Alzheon Inc.
Alzheimer’s disease treatments for genetically at-risk patients
This article was originally published in Start Up
Executive Summary
Martin Tolar, a neurologist and neuroscientist by training and longtime AD R&D leader and dealmaker, believes that tramiprosate, a red-algae derivative that failed Phase III trials in 2007, had, in fact, significant disease-modifying benefit for a specific subset, but still a majority, of patients in the study. He founded Alzheon Inc. around a prodrug of tramiprosate and related intellectual property to pursue what he sees as a high-speed, low-cost pathway to test whether trampirosate could become the first approved AD drug in more than a decade – and the first personalized to a genetically identifiable patient population.
394 Lowell Street
Suite 9
Lexington, MA 02420
Phone: (650) 392-9186
Web Site: www.alzheon.com
Contact: Martin Tolar, MD, PhD, President & CEO
Industry Segment: Biotechnology
Business: Developing treatments for Alzheimer’s disease
Founded: August 2013
Founder: Martin Tolar
Financing: Undisclosed
Investors: Undisclosed private investors
Employees: 12
Scientific Advisory Board: Keith Crutcher, PhD (ITECS Innovative Technology Market Development); Jeff Cummings, MD (Cleveland Clinic Lou Ruvo Center for Brain Health); Howard Fillit, MD (The Alzheimer’s Drug Discovery Foundation); Jakub Hort, MD, PhD (2nd Medical School, Charles University, Prague, Czech Republic); Diane Jorkasky, MD (Complexa Therapeutics); Louis Kirby, MD (ZettaScience); Pete Snyder, PhD (The Alpert Medical School of Brown University); Mike Weiner, MD (University of California, San Francisco)
Could red algae hold a key to fighting the Alzheimer’s disease plague? As far-fetched as that sounds, a quarter-billion dollars and 15 years have gone into the red algae-derived compound, 3-amino-1-propanesulfonic acid, a molecule known as tramiprosate and also homotaurine. Tramiprosate is a soluble small molecule that crosses the blood-brain barrier. Extensive human studies have shown it to be safe and well tolerated except for some nausea, and it inhibits amyloid aggregation and plaque formation, which, despite ongoing controversy over amyloid’s causative role, remains an important disease marker. Originator Neurochem and its successor Bellus Health put the agent labeled BLU8499 and called Alzhemed through two Phase III studies in 2,000 mild-to-moderate Alzheimer’s disease (AD) patients. More had already taken the drug in previous studies. But in 2007, the American Phase III trial failed and the European counterpart was halted. In the US data, Alzhemed was shown to perform no better than placebo in slowing disease progression.
Or so it seemed.
Martin Tolar, a neurologist and neuroscientist by training and longtime AD R&D leader and dealmaker, believes that a deeper analysis of the Alzhemed data reveals that it, in fact, had significant disease-modifying benefit for a specific subset, but still a majority, of patients in the study. He founded Alzheon Inc., around a prodrug of tramiprosate and related intellectual property to pursue what he sees as a high-speed, low-cost pathway to test whether trampirosate could become the first approved AD drug in more than a decade – and the first personalized to a genetically identifiable patient population.
Tolar knows the original tramiprosate, a small-molecule glycosaminoglycan mimetic, well. He sits on the board of Bellus Health. Given Neurochem’s inability to finance the drug’s further development as an ethical pharmaceutical after negative data in 2007 and the subsequent market crash in 2008, according to Tolar, Neurochem licensed it the following year to a Canadian firm, Ovos Natural Health, to market a nutraceutical version it calls Vivimind. He says that FB Health now owns the nutraceutical rights and has sales of around $1 million annually in Canada and Europe. Vivimind has caused controversy because its sales have been promoted with the Alzhemed/Bellus Health study outcome, which shows a reduction in hippocampal shrinkage in some subjects tested. Tolar feels the marketing approach does not hype claims, and says, “I am not aware of any nutraceutical with such a robust safety and efficacy package.”
After little more than a year as CEO of Knome Inc., a company that sells IT equipment, software, and expertise for rapid interpretation of genomic data, Tolar left to launch Alzheon. He says, “I always wanted to come back into Alzheimer’s drug development.”
Tolar understands well the risks that go with such work. Since the 2003 approval of Forest Labs Inc.’s memantine (Namenda), no other drug has succeeded. The past decade is strewn with the wreckage of large, costly clinical studies, several of which, like the one for Alzhemed, advanced to pivotal stages. In recent years VCs and pharma have been reluctant to invest further in the space until the science advances. Many are especially concerned because drugs that seemed to relieve brains of their plaque burden have not shown improvements according to the AD Assessment Scale–Cognitive (ADAS-Cog), the standard measurement tool used along with brain volume MRI imaging or PET imaging of plaque burden in the brain in determining any benefit against the disease.
