The FORUM Format

With a new name and a veteran CEO, Deborah Dunsire, FORUM Pharmaceuticals’ flag is waving high in the increasingly solitary struggle against CNS disease.

The cut and thrust between risk and reward stokes the fires of new drug innovation — and some of the industry’s biggest and most incendiary bets are being made by the smallest players. A case in point is the science and image rebranding exercise now underway at privately held, Boston-based EnVivo Pharmaceuticals, which on April 2 gave itself a new name — FORUM Pharmaceuticals, a maxim for networked collaboration – along with a fresh commitment to its promising late stage program on Alzheimer’s disease and schizophrenia.

Fueling FORUM’s business model is the search for novel pathways to treating diseases of the central nervous system. That model is distinctive in its sole focus on one of the challenging areas of drug discovery, with its innumerable scientific riddles and high costs marked by complex, lengthy trials. Why invest all this effort in a therapeutic segment that ranks at the top of the Tufts Center for the Study of Drug Development’s “pain index” of compound success rates and time to market?

According to FORUM CEO and industry veteran Deborah Dunsire, such disproportionate risks simply make the potential gains from therapy that much greater. “The level of unmet medical need surrounding diseases of the brain is immense,” said Dunsire in a recent interview in Pharm Exec. “The average Alzheimer patient experiences nearly a decade of deterioration progressing to mortality. Treatments to reduce that period of dependency carry a measurable public health benefit, in addition to improving patient quality of life, all at less cost to society.”

Late stage promise
Since assuming the post of CEO in July of last year, Dunsire has spent most of her time preparing for a critical Phase-III trial [COGNITIV AD] of its lead compound, encenicline [EVP-6124], which in an earlier Phase II(b) test showed statistically significant improvement against placebo in cognition and basic clinical functionality among patients with mild to moderate Alzheimer’s disease. Encenicline is already the subject of a Phase III program [COGNITIV CIAS] evaluating cognition improvements for patients with schizophrenia, particularly those facing significant side-effects from existing drug therapies. In January, the company revealed it would proceed with this larger, two dose, six month Alzheimer’s trial – involving 1,600 patients in 22 countries – under terms of a special protocol assessment agreement with the FDA.

That means if the trial is conducted in line with the agreed protocol and meets its designated end points, the FDA is on notice to approve the drug without further delay. And those end points are fairly specific, requiring demonstration of efficacy against the two most prominent metrics used by clinicians in evaluating cognition and functionality in cases of dementia: the AD Disease Assessment Scale Cognitive Subscale [ADAS-Cog] and the Clinical Dementia Rating Sum of Boxes [CDR-SB].

Supporting FORUM in the Phase-III trial are two Japanese partners, Mitsubishi and Tanabe, who will also coordinate all clinical work in Japan. Trial design is now underway and recruitment selection will start shortly. Despite the obvious challenges of finding the right patients for this complex field work, Dunsire is cautiously optimistic that the outcome will lead to a commercial launch for encenicline for both indications later in the decade – perhaps as early as 2016.

Finding that neural spark
Progress of the two trials is being closely watched by the clinical community on CNS disorders, where morale has been hit by big Pharma’s repeated failures in sponsoring trials seeking to provide even symptomatic relief for the mounting number of victims of Alzheimer’s and related dementia. Stoking the interest in encenicline is a mechanism of action that differs from the conventional therapeutic pathways for Alzheimer’s, which address the accumulation of beta amyloid plaque toxins in the brain. Instead, encenicline targets the brain’s nicotinic a7 receptor responsible for programming certain hippocampal and cortical neurons linked to sensory awareness, cognition and memory. “Encenicline is based on underlying science that indicates the potential of nicotine in stimulating electrical signals across neurons. It addresses the circuiting problems that researchers believe is at the heart of the cognitive deterioration associated with these key CNS disorders.”

As an orally administered small molecule pill, encenicline also seems effective in penetrating the blood brain barrier that limits the efficacy of most drug-based treatments.

Bigger workplace culture
Meanwhile, the company is gearing up for the long haul, adding staff and initiating work around other promising compounds in its CNS pipeline. “We are a growing enterprise – in 2012, we had 70 employees; since I joined in 2013, we are up to 160 – this year, we intend to expand staff to 250,” Dunsire told Pharm Exec.

An experienced people manager from her previous stints at Novartis Oncology and as CEO of Millennium Pharmaceuticals prior to its acquisition by Takeda in 2008, Dunsire says institutionalizing a spirit of accountability is the necessity of the moment. “Because we are importing such a large number of people from outside, I am focused on building a distinct company culture – a FORUM culture, rather than the amalgam of experiences that our hires may be bringing from their previous employers. In particular, I want to instill a real passion about this enterprise, grounded in our mission to tackle diseases and conditions that many of our R&D peers have abandoned.”

FORUM is wholly owned by Fidelity Biosciences, the venture capital arm of the mutual fund giant, which gives it an extra measure of stability in addressing these challenges. “Fidelity has given us 100 per cent support for our strategic positioning as a purpose-built enterprise for serious brain diseases,” said Dunsire. FORUM has access to other sources of capital and could file for an IPO, if conditions warrant – but Dunsire says she and her Board find no pressing need for such a course of action right now, but constantly evaluate the environment to see if a change is warranted.

Three metrics of success
Dunsire is piloting a course mined with potential pitfalls, the most important of which is the unpredictability of the diseases around which the company has staked its future. Investors with far more resources have tried, failed and exited the segment over the past five years. Asked to lay out her metrics of success for the next three years, Dunsire cites three: (1) finalize the two late stage trial programs on Alzheimer’s and schizophrenia and prepare them for commercial launch; (2) progress the pipeline around candidates for additional therapies aimed at treating diseases of the brain; and (3) to initiate, with other stakeholders, industry-leading initiatives around a personalized medicine approach to senile dementia. In fact, Dunsire’s stake in this endeavor is equally personal, an extension of her well-known religious faith to the secular promise of science to do something good where today there is nothing but heartbreak for many.