This is Part 2 of a two-part series. See Part 1.
Updated on 23 October 2009.
15 October 2009. While the Alzheimer disease field awaits a bona fide drug that goes beyond temporary relief of symptoms to actually slow disease progression, patients and caregivers may be increasingly open to products claiming even the slightest hint of promise—however untested those claims may be. It appears that some investors are banking on this very attitude. Hoping for a cheaper and quicker route to market, they have prodded several companies to veer off the AD drug development course and instead sell their products as nutraceuticals or medical foods. Items with these designations do not undergo pre-market review by the U.S. Food and Drug Administration and, as such, bypass the gauntlet of safety and efficacy trials typically required for drug approval (see Part 1 of this series).
“I believe the current situation is unfortunate,” said Paul Aisen, University of California, San Diego, who heads the Alzheimer’s Disease Cooperative Study. “It’s very difficult for consumers to even tell that medical foods are marketed without any basis for efficacy.”
Aisen led the Phase 3 trial for tramiprosate (Alzhemed), a compound once being developed by Neurochem of Laval, Québec, as an amyloid inhibitor for treatment for AD. Results of that trial, which involved 1,052 AD patients at 67 North American sites, were ruled inconclusive by the FDA in 2007 (see ARF related news story). The following year, the company changed its name to Bellus Health and began selling the same compound (also known as 3-amino-1-propanesulfonic acid or homotaurine, an amino acid found naturally in seaweed) under the brand name VivimindTM in Canadian drug stores and over the Internet (see ARF related conference story and ARF related news story).
With terms cleverly chosen to target healthy baby boomers, the company website describes VivimindTM as a “patented, science-based natural health product shown to protect memory function.” The site draws from post-hoc analysis of Phase 3 magnetic resonance imaging (MRI) data to claim that the compound works by slowing shrinkage of the hippocampus. These findings were published several months ago (Gauthier et al., 2009).
These claims distract from the bottom line, Aisen said. “There may be a number of factors that contribute to the negative result, including methodological issues, but the fact remains that the trial was negative,” he told ARF. “I do not think there is a basis for recommending tramiprosate to people with AD.” Regarding the possibility that the compound slows hippocampal atrophy, Aisen said, “It’s interesting...but until you have confirmed it in an independent trial, it’s just exploratory and entirely inconclusive because you’re playing with the data after the fact.”
Nevertheless, VivimindTM sells for CAD$45 per 60-tablet box, and by some measure, people are buying it. Gross sales totaled $82,000, though marketing and selling expenses from commercialization of VivimindTM amounted to 560,000 over the same time period, according to a fiscal report from the company’s website.
Over the summer, the company announced that it received permission to sell VivimindTM as a food supplement in Italy (see news release). In the same report, company officials said they have filed a pre-market notification of a New Dietary Ingredient for homotaurine with the FDA, and are “pursuing mandatory associated regulatory activities to obtain marketing approval” of the compound as a dietary supplement.
Risks for Consumers and Investors
With medical foods, the regulatory loophole can be harder to recognize. Medical foods generally require a prescription, make claims for specific diseases, and must meet certain safety and manufacturing standards—making them appear almost like drugs to the lay consumer. In marketing literature, manufacturers couch their food products in drug language, with implicit assumptions of efficacy and FDA review. For example, Pan American Laboratories (PAMLAB) L.L.C. of Covington, Louisiana, is described on the company website as “a fully integrated pharmaceutical company...specializing in prescription medical foods.” A product website describes one of these food products, Cerefolin, as caplets “indicated for the distinct nutritional requirements of individuals under a physician's treatment for neurovascular oxidative stress and/or hyperhomocysteinemia, with particular emphasis for those individuals diagnosed with or at risk for mild to moderate cognitive impairment, vascular dementia, Alzheimer's disease, and/or recurrent or ischemic stroke.” The website for AxonaTM, the ketogenic drink mix that targets metabolic deficiencies associated with AD, assures lay readers that “claims for both medical foods and drugs must be supported by solid laboratory and clinical data.”
However, the FDA’s definition does not specify efficacy requirements for medical foods. “Because we understand that medical foods don't undergo the FDA's stringent review like treatment options, we cannot be assured that they are actually going to show effectiveness,” said Maria Carrillo of the Alzheimer’s Association, which issued a statement [.pdf]
on medical foods earlier this spring. “If (companies) are making claims for treatment effects that improve cognition and AD, we really do need to see the large Phase 3 trial.”
Even though medical foods are formulated with ingredients “generally regarded as safe” (GRAS), safety concerns do not disappear altogether. “It's important for people to realize that though these are nutritional supplements, they are chemicals,” Carrillo said. “They can counteract other medications or even other concomitant factors, e.g., heart disease, high blood pressure. They could exacerbate some things while helping others.”
With medical foods, there also is no post-approval safety monitoring as there is with drugs.
