Adaptive Trial Design and Combo Drugs Needed in Alzheimer’s

FDA’s head of neurology products told industry execs at the Prix Galien Forum that the agency is open to alternative clinical trial designs in Alzheimer’s disease, and would like to see more combination products in clinical testing.

FDA is immovable on the requirement that a drug be “effective” as a prerequisite to approval, said Russel Katz, director, division of neurology products at FDA, on a panel at the Prix Galien Forum last Tuesday. Once that requirement is met, insisted Katz, the agency is flexible in other areas, including the consideration of alternative clinical trial design for drugs targeting Alzheimer’s disease, like adaptive trial design, and “seamless phase II/III” trials, which can be used to speed up the regulatory process.

With respect to biomarkers and surrogate endpoints as measures of a product’s effectiveness, Katz said it’s “understood that there’s an allowance for uncertainty…more so than in other [therapeutic areas].” The standard for product evaluation, Katz said, is whether or not it’s “reasonably likely” that “an effect on surrogate endpoints or biomarkers predicts efficacy” in patients.

Katz also made a pitch for combination therapies as a would-be-welcomed approach to Alzheimer’s disease. Unlike other therapeutic areas, “there is a tremendous reluctance to test combination therapies” for Alzheimer’s disease, he said. Disease modifying drugs for Alzheimer’s – as opposed to products like Namenda or Aricept that help patients manage side effects or certain aspects of the disease – aren’t likely to hit the market in the near term, even though panelists predicted that caring for Alzheimer’s disease patients would top $1 trillion annually by 2020 in the absence of a significantly efficacious new therapy.

One of the problems, according to panelist William Thies, chief medical and scientific officer at the Alzheimer’s Association, is that there “isn’t true agreement on biomarkers that predict clinical benefit,” but “in the next 12 to 18 months, there will be.” If the beta amyloid target, for example, could be validated beyond dispute, it would embolden pharmaceutical companies to “go forward more often with potential drug candidates,” said moderator Michael Rosenblatt, EVP and chief medical officer, at Merck.

Despite mixed reactions to the phase 3 EXPEDITION trial data, and slightly more positive reactions to the data remix performed by the Alzheimer’s Disease Cooperative Study, an independent national research consortium, Lilly’s solanezumab trials have helped to further “establish some biomarkers and endpoints,” said panelist Dennis Selko, Harvard Medical School professor and co-director, Center of Neurologic Diseases, at Brigham and Women’s Hospital.

Aside from the fact that Alzheimer’s disease affects “the most complicated functions of the most complicated organ,” per Thies, two other key blockages exist on the pathway toward new therapies: the first is a lack of sufficient funding for basic research. Four hundred and fifty million dollars is spent annually on basic research into Alzheimer’s, compared with $6 billion in cancer, and between $4 and $5 billion in heart disease, said Thies. Proper funding for basic research in Alzheimer’s would be around $2 billion annually, he said.  The second barrier to progress is the sluggish nature of clinical trials in this space. There’s not a ready-made population to participate, so it often takes “two years to recruit your cohort, and two years to conduct the trial,” and often longer, said Theis.

Meryl Comer, president of the Geoffrey Beene Foundation’s Alzheimer’s Initiative, noted that the average Alzheimer’s caregiver – often a patient’s son or daughter – is on average 47.5 years old, and still very much in need of a full time job, and often supporting children of his or her own. Comer found out that she is predisposed for Alzheimer’s disease herself, after reading the results of a genome scan on national television. Comer said the reason she agreed to reveal her genetic information on ABC’s Nightline was to “make a public statement.” Instead of fretting over anecdotal evidence related to inheritance and instances of the disease among family members, it’s better to get tested, and find out definitively, early on, she said. As a result, “I will go into early-stage or preventative trials,” to help move the science forward, said Comer. The decision to have her genome sequenced was personal, too. “I don’t want my son to have to care for me…I don’t want to be remembered that way,” she said.