of Ronopterin varies from batch to batch up to 10 % (from 2.03 HC1 to 2.24 HC1).
  • the hydrochloride was neutralised in the present invention by addition of sodium hydroxide and sodium-phosphate buffer to obtain an isotonic solution with a physiological pH value. Therefore, also the content of the molecules generated during neutralisation (sodium chloride, di sodium hydrogen phosphate and sodium dihydrogen phosphate) varies according to the hydrochloride content of the respective Ronopterin batch.
  • the given limits of tolerance are necessary to meet the specifications of the quality relevant parameters pH and osmolality.
  • the qualitative composition of 1g Ronopterin vials is listed in Table 2.
  • Ronopterin ad 10g sodium hydroxi de/sodium hydrogen phosphate solution buffer with a final pH of 7.4 as described in US patent 10,016,431 or WO 2015/150294 was selected to be aseptically processed, sterilised by membrane filtration and filled into 50 mL glass vials. Subsequently, this solution was freeze-dried according to a selected lyophilisation program that produced a lyophilised product with excellent stability. In this solid composition, Ronopterin is present as free base 4-Amino-5,6,7,8-tetrahydro-L-biopterin. The vials are closed under nitrogen, sealed with freeze-drying stoppers and closed with white vacuum closures.
  • the excipients are added in order to provide an isotonic solution with physiological pH after reconstitution with 50 mL water ad inject.
  • the pH of the final isotonic solution is 6.5 to 7.6.
  • the final concentration of the drug substance VAS203 (Ronopterin) is 20 mg/mL.
  • Example 3 Phase III clinical trial A phase III trial of Ronopterin infusion to adult TBI patients (18-60 years) with acute moderate and severe TBI was performed. Based on the results of the earlier phase II study, the NOSTRA (NO Synthase in TRAumatic Brain Injury) phase III trial was designed to detect clinically relevant differences in clinical outcome (Extended Glasgow Outcome Score at 6 months after injury) as primary endpoint.
  • NOSTRA NO Synthase in TRAumatic Brain Injury
  • NOSTRA III was a multicentre, prospective, two parallel groups, blinded, placebo-controlled, randomised phase III trial of Ronopterin infusion for 48 hours in adult intensive care patients with acute moderate and severe TBI.
  • the primary objective was to demonstrate that the extended Glasgow Outcome Score (eGOS) 6 months after injury is improved following administration of Ronopterin compared to placebo.
  • the detailed study protocol is described by Tegtmeier et al. Efficacy of Ronopterin (VAS203) in Patients with Moderate and Severe Traumatic Brain Injury (NOSTRA phase III trial): study protocol of a confirmatory, placebo- controlled, randomised, double blind, multi-centre study. Trials. 2020. A total of 224 evaluable patients with moderate and severe TBI were enrolled in 32 centres in Austria, France, Germany, Spain, and United Kingdom. The trial started on 24 August 2016 with lastpatient last-visit on 17 June 2020.
  • the inclusion and exclusion criteria were designed to exclude patients with unsurvivable injuries and patients at risk of renal failure.
  • For complete inclusion and exclusion criteria see Tegtmeier et al., Trial 2020, vide supra.
  • the centres treated the patients according to their established standard of care; all centres were requested to follow the standardised TBI clinical practice according to the current guidelines [Carney],
  • the trial was conducted as a double blinded trial. Patients, site investigators, site research coordinators, the sponsor, central CT scan assessor and the staff in charge of treating the patients and evaluating the outcome were blinded.
  • the ready-to-use infusion solution of Ronopterin and placebo was prepared in an opaque syringe by unblinded staff not involved in the care of trial patients. Depending on the local organisation this was a medical employee from another ward or the central pharmacy.
  • Ronopterin and placebo (0.9% saline) were infused continuously via central venous catheter at a constant rate.
  • a total dose of 17 mg/kg body weight of Ronopterin was infused for 48 hours (daily dose 8.5 mg/kg body weight).
  • the dose for each patient was calculated automatically based on the individual body weight, resulting in an individual infusion rate for each patient.
  • the primary outcome was the difference between eGOS in Ronopterin and placebo treated patients at 6 months after trauma.
  • the eGOS was determined by a face to face meeting by trained assessors.
  • the prognostic factor according to Steyerberg et al. (Steyerberg et al. Predicting outcome after traumatic brain injury. PLoS Med 2008 5(8)) predicts the probability of 6 months mortality or probability of 6 months unfavorable outcome.
  • the prognostic factor was analyzed by a t-test on a two-sided alpha level of 0.05. The mean difference of the score under Ronopterin and Placebo with its 95%-confidence interval were summarized for comparability at baseline.
