Analyses from Phase 3 Studies Published in The Journal of the Prevention of Alzheimer’s Disease Show Strongest Clinical Benefit of Tramiprosate in APOE4/4 Homozygous Patients with Mild AD at Baseline

Results Support Selection of APOE4/4 Patients at the Mild Stage of AD for Pivotal Study of ALZ-801, a Novel ‘Precision Medicine’ Approach to Alzheimer’s

FRAMINGHAM, Mass., June 22, 2017 – Results published today by Alzheon, Inc., in The Journal of the Prevention of Alzheimer’s Disease (JPAD) describe analyses of Phase 3 data for the investigational amyloid-targeted drug, tramiprosate, in patients with Alzheimer’s disease (AD).  The new analyses group patients according to APOE4 genotype and disease severity, and show tramiprosate’s largest efficacy signals in APOE4/4 homozygous patients with Mild Alzheimer’s disease.  This preferential efficacy in APOE4/4 patients at the Mild stage of AD is consistent with the role of APOE4 and beta amyloid (Aβ) in AD, which includes the following key observations:

  • APOE4/4 patients have a higher burden of Aβ oligomers compared to APOE4 non-carriers;
  • Soluble toxic Aβ oligomers play a key role early in the Alzheimer’s disease process;
  • Tramiprosate inhibits formation of Aβ oligomers at clinically relevant concentrations achieved in AD patients.

These peer reviewed results published in JPAD are available through open access jpreventionalzheimers.com22June2017. These analyses further expand on Alzheon’s previous findings from the tramiprosate Phase 3 studies that showed the APOE4 gene dose effect, with the largest clinical benefit in patients with two APOE4 alleles (APOE4/4 homozygotes).1  In the current study, APOE4/4 homozygotes were analyzed based on their disease severity at the beginning of the Phase 3 study, to elucidate those patients most responsive to treatment.  The subgroup with Mild disease at baseline (MMSE 22 and higher) showed larger efficacy signals on both cognition and function.  The cognitive effect increased significantly with time, suggesting a potential disease-modifying effect of tramiprosate.  This clinical profile is consistent with the recently discovered molecular mechanism of action, where tramiprosate inhibited monomer aggregation and formation of toxic Aβ oligomers.2 

“We are now seeing a convergence of new insights on how amyloid-targeted therapies can be optimized to treat Alzheimer’s disease patients,” said Dr. Jeffrey Cummings, Director, Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and Professor of Neurology at Cleveland Clinic.  “A new understanding of amyloid pathogenesis has evolved from the recent studies on the molecular mechanism of tramiprosate.  These observations better position us to develop new therapies for Alzheimer’s and to choose populations most likely to respond to treatment.”

“Our published results in JPAD represent the culmination of research efforts at Alzheon in which we have ‘connected the dots’ for directing our anti-amyloid treatment to the patient population most likely to benefit.  We are advancing the clinical development of ALZ-801 based on the new guideposts in the field of Alzheimer’s – precision medicine and the role of beta amyloid oligomers, as well as our own discoveries of the inhibition of formation of Aβ oligomers by tramiprosate, and clinical data showing that APOE4/4 patients at the Mild stage of disease are most responsive to tramiprosate, the active agent in optimized prodrug ALZ-801,” said Martin Tolar, MD, PhD, Founder, President and CEO of Alzheon.  “Alzheon has defined a new, highly targeted path for developing innovative medicines for Alzheimer’s, such as ALZ-801, by directing treatment to the right patients, with the right drug, and at the right stage of their disease.”

The manuscript, titled “Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification Potential,” is featured in the advanced online publication of JPAD with lead authors from Alzheon and key academic researchers in AD.  The published results describe the evaluation of tramiprosate efficacy in APOE4/4 homozygous AD patients according to the Mini-Mental State Examination (MMSE) scores at baseline, in both the North American Phase 3 study, and the pooled data from the North American and European studies.  The largest efficacy signals were observed in patients with Mild AD, defined as MMSE of 22 to 26.  The safety profile in the APOE4/4 subgroup was similar to the overall population1, with the most common adverse events (that were higher in the active dose arms) being nausea, vomiting, depression and decreased weight.

The results published in JPAD support Alzheon’s clinical development of ALZ-801, a substantially optimized oral prodrug of tramiprosate, including the design of the initial pivotal clinical trial to evaluate ALZ-801 in AD patients who are APOE4/4 homozygotes with Mild AD.  The design of the pivotal program for ALZ-801 is distinguished by using a precision medicine approach to drug development for Alzheimer’s disease.

“ALZ-801 represents a new class of oral agents with disease-modifying potential, and based on our clinical analyses and discovery of the molecular mechanism of action, we have defined the patient selection criteria for the upcoming confirmatory study of ALZ-801 in homozygous APOE4/4 patients with Mild AD,” said Susan Abushakra, MD, Chief Medical Officer of Alzheon.  “With these promising efficacy data, the favorable long-term safety profile of tramiprosate, and the improved gastrointestinal tolerability of ALZ-801, we are poised to initiate the pivotal program with ALZ-801 for patients in need of effective treatment.”

About Alzheon

Alzheon, Inc. is committed to developing innovative medicines by directly addressing the underlying pathology of devastating neurodegenerative disorders.  Our lead Alzheimer’s clinical candidate, ALZ-801, is a Phase 3-ready, first-in-class, small molecule oral inhibitor of amyloid aggregation and neurotoxicity – hallmarks of Alzheimer’s disease.  ALZ-801 is a novel prodrug that builds on the safety and efficacy profile of the active compound tramiprosate, which has been evaluated in clinical trials involving over 2,000 Alzheimer’s patients.  Our clinical expertise and technology platform is focused on developing drug candidates using a precision medicine approach based on individual genetic and biological information to advance therapies with the greatest impact for patients.

1Abushakra et al: Clinical Benefits of Tramiprosate in Alzheimer’s Disease Are Associated with Higher Number of APOE4 Alleles: The “APOE4 Gene-Dose Effect” Journal of Prevention of Alzheimer’s Disease October 2016; 3(4): 219-228. jpreventionalzheimer.com24Oct2016
2Kocis, P et al: Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data, CNS Drugs, June 2017; 31(6): 495-509. https://link.springer.com/article/10.1007/s40263-017-0434-z
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