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EP-4275750-B1 - TREATMENT OF ALZHEIMER'S DISEASE IN A PARTICULAR PATIENT POPULATION

EP4275750B1EP 4275750 B1EP4275750 B1EP 4275750B1EP-4275750-B1

Inventors

  • ABUSHAKRA, Susan
  • POWER, Aidan
  • TOLAR, Martin
  • HEY, JOHN
  • YU, JEREMY
  • KOCIS, PETR

Dates

Publication Date
20260506
Application Date
20160909

Claims (13)

  1. A pharmaceutical composition comprising tramiprosate, valyl-3-amino-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of Alzheimer's disease in a subject that (i) is APOE4+, and (ii) has a baseline Mini-mental Examination (MMSE) score of 16-19, within sixty days prior to the first administration of the composition.
  2. The pharmaceutical composition for use of claim 1, wherein the method comprises administration of 150 mg BID tramiprosate, 265 mg BID of valyl-3-amino-1-propanesulfonic acid, or an equivalent amount of a pharmaceutically acceptable salt thereof.
  3. The pharmaceutical composition for use of claim 1, wherein the pharmaceutical composition delivers a dose of tramiprosate in a range of 100 mg-150 mg/dose.
  4. The pharmaceutical composition for use of claim 3, wherein the pharmaceutical composition comprises between 260 and 270 mg of valyl-3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof, and wherein the composition is formulated as an instant release, oral tablet or capsule.
  5. The pharmaceutical composition for use of claim 4, wherein the composition comprises 265 mg of valyl-3-amino-1-propanesulfonic acid.
  6. The pharmaceutical composition for use of any one of claims 1 and 3-5, wherein the pharmaceutical composition is administered twice daily.
  7. The pharmaceutical composition for use of any one of claims 1-6, wherein the subject is 85 years old or younger.
  8. The pharmaceutical composition for use of any one of claims 1-7, wherein the treatment decreases cognitive decline in the subject.
  9. The pharmaceutical composition for use of any of claims 1-8 wherein the baseline MMSE was obtained within thirty days prior to the first administration of the composition.
  10. The pharmaceutical composition for use of any one of claims 1-9, wherein the subject is APOE4/4 homozygous.
  11. The pharmaceutical composition for use of any one of claims 1-9, wherein the subject is APOE4 heterozygous.
  12. A method of determining a subject's suitability for treatment with tramiprosate, valyl-3-amino-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof, comprising determining the APOE4 status of the subject and the severity of the subject's Alzheimer's disease, wherein if the subject is APOE4 + and has a baseline MMSE score of 16-19, the subject is determined to be suitable for treatment.
  13. The method of claim 12, wherein the subject is determined to be suitable for treatment with 150 mg BID tramiprosate or 265 mg BID valyl-3-amino-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof.

Description

FIELD OF THE INVENTION The present disclosure is generally related to treatment of Alzheimer's disease (AD) in a specific patient population. BACKGROUND OF THE INVENTION AD is a progressive degenerative disease of the brain primarily associated with aging. Prevalence of AD in the United States in 2000 was close to 4.5 million. It was estimated that about one in ten individuals over 65 and nearly half of those over 85 are affected by AD. Approximately 360,000 patients will be diagnosed with AD each year in the United States alone. Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually and progressively, and typically lead to severe impairment and eventual death within twelve years of diagnosis. AD is characterized by two major pathologic observations in the brain: neurofibrillary tangles and beta amyloid (or neuritic) plaques comprised predominantly of an aggregate of a peptide fragment known as beta amyloid peptide (Aβ). Individuals with AD exhibit characteristic Aβ deposits in the brain (Aβ plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles. Neurofibrillary tangles occur not only in AD but also in other dementia-inducing disorders. Abushakra et al. (NEUROBIOLOGY OF AGING, vol. 39, March 2016, page S22) report data from two Phase 3 trials relating to cognitive efficacy of tramiprosate in APOE4/4 homozygous and APOE4 heterozygous patients. SUMMARY OF THE INVENTION The present disclosure is based, inter alia, on the discovery that homotaurine (3-amino-1-propanesulfonic acid (3-APS), tramiprosate, or Alzhemed™) and its valine prodrug form, ALZ-801, have stronger therapeutic effects on specific subsets of human patients. In particular these drugs show more efficacy in patients that are heterozygous for the Apolipoprotein E4 (APOE4) gene and have moderate AD; as well as in patients that are homozygous for the APOE4 gene and have mild-moderate or mild AD. In a first aspect of the invention, there is provided a pharmaceutical composition for use in a method for the treatment of Alzheimer's disease, as defined in claim 1. Methods of treatment of the human body by therapy, referred to in this description, are not part of the present invention as such. Any references to the methods of treatment in this description are to be interpreted as references to pharmaceutical compositions of the present invention for use in those methods. ALZ-801 (valyl-3-amino-1-propanesulfonic acid) is a novel, orally bioavailable, small-molecule prodrug of tramiprosate with improved pharmacokinetics and oral tolerability over tramiprosate, shown below: To our knowledge, nothing in the art has provided any reason to predict that an APOE4-positive patient can respond to tramiprosate or a prodrug thereof (e.g., ALZ-801) differently depending on the severity of AD. The severity of AD can be measured through the use of the Mini-mental State Examination (MMSE). As used herein, "baseline MMSE" refers to a MMSE score obtained within 60 days, preferably within 30 days, prior to initial treatment. A baseline MMSE score of 20-26 is considered to be mild AD; while a baseline MMSE score of 16-19 is considered to be moderate AD. In the present application, we subdivide moderate AD into "mild-moderate AD" defined as a baseline MMSE score of 18-19 and "more moderate AD" defined as a baseline MMSE score of 16-17. We also subdivide mild AD into "less mild AD" defined as a baseline MMSE score of 20-21 and "more mild AD" defined as a baseline MMSE score of 22-26. Applicants have surprisingly discovered based on clinical data, that APOE4-heterozygous patients suffering from moderate AD respond unexpectedly better to treatment with tramiprosate or a prodrug thereof (e.g., ALZ-801) than the other AD patients (e.g., APOE4 negative/moderate AD; APOE4 heterozygous with mild AD). Accordingly, the present disclosure provides a novel method of treating AD in an APOE4-heterozygous patient that has moderate AD. In addition, Applicants have surprisingly discovered based on clinical data, that APOE4/4 homozygous patients suffering from mild AD or mild-moderate AD respond unexpectedly better to treatment with tramiprosate or a prodrug thereof (e.g., ALZ-801) than the other AD patients (e.g., APOE4/4 homozygous patients with more moderate AD). In particular, APOE4/4 homozygous patients with mild AD (baseline MMSE score of 20-26) and mild-moderate AD (baseline MMSE score of 18-19) tend to show a higher improvement on tramiprosate at 150mg BID than those with MMSE < 18 at baseline. Additionally, ApoE4/4 homozygous patients with baseline MMSE ≥22 showed the highest efficacy and a progressive increase in cognitive benefit compared to placebo over the 78 weeks of the study. The same is