  • the NOSTRA phase III trial was designed to detect a treatment effect as statistically significant on an alpha level of 0.05 with a statistical power of 92%, 220 evaluable patients were needed for the full analysis set. To account for patients lost for follow up and withdrawals, number of recruited patients was increased by 5% to 232 patients. However, as number of withdrawals and lost-to-follow up was very low, the study was successfully completed after recruitment of evaluable 224 patients.
  • the null-hypothesis of no shift across the 8 ordered categories of eGOS for the two treatment groups was tested after six months based on a proportional odds model stratified by age (18- 39 years and 40-60 years).
  • the treatment effect was estimated using ordinal Logistic regression model as the (proportional) odds ratio of Ronopterin versus Placebo.
  • Treatment and age (18-39 years and 40-60 years) were included in the model.
  • the proportional odds assumption was tested using a Chi-Square Score Test.
  • DMC Data and Safety Monitoring Committee
  • the main objective of the post hoc analyses was to estimate the effect size of VAS203 compared with placebo for the primary endpoint eGOS-I in the subgroups time to infusion ⁇ 12 hours and >12 hours.
  • Supportive analyses were conducted by age group ( ⁇ 40 years, >40 years) because age group was used as a stratification factor in the study. Comparability between treatment groups regarding demographics as well as severity and location of disease was investigated using similar methods as in the main CSR.
  • the proportions of patients per eGOS-I level at 3 months and at 6 months were calculated.
  • the proportion of patients with changes from 3 to 6 months were calculated by eGOS-I level, and in addition categorised as decreased (i.e. any decrease in eGOS-I level from 3 to 6 months), unchanged (i.e. no change in eGOS-I level from 3 to 6 months), and increased (i.e. any increase in eGOS-I level from 3 to 6 months).
  • the binary variable eGOS-I increase was defined as “yes” if there was an increase of at least 1 level from 3 to 6 months. If there was no change or a decrease of at least 1 level from 3 to 6 months, the variable was defined as “no”.
  • nominal logistic regression was used, including treatment group and age group ( ⁇ 40 years, >40 years) as factors and eGOS-I at 3 months as covariate to adjust for potential differences at 3 months.
  • Obtained odds ratios for the comparison of the VAS203 and placebo groups of >1 mean that the eGOS-I increase occurred more often in the VAS203 group than in the placebo group, whereas odds ratios of ⁇ 1 mean that the eGOS-I increase occurred less often in the VAS203 group than in the placebo group.
  • the analyses were done for all patients in the full analysis set (FAS) and for the subgroups defined by time to infusion ( ⁇ 12 h, >12 h) and age group ( ⁇ 40 years, >40 years).
  • the analyses were based on ADaM datasets produced for the main CSR in 2020.
  • 4 missing values for time to infusion were imputed in collaboration with the Sponsor based on calculation from related variables.
  • Four eGOS-I values were missing at 3 months; the respective patients were excluded from analyses of this variable.
  • a corrected value for time to admission to study centre (for 1 patient, the date for admission to study centre had been incorrectly captured in the CRF). This value was changed via hard coding following authorisation of a post-lock database change by the Sponsor.
  • the mean age was 39.3 years (SD+/-13.2) the mean body mass index was 25.5 kg/m 2 (SD +Z-3.9).
  • eGOS In patients with time to infusion ⁇ 12 hours, eGOS was higher by 1 eGOS level in the Ronopterin compared to placebo treated patients (median 6 vs 5; ns); in patients with time to infusion > 12 hours, eGOS was similar in both treatment groups at 6 months (median 5 vs 5).
  • Fig. 4 shows the distribution of proportion of patients between Placebo and Ronopterin (VAS203)-treated patients reflecting changes in eGOS from 3 to 6 months for all patients and all times to infusion.
  • Fig. 4A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 4B shows the change in eGOS from 3 to 6 months by category
  • Fig. 4C shows the increase of eGOS level by number of patients
  • Fig. 4D shows the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (24 vs.
  • Fig. 4 shows for the Ronopterin-treated group more patients with higher increase in eGOS over time, however the increase is not (statistically) significant (Fig. 4D). In addition, Fig. 4 shows for the Ronopterin-treated group that there are less patients with a decrease in eGOS over time, however this decrease is not (statistically) significant.
  • Fig. 5 shows the distribution of proportion of patients of all ages between Placebo and Ronopterin-treated patients with changes in eGOS from 3 to 6 months, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Fig. 5 shows for the Ronopterin-treated group a significant increase in proportion of patients with increased eGOS.
