Tag Archives: Alzheimer’s Disease

By Steve Dickman, CEO, CBT Advisors

July 29, 2013 (originally published on Xconomy)

Just because a biotech company has landed a high-profile chief executive, does that mean its product is going to work? I’ve been asking myself that question in the wake of the unexpected July 11 announcement of the hiring of a biotech superstar, the Novartis veteran and former Millennium Pharmaceuticals CEO Deborah Dunsire, by the Boston-area central nervous system (CNS) therapeutics company EnVivo Pharmaceuticals. Dunsire takes the reins in mid-August.

Photo courtesy Millennium: the Takeda Oncology Company

At the very least, the hiring of Dunsire is a bullish sign for EnVivo’s late-stage product, an alpha-7 nicotinic receptor agonist. The product, called EVP-6124, is in the midst of two 700-patient, late-stage clinical trials in the very challenging indication of schizophrenia. Given the lack of new therapeutics for schizophrenia, that is exciting enough, but the real potential for EVP-6124 is in the even more challenging indication of Alzheimer’s disease. Two Phase 3 trials are due to begin by the end of 2013 and run through 2015.

It is impossible to say today whether any of these trials will result in an approved drug. But Dunsire’s choice to join EnVivo was deeply surprising to a Boston biotech community that had eagerly awaited news of her next move. A look at the reasons we were caught by surprise will illuminate the risks in drug development for tough CNS indications; the side benefits that will accrue if the drug works; and the synergies inherent in the combination of Dunsire and EnVivo.

When I considered why Dunsire’s choice was so unexpected, I came up with three basic reasons:

(1) EnVivo has flown a bit under the radar. With a single VC investor, the company is anything but a “Boston mafia” biotech investment. Under the steady-handed direction of its former CEO Kees Been, EnVivo has quietly grown from perhaps 30 people when I briefly consulted there in 2005 to a recent headcount of 130. So it has competed successfully in the region’s ever-sharper “war for talent.” But in terms of its stakeholders at least, it is far from the biotech mainstream.

(2) The indications that EnVivo is pursuing are exclusively in the CNS arena. They do not include cancer. That seems like a jump for Dunsire, who focused on oncology for much of her time at Novartis and all of her time at Millennium.

(3) Unlike at Novartis, where Dunsire was in a position to work with a whole portfolio of therapies and focus on the ones likely to perform the best, and unlike at Millennium, where the blockbuster product Velcade (bortezomib) was already approved and on a path to success when she joined in July, 2005, here Dunsire is jumping into a very tough field, betting most of her chips on a single product and doing so without the benefit of CNS experience.

Let’s take those one by one. They’re easy to demolish. First off, EnVivo is not, in fact, a traditional VC-backed biotech. The partners and staff at a single Boston-area venture firm, Fidelity Biosciences, have played a very active role in managing it. One staff member negotiated the license for EVP-6124 in 2004 and a different one, partner Robert Weisskoff, has actually been running the company as interim CEO since March of this year. Still, the company is, according to a Boston-area biotech CEO, “not market tested” because it never had to raise money from other (skeptical) venture capitalists. One could say that comments like this are motivated by jealousy: what CEO wouldn’t want a company to run for which he or she is unlikely to ever have to raise outside capital? But there is also some substance to this critique, since it points to a higher than usual level of uncertainty about the company’s products and its value proposition.

This uncertainty about EnVivo’s prospects would stand – were it not for the general eagerness that I’ve heard about in the pharmaceutical industry to offer generous partnership terms for EVP-6124, terms that EnVivo has chosen not to accept. Pharma has been wrong about neuro compounds many times before. But EVP-6124 has plenty of would-be backers in the industry and I have to believe that Dunsire spoke to at least some of them before making her decision to join.

Second, EnVivo does not work on cancer therapeutics. The highlight of Dunsire’s 17-year career at Novartis was when she led the launch of Gleevec (imatinib), which at the time of its launch in 2001 was the most exciting (if narrowly applied) cancer drug to come along in years.

