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EP-4313104-B1 - DC009 FOR TREATING ACUTE ISCHEMIC STROKE

EP4313104B1EP 4313104 B1EP4313104 B1EP 4313104B1EP-4313104-B1

Inventors

  • LIN, JUNG-CHIN
  • YEH, Sheng-Wen
  • PENG, SHIQI
  • ZHAO, MING
  • CHOU, DAVID CHIH-KUANG

Dates

Publication Date
20260513
Application Date
20220321

Claims (15)

  1. The compound DC009 for use in a method of treating acute ischemic stroke in a human, wherein the dose is about 0.01-0.075 mg/kg/dose.
  2. The compound for use according to claim 1, wherein the dose is about 0.025-0.05 mg/kg/dose.
  3. The compound for use according to claim 2, wherein the dose is about 0.025 mg/kg/dose.
  4. The compound for use according to claim 2, wherein the dose is about 0.05 mg/kg/dose.
  5. The compound for use according to any one of claims 1-4, wherein the dose is administered at least once per day, optionally wherein the dose is administered twice a day.
  6. The compound for use according to any one of claims 1-5, wherein the dose is administered at dosage intervals of about 3-12 hours.
  7. The compound for use according to any one of claims 1-6, wherein the dose is administered at least once per day for 2 days or for 3 days.
  8. The compound for use according to claim 4, wherein the dose is administered at least twice a day for 3 days.
  9. The compound for use according to claim 8, wherein the dose is administered at dosage intervals of about 3-12 hours.
  10. The compound for use according to any one of claims 1-9, wherein the compound is administered to the subject immediately or within 1-24 hours after the onset of acute ischemic stroke.
  11. The compound for use according to any one of claims 1-10, wherein the compound is administered by intravenous infusion and/or bolus injection.
  12. The compound for use according to any one of claims 1-10, wherein the compound is administered by intravenous infusion.
  13. The compound for use according to claim 12, wherein the compound is administered by intravenous infusion over a period of 5-60 minutes.
  14. The compound for use according to any one of claims 1-13, wherein the compound is co-administered with aspirin, clopidogrel, apixaban or dabigatran.
  15. The compound for use according to any one of claims 1-14, wherein the Cmax in the plasma of the subject after dosing is less than 200 ng/mL.

Description

FIELD OF THE INVENTION This invention relates to a method of treating acute ischemic stroke in humans using a low dose of 3 S-6,7-dihydroxy-1,1-dimethyl-1,2,3,4- tetrahydro-isoquinoline-3-acyl-Lys(Pro-Ala-Lys) (DC009) (CAS RN: 1639303-73-3). BACKGROUND OF THE INVENTION Stroke is classically characterized as a neurological deficit attributed to an acute focal injury of the central nervous system by a vascular cause. Ischemic strokes account for about 87% of all strokes; 10% are intracerebral hemorrhage strokes, whereas 3% are subarachnoid hemorrhage strokes. Annually, 15 million people worldwide suffer a stroke; in the United States, on average, someone experiences a stroke every 40 seconds. Globally, stroke is the second leading cause of death above the age of 60 years and is the leading cause of disability. Alteplase (Activase®), a recombinant tissue-type plasminogen activator (rtPA), was the first medication approved for the treatment of ischemic stroke by the US Food and Drug Administration in 1996 (BLA 103172/S-1055). Although alteplase has been shown to improve the outcome of subjects with acute ischemic stroke (AIS), its use has been limited as it is approved for administration only within 3 hours (in the United States) or 4.5 hours after symptom onset, and it causes nearly 5-fold risk of symptomatic intracerebral hemorrhage. Due to the above-mentioned reasons, the usage rate of alteplase is low, and only approximately 5% of stroke patients are administered alteplase. As such, there is a need to develop treatments that can offer similar efficacy to alteplase but with a lower increase of bleeding and/or a longer therapeutic window. DC009 is a peptide-tetrahydroisoquinoline conjugate, which has a chemical name of 3S-6,7-dihydroxy-1,1-dimethyl-1,2,3,4- tetrahydro-isoquinoline-3-acyl-Lys(Pro-Ala-Lys) or L-Lysine, N6-(L-prolyl-L-alanyl-L-lysyl)-N2-[[(3S)-1,2,3,4-tetrahydro-6,7-dihydroxy-1,1-dimethyl-3-isoquinolinyl]carbonyl] (CAS RN: 1639303-73-3). DC009 is a binary conjugate that can be formed by coupling a thrombolytic peptide (Pro-Ala-Lys) and a tetrahydroisoquinoline compound having two C1-4 alkyl groups via a Lysine linking arm. The structure of DC009 is shown in FIG.1A, the amide bond between the Lysine linking arm and the Pro-Ala-Lys peptide is shown in FIG.1B. QIQI FENG ET AL., J. MATER. CHEM. B, vol. 4, no. 36, 2016, pages 5991-6003, discloses the thrombolytic and anti-thrombotic activities of nanomolar doses of DC009 in a mouse thrombosis model. Pharmaceutical development is a stepwise process involving an evaluation of both animal and human efficacy and safety information. The goals of the non-clinical safety evaluation generally include characterization of toxic effects; this information is used to estimate an initial safe starting dose and dose range for the human trials and to identify parameters for clinical monitoring for potential adverse effects. All relevant preclinical data, including information on the pharmacologically active dose, the full toxicologic profile of the compound, and the pharmacokinetics (absorption, distribution, metabolism, and excretion) of the therapeutic, should be considered. Maximum recommended starting dose (MRSD) for first-in-human clinical trials of new molecular entities in adult healthy volunteers should be determined by dividing the human equivalent dose (HED) derived from the animal no observed adverse effect levels (NOAEL) by a safety factor. The default safety factor normally used is 10, which is a historically accepted value, but it should be evaluated based on available information. This is a non-binding recommendation by FDA and Center for Drug Evaluation and Research (CDER). However, a safety factor of 10 may not be appropriate for all cases. The safety factor should be raised when there is reason for increased concern, and lowered when concern is reduced because of available data that provide added assurance of safety. (Guidance for Industry "Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers", www.fda.gov/media/72309/download) The development of therapies for acute ischemic stroke (AIS) is a difficult and challenging endeavor, due to the complexity of the pathophysiology and clinical aspects of this heterogeneous disorder. Recombinant Tissue Plasminogen Activator (rtPA) initiated within 3 hours of stroke onset is the only one currently approved therapy for AIS. There are only limited track records to assess the use of animal models in the development of AIS therapies. A large number of interventions demonstrated efficacy in animal models of AIS and these interventions, primarily neuroprotective agents, have not been shown to improve AIS outcome in patient (Fisher, al, Stroke. Volume 36, Issue 10, 1 October 2005; Pages 2324-2325). The discrepancy in results regarding neuroprotective agents in animal experiments compared to clinical trials is a major problem. While many neuroprotective age