  • Figs.5A to 5D show the results for early infusion ( ⁇ 12 hours), with Fig. 5A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 5B showing the change in eGOS from 3 to 6 months by category, Fig. 5C showing the increase of eGOS level by number of patients and Fig. 5D showing the odds-ratio for the eGOS increase.
  • Figs.5A to 5D show that for early infusion ( ⁇ 12 hours) Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 5A).
  • Figs.5E to 5H show the results for late infusion (>12 hours), with Fig. 5E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 5F showing the change in eGOS from 3 to 6 months by category, Fig. 5G showing the increase of eGOS level by number of patients and Fig. 5H showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 5E). Overall, increase in eGOS by at least 2 levels is encountered more often in Ronopterin- treated patients (15 vs 10), see Fig 5G.
  • Fig. 6 shows the change in eGOS levels from 3 to 6 months, for patients with an age of 18-39 years and at all times to infusion.
  • Fig. 6A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 6B shows the change in eGOS from 3 to 6 months by category
  • Fig. 6C shows the increase of eGOS level by number of patients
  • Fig. 6D shows the odds-ratio for the eGOS increase.
  • Fig. 6 shows that in the Ronopterin-treated group, there are more patients with higher increase in eGOS over time, however this increase is not significant (see Fig. 6D) while in the Ronopterin-treated group, there are less patients with decrease in eGOS over time, however this decrease is not significant.
  • Fig. 7 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for patients aged 18-39 years, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Figs.7A to 7D show the results for early infusion ( ⁇ 12 hours), with Fig. 7A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 7B showing the change in eGOS from 3 to 6 months by category, Fig. 7C showing the increase of eGOS level by number of patients and Fig. 7D showing the odds-ratio for the eGOS increase.
  • Figs.7A to 7D show that for early infusion ( ⁇ 12 hours) Ronopterin-treated patients show an increase in eGOS levels up to 3 levels (Fig. 7A).
  • Fig. 7C shows that overall, an increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients compared to placed (4 vs 1). The increase in proportion of patients with an increase by at least 1 level is significant compared to Placebo-treated patients, see Fig. 7B and Fig. 7D.
  • Figs.7E to 7H show the results for late infusion (>12 hours), with Fig. 7E showing the change in eGOS from 3 to 6 months by eGOS level, Fig.
  • Fig. 7F showing the change in eGOS from 3 to 6 months by category
  • Fig. 7G showing the increase of eGOS level by number of patients
  • Fig. 7H showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 3 levels (Fig. 7E).
  • Fig. 7E shows an increase in eGOS levels up to 3 levels.
  • Fig. 7E Overall, increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (10 vs 8), see Fig. 7G.
  • Fig. 8 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for patients aged 40-60 years.
  • Fig. 8A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 8B shows the change in eGOS from 3 to 6 months by category
  • Fig. 8C shows the increase of eGOS level by number of patients
  • Fig. 8D shows the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (10 vs. 4), see Fig. 8C.
  • Fig. 8 shows for the Ronopterin-treated group more patients with higher increase in eGOS over time, however the increase is not (statistically) significant (Fig. 8D)
  • Fig. 8 shows for the Ronopterin-treated group that there are less patients with a decrease in eGOS over time, however this decrease is not (statistically) significant.
  • Fig. 9 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for patients aged 40-60 years, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Figs.9A to 9D show the results for early infusion ( ⁇ 12 hours) with Fig. 9A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 9B showing the change in eGOS from 3 to 6 months by category, Fig. 9C showing the increase of eGOS level by number of patients and Fig. 9D showing the odds-ratio for the eGOS increase.
  • Fig. 9A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 9B showing the change in eGOS from 3 to 6 months by category
  • Fig. 9C showing the increase of eGOS level by number of patients
  • Fig. 9D showing the odds-ratio for the e
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin- treated patients (5 vs. 2), see Fig. 9C.
  • Fig. 9A to Fig. 9D show for patients with an age > 40 years and administration of Ronopterin ⁇ 12 hours a trend to more patients with an increase in their eGOS levels (eGOS responders).
  • Figs.9E to 9H show the results for late infusion (>12 hours), with Fig. 9E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 9F showing the change in eGOS from 3 to 6 months by category, Fig.
  • Fig. 9G showing the increase of eGOS level by number of patients and Fig. 9H showing the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 9E).
  • Fig. 9E shows an increase in eGOS levels up to 4 levels.
  • Fig. 9G shows a summary of the Odds Ratios (OR) for increases in eGOS levels from 3 to 6 months for early and late infusion and the age groups 18-39 and 40-60 years ( ⁇ 40 and > 40 years).
