Alzheon CEO Martin Tolar, MD, PhD

Alzheon says it expects to fund the completion of a pivotal Phase III trial and regulatory filings later this year for its lead candidate, a treatment for early Alzheimer’s disease (AD), with proceeds from a $100 million Series E financing the company said it completed today.

ALZ-801, also called valiltramiprosate, is under study in the Phase III APOLLOE4 trial (NCT04770220), which is fully enrolled with 325 patients who were screened from more than 6,000 patients. APOLLOE4 is designed to assess the safety and efficacy of ALZ-801 compared to placebo in early Alzheimer’s patients—specifically carriers of two ε4 alleles of apolipoprotein E gene (APOE4/4 homozygotes), who have the highest genetic risk of Alzheimer’s disease.

The double-blind, randomized trial is set to be completed in mid-2024, with Alzheon planning to submit a new drug application (NDA) before year’s end. If that happens, the company said, ALZ-801 would potentially become the first oral disease-modifying therapy indicated for a form of AD.

“Our goal is to build commercial capabilities and make ALZ-801/valiltramiprosate widely accessible to appropriate patients as quickly as possible,” Alzheon CEO Martin Tolar, MD, PhD, told GEN Edge. “We have been building our commercial infrastructure for the past two years and feel confident in a go-it-alone strategy for the U.S. launch. Simultaneously, we are also building our ex-U.S. channels and capabilities.”

ALZ-801 is designed to block the aggregation of amyloid monomers into oligomers which initiate and drive Alzheimer’s disease.

“As we were refining our approach, we realized that APOE4/4 homozygotes represent a unique patient population with a distinct pattern of disease. We wanted to be confident in selecting a patient population where our therapy could demonstrate clinically meaningful and robust efficacy benefits. Therefore, APOE4/4 homozygotes were a natural starting point,” Tolar said.

Last year, ALZ-801 completed a Phase II biomarker trial (NCT04693520) consisting of a broader population of APOE4 carriers, both homozygotes and heterozygotes. The two-year, 84-patient biomarker study is completing a fourth-year extension following positive results from the core portion of the study. Those results showed significant biomarker effects and clinical stabilization over two years of treatment.

Bolstering confidence

“This data bolstered confidence in our mechanism of action and showed that Phase III program in all APOE4 carriers is warranted,” Tolar explained. “There is enormous need for a treatment that can be used by APOE4/4 homozygotes with AD. These patients carry a high risk of brain edema and microhemorrhage, described on magnetic resonance imaging (MRI) scans as amyloid-related imaging abnormalities (ARIA).”

Tolar noted that the FDA has subjected the whole class of antibodies, including anti-amyloid antibodies such as Eisai/Biogen’s Leqembi® (lecanumab-irmb), to carrying a boxed warning that cites the increased risk of serious brain edema and microhemorrhage complications in APOE4/4 homozygotes and requires a high number of monitoring MRI scans during the first year of treatment.

“The ALZ-801/valiltramiprosate safety profile, showing no increased risk of ARIA, may substantially side-step this issue as well as other infusion-related hurdles, including infusion reactions and immunogenicity with hypersensitivity reactions,” Tolar said.

“AD patients with APOE4/4 homozygous genotype are in desperate need of treatments that avoid this high risk of ARIA,” he added. “Our goal is to address this unmet medical need with the oral tablet ALZ-801/valiltramiprosate, and we believe we are well positioned to do so with the upcoming readout of our pivotal APOLLOE4 Phase III trial of ALZ-801 in the coming months.”

Reshaping the landscape

After decades of failures by big pharma and small biotechs alike, the Alzheimer’s drug landscape is being reshaped by a pair of new drugs. Next month marks one year since Eisai and Biogen won full FDA approval for Leqembi®, a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody designed to treat Alzheimer’s by targeting aggregated soluble and insoluble forms of amyloid beta (Aβ).

Since July 2022, Eli Lilly has been pursuing FDA approval for its amyloid plaque-targeting therapy donanemab as a treatment of early symptomatic Alzheimer’s disease. Lilly initially expected a decision in the first quarter of this year, only to be told in May the agency would decide after hearing from its Peripheral and Central Nervous System Drugs Advisory Committee.

On Monday, the advisory committee effectively recommended approval of donanemab, through two 11–0 votes unanimously concluding that it was effective in treating patients with mild cognitive impairment, based on available data—and that the benefits of the drug outweighed its risks. The FDA has final say, though it typically follows the recommendations of its advisory committees.

“We are pleased with the panel’s recommendation and look forward to bringing the treatment to patients,” Mark Mintun, Lilly’s group vice president of neuroscience research and development, said in a statement.

A day earlier, the FDA accepted for review Eisai’s Supplemental Biologics License Application (sBLA) for a monthly intravenous maintenance dosing form of Leqembi. The agency also set a Prescription Drug User Fee Act (PDUFA) target action date of January 25, 2025, Eisai and Biogen said.

The companies to date have fared better with Leqembi than with their earlier controversial yet approved Alzheimer’s disease drug Aduhelm® (aducanumab-avwa). In January, Biogen announced it would halt the development and commercialization of Aduhelm in order to shift resources to Leqembi and other Alzheimer’s treatments, following three years in which Aduhelm sales failed to match forecasts, and the drug failed to obtain coverage from the Centers for Medicare and Medicaid Services (CMS).

First in class

ALZ-801 is a first-in-class oral disease-modifying therapy shown in mechanism-of-action studies to fully block the formation of neurotoxic soluble beta amyloid oligomers at the Phase III clinical dose of 265 mg twice daily. Earlier clinical studies have shown the potential of ALZ-801 to generate positive clinical efficacy in the population being studied in APOLLOE4, patients with two copies of APOE4/4—the Alzheimer’s population reported in past studies to carry the highest risk of developing AD.

Those earlier studies also showed a favorable safety profile for ALZ-801, with no increased risk of brain vasogenic edema in more than 3,000 Alzheimer’s patients, according to Alzheon.

“We believe that a clearly defined patient population and a simplified patient journey enabled by oral treatment will allow for scalability, which is not easily feasible with the current intravenous infusion of anti-amyloid antibodies,” Tolar said.

Alerce Medical Technology Partners led the group of investors that raised the Series E round. None of those other investors were disclosed in Alzheon’s announcement of the financing.

“Alzheon’s ALZ-801 provides an innovative precision-medicine solution in an emerging Alzheimer’s pipeline with a path to potential approval in 2025,” Muneer Satter, Alerce’s founder and managing partner, stated. “We are incredibly excited to support the Alzheon team in their latest round of financing.”

Alzheon completed an oversubscribed $50 million Series D financing in 2022, with the capital raised from undisclosed investors. The company won a $10 million Series A round in 2015, followed by a $19.8 million Series B in 2018, and a $47 million grant (R01AG065253) from the NIH’s National Institute on Aging in 2020.

Twice in 2018, Alzheon filed registration statements with the U.S. Securities and Exchange Commission (SEC) seeking to carry out an initial public offering. The company postponed its first offering of 5 million shares at a price range of $13–$15, and in January 2019 withdrew its second IPO filing, a smaller offering seeking to sell 6 million shares at a $4–$6 range.

Alzheon’s current headcount is approximately 30 full-time employees, with vendors and consultants joining with the company to complete the pivotal APOLLOE4 Phase III trial, evaluate data, and, pending the results, begin work toward an NDA filing.

“We plan to rapidly expand our team and capabilities based on the topline results,” Tolar said. “With this round of financing, we are well-positioned to complete all our critical development, regulatory and commercial work, and initiate the transition to a commercial organization.”

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