Furthermore, it’s not clear how well medical foods would do in the market if insurance plans do not cover them. AxonaTM hit the market in March, and costs about $3.70 per daily packet. “We don’t have any firm numbers on how many scripts are covered by insurance,” said Sam Henderson, executive director of research at Accera, Broomfield, Colorado, which develops AxonaTM. “Anecdotally, we know it has been covered in some cases, but my guess is that most people are paying cash.” Henderson told ARF the company prefers not to share sales data at this time.
Duel of the Breakfast Foods
Another therapeutic drink may be poised to challenge AxonaTM in the AD medical food arena several years later. This one, SouvenaidTM, is a once-a-day milkshake loaded with ingredients (including DHA, omega-3 fatty acids, and antioxidants) said to help build neuronal membranes and synapses. It is developed not by a pharma or biotech company, but by Nutricia, a medical nutrition company under Groupe Danone, Paris (Dannon to Americans). In a trial of 212 early AD patients at 28 U.S. and European sites, consuming the drink once a day for 12 weeks moved scores on one of the primary outcome measures—a delayed verbal memory task (WMS-r)—but did nothing for the other (an extended ADAS-Cog battery called ADAS-Cog-13). Lead investigator Philip Scheltens of Vrije University Medical Center in Amsterdam, The Netherlands, reported these 12-week data at the 2008 International Conference for Alzheimer’s Disease in Chicago (see ARF related conference story). A manuscript describing the findings is under review at the journal Alzheimer’s & Dementia, Scheltens told ARF via e-mail.
Because it is not a unique chemical entity but rather a patented combination of basic ingredients, SouvenaidTM is not a drug, Scheltens noted. It falls under Foods for Special Medical Purposes (FSMP), an E.U. designation similar to medical foods in the U.S. in that products are subject to food legislation on labeling and manufacturing, but require a doctor’s prescription (see FSMP guidelines). The regulatory path for FSMPs differs from country to country, as do reimbursement guidelines.
SouvenaidTM is not yet available anywhere in the world, even though it could be licensed in Europe as an FSMP based on available data, according to Scheltens. “As PI of the trial program, I insisted on gathering more evidence first,” he wrote to ARF. Enrollment is ongoing for three larger trials: a six-month U.S. trial that tests SouvenaidTM as an add-on to cholinesterase inhibitors in people with mild to moderate AD, a six-month E.U. trial in drug-naïve, mild to very mild patients, and a 24-month trial of prodromal AD patients (defined as per Dubois et al., 2007). The six-month U.S. trial will use 24-week change in ADAS-Cog as its primary outcome measure, while the six-month E.U. trial will use the Neuropsychological Test Battery (NTB). Both are sponsored by Danone Research B.V. in Wageningen, The Netherlands. A modified version of the NTB (Harrison et al., 2007) will serve as the primary endpoint for the 24-month prodromal AD study. This trial is sponsored by the European LipiDiDiet project, which focuses on using lipids in therapeutic and preventive approaches to aging and dementia.
The Way Forward
One might presume that the design of the SouvenaidTM program was influenced by the fate of Alzhemed—an AD compound that shifted from putative drug to dietary supplement after a negative Phase 3 trial (see ARF related conference story and ARF related news story). However, Scheltens said his team was “committed to the Phase 2 trial and the classification of Souvenaid as a medical food one to two years before (they) knew the direction Alzhemed was going.”
With three Phase 3 trials in the works, it appears that SouvenaidTM is being held to the same efficacy standards required for approved drugs. “We have applied pharma standards to this medical food product,” Scheltens wrote. “This is highly appropriate and, in my view, the only way forward. When it comes to efficacy requirements, my understanding is that medical foods should deliver proven benefits to patients, just as drugs do.”
If the Accera and Neurochem experiences are any guide, some suspect this trial strategy could be a win-win for Nutricia, because with positive results Souvenaid could be sold with stronger claims, and without such results, perhaps as a food supplement with lesser claims. Accera, the company that moved its product to market as a medical food after it missed its primary end point in phase 2, has among its investors Inventages Venture Capital Investment Inc. This group is the private equity and venture capital arm of Nestle SA, the world's largest food company.
Meanwhile, as the field gets a better handle on the utility of various biomarker and imaging modalities (see ARF ADNI update), trials will be designed in ways to improve chances of demonstrating efficacy. One element that will figure prominently in newer AD trials is the shift toward analysis of milder patients, as one of the Souvenaid trials is already doing (see ARF related conference story). “It’s very clear that the disease modification needs to happen in advance of damage to the brain,” said Barry Greenberg in an interview with ARF. Greenberg joined the University Health Network in Toronto, Ontario, after leaving Neurochem. Regarding Alzhemed and other compounds that have been tested in established disease, “there is a possibility they might have shown more of a signal if they had been started in identifiable pre-symptomatic patients,” Greenberg said. “Five years from now, I think we’ll be doing trials differently from how we do them today. We’re going to be able to identify patients who can be treated before their brains are too damaged to be repaired.”—Esther Landhuis.
This is Part 2 of a two-part series. See Part 1.