  • an odds ratio of 1 means that there no difference between the odds in both groups, while an odds ratio of >1 means that the odds of the first group are higher and an odds ratio of ⁇ 1 means, that the odds of the first group are lower.
  • Fig. 11 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for male patients.
  • Fig. 11A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 11B shows the change in eGOS from 3 to 6 months by category
  • Fig. 11C shows the increase of eGOS level by number of patients
  • Fig. 11D shows the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (22 vs. 9), see Fig. 11C.
  • Fig. 11C shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for male patients.
  • Fig. 11A shows the change in eGOS from 3 to 6 months by eGOS
  • Fig. 12 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for male patients, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Figs.llA to 12D show the results for early infusion ( ⁇ 12 hours) with Fig. 12A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 12B showing the change in eGOS from 3 to 6 months by category, Fig. 12C showing the increase of eGOS level by number of patients and Fig. 12D showing the odds-ratio for the eGOS increase.
  • Fig. 12A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 12B showing the change in eGOS from 3 to 6 months by category
  • Fig. 12C showing the increase of eGOS level by number of patients
  • Fig. 12D showing the odds-ratio for the eGOS increase
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels and the overall increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (9 vs 2), see Fig. 12C.
  • Fig. 12A to Fig. 12D show for male patients and administration of Ronopterin ⁇ 12 hours that the increase in proportion of patients with an increase by at least 1 level is significant compared to Placebo-treated patients.
  • Figs.l2E to Fig.l2H show the results for late infusion (>12 hours), with Fig. 12E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 12F showing the change in eGOS from 3 to 6 months by category, Fig.
  • Ronopterin-treated patients show an increase in eGOS levels up to 4 levels (Fig. 12E). Overall, increase in eGOS by at least 2 levels is encountered more often in Ronopterin-treated patients (13 vs 7), see Fig. 12G.
  • Fig. 13 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for female patients.
  • Fig. 13A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 13B shows the change in eGOS from 3 to 6 months by category
  • Fig. 13C shows the increase of eGOS level by number of patients
  • Fig. 13D shows the odds-ratio for the eGOS increase.
  • Ronopterin-treated patients show an increase in eGOS levels up to 2 levels and the overall increase in eGOS by at least 2 levels is encountered less often in Ronopterin-treated patients (2 vs 4), see Fig. 13C.
  • Fig. 13 shows for the Ronopterin-treated group less female patients with higher increase in eGOS over time, however the increase is not (statistically) significant (Fig. 13D).
  • Fig. 14 shows the distribution of proportion of patients between Placebo and Ronopterin- treated patients with changes in eGOS from 3 to 6 months for female patients, depending on the time to infusion within 12 hours and after 12 hours after traumatic brain injury.
  • Figs.l4A to 14D show the results for early infusion ( ⁇ 12 hours) with Fig. 14A showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 14B showing the change in eGOS from 3 to 6 months by category, Fig. 14C showing the increase of eGOS level by number of patients and Fig. 14D showing the odds-ratio for the eGOS increase.
  • Fig. 14A shows the change in eGOS from 3 to 6 months by eGOS level
  • Fig. 14B showing the change in eGOS from 3 to 6 months by category
  • Fig. 14C showing the increase of eGOS level by number of patients
  • Fig. 14D showing the odds-ratio for the eGOS
  • Ronopterin-treated patients show an increase in eGOS levels up to 2 levels and the overall increase in eGOS by at least 2 levels is encountered less often in Ronopterin-treated patients (0 vs 1), see Fig. 14C.
  • Fig. 14A to Fig. 14D show for female patients and administration of Ronopterin ⁇ 12 that there are less female eGOS responders but that there is higher Good Recovery at 3 months.
  • Figs.l4E to Fig.l4H show the results for late infusion (>12 hours), with Fig. 14E showing the change in eGOS from 3 to 6 months by eGOS level, Fig. 14F showing the change in eGOS from 3 to 6 months by category, Fig.
  • Fig. 14G showing the increase of eGOS level by number of patients and Fig. 14H showing the odds- ratio for the eGOS increase.
  • Ronopterin-treated female patients show an increase in eGOS levels up to 2 levels (Fig. 14E).
  • Fig. 14E shows an increase in eGOS levels up to 2 levels.
  • Fig. 14E shows an increase in eGOS levels up to 2 levels.
  • Fig. 15 shows the impact of time to infusion, sex, and age on the proportion of Good Recovery (eGOS value of 7 or 8) in Placebo and Ronopterin-treated patients expressed as Odds Ratio with 95% Confidence Intervals.
  • Fig.l6A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients
  • Fig.l6B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients
  • Fig. 16C shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in female patients and
  • Fig.l6A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients
  • Fig.l6B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients
  • Fig. 16C
  • 16D shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients.