In the meantime, the unmet need from AD already costs $600 billion annually worldwide, and its looming public health catastrophe threatens to swamp world economies. To develop Alzheon’s prodrug, Tolar has drawn together experts he has worked with over the years, including John Hey, PhD, now the start-up’s chief scientific officer, who built the beta-secretase platform at CoMentis, Inc., where Tolar held various positions including chief business officer, EVP, chief scientific officer, and also VP of strategic and corporate development. Tolar negotiated CoMentis’ $100 million up-front beta-secretase AD collaboration agreement with Astellas Pharma. [See Deal] In addition, he previously served at Pfizer Inc., in a variety of leadership positions in clinical and business development. A Pfizer colleague, Mark Versavel, MD, PhD, is now Alzheon’s chief medical officer. Versavel played a leading role in approval of number of neurological drugs including Lyrica (pregabalin) for pain at Pfizer, and Lunesta (eszopiclone) for sleep and Stedesta (eslicarbazepine) for epilepsy at Sepracor/Sunovion. The new Alzheon team took a fresh look at the Alzhemed data for potential overlooked opportunities.
A “Eureka!” moment came when they discovered the drug seemed to work for an identifiable subset of subjects: individuals known to have genetic risk factors for the sporadic, not the familial, disease.
Neurologists consider presence of the apolipoprotein E-e4 (ApoE4) allele the most significant AD genetic risk factor. Although one in four people carry the ApoE4 gene, it occurs in 65% to 80% of all people who develop AD. Those with two ApoE4 alleles are highly predisposed to the disease.
When Tolar’s team isolated that ApoE4-positive population in the Alzhemed Phase III data, which comprised 599 – about 60% – of the 1,052 subjects enrolled in the first North American Phase III study (the European study enrolled 975 subjects but was terminated early after the first study readout), he says that the data readout showed a statistically significant and clinically relevant 2-point improvement on the ADAS-Cog in 599 ApoE4-positive subjects at 6 months and at 12 months, and those improvements were sustained in an assessment at 18 months. Moreover, at 18 months, in a subset of 265 of those patients, the patients had a dose-dependent decrease in brain atrophy based on MR imaging of hippocampal volume. Tolar claims the findings are “the strongest patient-efficacy data set in the industry by showing the cognition efficacy, reduction of atrophy on MRI, and even an effect on amyloid levels in cerebrospinal fluid in a very large number of Alzheimer’s patients.”
“Tramiprosate did not hit the whole population,” he says, “but 60% of the 1,052 treated patients had a clear impact. This is the Alzheimer’s population you want to go after. This is the core of the disease population.”
However, while demonstrated as safe in clinical studies and through its use for around five years as a nutraceutical after the trials concluded, the existing tramiprosate molecule did have problems. Manufacturers had trouble with the drug formulation leading to PK issues. Patients also had minor tolerability issues when taking it, mainly nausea. Finally, the drug is, of course, readily available in generic form. However, Alzheon says it has licensed from Bellus a prodrug form of tramiprosate, now labeled ALZ-801, with 14 years of patent life left. [See Deal] Tolar notes that Bellus had already run a Phase I toxicology study of the prodrug in 67 healthy elderly subjects that confirmed improved tolerability and showed none of the PK issues.
With undisclosed Series A funding from two wealthy individuals whom he describes as “experienced biotech backers,” Tolar launched Alzheon, taking an exclusive license on ALZ-801 from Bellus Health, along with other related intellectual property that could lead to a pipeline of treatments for AD symptoms. [See Deal] Alzheon will pay Bellus a portion of the revenues it receives from any drug plus sales royalties. Tolar has begun discussions with institutional investors to provide additional backing for the company.
Tolar thinks the pathway forward for ALZ-801 should, for an AD agent, be remarkably cheap and quick. The company needs to do some formulation work yet, but expects to commence a pivotal study late in 2014 that will require 460 patients and take just two years to complete, at a cost of about $20 million. “If we prospectively confirm the data we saw, this is potentially registerable by 2017,” he says. “It’d be a biotech opportunity to get to billions in value.”
Before going to Knome, Tolar had served as the president and CEO of NormOxys, Inc., since late 2009. While there he built the company around its novel cancer therapeutics from a research project into clinical development. In his career at CoMentis and at Pfizer he says, “I did due diligence on everything out there,” giving him a strong sense of the value he sees in ALZ-801. “We believe that the ALZ-801 prodrug offers an incredible opportunity to optimize the impressive clinical effects of tramiprosate that have already been shown in Alzheimer’s patients – namely for improved pharmacokinetics, maximized exposure/efficacy, and tolerability. Our ultimate goal is dedicated development of the drug in the at-risk ApoE4-positive Alzheimer’s population – this has never been done before and opens a completely new, personalized medicine avenue for drug development in Alzheimer’s.”