  • Fig.16 at 3 months, male patients show lower proportion of eGOS levels 7 and 8 (Good Recovery) compared to female patients, reflecting more beneficial impact in female patients.
  • male patients show an increase in proportion of eGOS levels 7 and 8 compared to 3 months.
  • Female patients show an increase in Good Recovery from 3 to 6 months.
  • Fig.l7A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients for early infusion ( ⁇ 12 hours)
  • Fig.l7B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients for late infusion (> 12 hours)
  • Fig. 17C shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients for early infusion ( ⁇ 12 hours)
  • Fig.l7A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in male patients for early infusion ( ⁇ 12 hours)
  • Fig.l7B shows the proportion of patients for the 8
  • 17D shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in male patients for late infusion (> 12 hours).
  • early infusion ⁇ 12 hours
  • Late infusion > 12 hours
  • early infusion is associated with an increase in proportion of male patients with Good Recovery (eGOS 7 and 8) which, however, is less pronounced compared to Placebo-treated patients from 3 to 6 months.
  • early infusion is associated with higher proportion of Good Recovery at 6 months in the Ronopterin-treated male patients.
  • Fig.l8A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in female patients for early infusion ( ⁇ 12 hours)
  • Fig.l8B shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients for late infusion (> 12 hours)
  • Fig. 18C shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients for early infusion ( ⁇ 12 hours)
  • Fig.l8A shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 3 months in female patients for early infusion ( ⁇ 12 hours)
  • Fig.l8B shows the proportion of patients for the 8 e
  • 18D shows the proportion of patients for the 8 eGOS levels in Placebo and Ronopterin-treated patients at 6 months in female patients for late infusion (> 12 hours).
  • early infusion ⁇ 12 hours
  • Late infusion > 12 hours
  • early infusion is associated with an increase in proportion of female patients with Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated patients from 3 to 6 months.
  • Late infusion is associated with an increase in proportion of female patients with Good Recovery (eGOS 7 and 8) exceeding the proportion in Placebo-treated patients from 3 to 6 months.
  • early infusion is associated with higher proportion of Good Recovery at 6 months in the Ronopterin-treated female patients.
  • ICP intracerebral haematoma
  • AE or SAE An increased ICP or e.g., intracerebral haematoma are normally classified as an AE or SAE.
  • TBI this and other pathophysiological responses of the brain can typically be expected and, thus, were recommended not to be considered as AE or SAE.
  • the apparent increase in ICP increased compared to placebo may be due to the over-reporting of some centres.

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Abstract

La présente invention concerne l'utilisation de composés de bioptérine tels que la 4-Amino-(6R,S)-5,6,7,8-tétrahydro-L-bioptérine pour le traitement de patients atteints d'une lésion cérébrale. L'invention concerne également l'utilisation de tels composés de bioptérine pour augmenter la valeur de l'échelle de résultats deGlasgow étendue (GOS-E) de patients atteints d'une lésion cérébrale, ce qui permet d'améliorer l'état du patient.
PCT/EP2021/084183 2021-12-03 2021-12-03 Procédés de traitement de patients atteints d'une lésion cérébrale et procédés d'augmentation de la valeur de l'échelle de résultats de glasgow étendue de patients atteints d'une lésion cérébrale Ceased WO2023099013A1 (fr)

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EP21830625.6A EP4440578A1 (fr) 2021-12-03 2021-12-03 Procédés de traitement de patients atteints d'une lésion cérébrale et procédés d'augmentation de la valeur de l'échelle de résultats de glasgow étendue de patients atteints d'une lésion cérébrale
PCT/EP2021/084183 WO2023099013A1 (fr) 2021-12-03 2021-12-03 Procédés de traitement de patients atteints d'une lésion cérébrale et procédés d'augmentation de la valeur de l'échelle de résultats de glasgow étendue de patients atteints d'une lésion cérébrale
CA3235704A CA3235704A1 (fr) 2021-12-03 2021-12-03 Procedes de traitement de patients atteints d'une lesion cerebrale et procedes d'augmentation de la valeur de l'echelle de resultats de glasgow etendue de patients atteints d'une lesion cerebral
AU2021476139A AU2021476139A1 (en) 2021-12-03 2021-12-03 Methods of treating patients suffering from brain injury and methods of increasing the value of the extended glasgow outcome scale of patients suffering from brain injury
TW111146425A TW202342049A (zh) 2021-12-03 2022-12-02 治療患有腦損傷的患者的方法以及增加患有腦損傷的患者的擴展版格拉斯哥結局量表的值的方法

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