At the Convergence Forum life sciences conference in Chatham, MA, in mid-May Dunsire appeared in a “fireside chat” with fellow Boston biotech entrepreneur Katrine Bosley. It felt like everyone in the room had one big question for Dunsire: What next? There, Dunsire spoke in tones both humble and proud of the impact Gleevec has had. Gleevec, she said, “has turned CML into a chronic disease.” One patient Dunsire knows personally was “told that she would die before being treated with Gleevec in 1998.” That patient, Dunsire said, “is still running marathons. People who lived three to five years are now living fifteen years and showing no evidence of disease.”

So, like an Olympic champion returning to competition after some time off, it would make sense that Dunsire would try to get “runner’s high” again from launching a meaningful drug. How many more Gleevecs will there be in cancer?  At Convergence, Dunsire said that there are “vanishingly few cancers in which we might get there.”

Perhaps more to the point: how many of those rare drugs are wholly owned by small biotech companies that are not financially compelled to partner them with the pharmaceutical industry? Sticking with cancer might well have pushed Dunsire over to the pharma side of the industry. And arguably, Dunsire could have joined an oncology-focused pharmaceutical company as CEO. She certainly has the street cred. But by getting out of cancer, she has given herself a chance for a second compelling success that outstrips expectation and, more importantly, helps patients. Dunsire even gave a clue to the audience at Convergence when she said “I want to focus on the areas where we don’t have good therapies. Cancer. Neurosciences.”

Finally, what about the risk? Isn’t EVP-6124 a risky bet? The answer to that has to be an unequivocal “yes.” No drug in this class (the alpha-7 agonists) has worked. Targacept, the publicly traded CNS company in North Carolina, in 2012 was the latest to fail with an alpha-7 agonist, albeit in attention deficit hyperactivity disorder (ADHD). The Targacept drug, TC-5619, is still in trials in schizophrenia and Alzheimer’s. Like EVP-6124, that drug had had positive data in an earlier Phase 2 study.

But in biotech, it is always critical to look not just at the risk but also at the upside. Imagine what will happen if EVP-6124 works. It will not only become a multibillion dollar blockbuster, the likes of which have not been seen in the pharmaceutical industry for some time. (Acetylcholinesterase inhibitors that act symptomatically, not mechanistically, and that cause unpleasant and debilitating side effects in briefly delaying the inevitable cognitive decline in AD, currently earn north of $2 billion in revenue). It will also help patients in a palpable way.

There is another factor to consider in contemplating the potential for EVP-6124 and for EnVivo. Any analysis of Dunsire’s motivation to join EnVivo cannot ignore the man behind its sole VC investor. That is Edward “Ned” Johnson III, 83, whose family owns Fidelity Investments. At a $6.5 billion net worth, Johnson is the 52nd-wealthiest person in the country according to Forbes. Among his many contributions to AD research, he founded and funded the important AD research portal Alzforum.org. As if to underscore his commitment to the company and the field, Johnson supported Fidelity Biosciences when it bought out all the other investors in 2008, becoming the sole shareholder in one of the few biotech companies developing a novel AD therapy. This is an unusual model but also one that might help explain how Dunsire could be convinced of the investors’ support for the company no matter what. The investor (singular, not plural) has a burning desire to leave a legacy.

The fact is that EnVivo is the rare biotech that can commercialize its own product. Johnson’s wealth makes that possible – even if, as some have speculated, the eventual cost to his firm’s fund for product development of this one product tops $600 million.

After so many failures of bold and not-so-bold products, AD drug development lately has contracted a bad case of incrementalism. The cost of Phase 3 trials is so prohibitive at $100 million per trial and up – and some products may require more than one Phase 3 trial before receiving regulatory approval – that until now only pharmaceutical companies have been able to afford these trials and even those companies are becoming skittish about anything but those approaches that, judged by today’s science, seem most likely to succeed. A successful EnVivo could change that paradigm and tackle the development of truly innovative drugs, including those based on full-on mechanistic approaches. Now that’s what I call upside. And it explains Dunsire’s choice better than any other explanation I can imagine. Now, EVP-6124 just has to work. As Johnson told me in a chance encounter on an airplane last year, it is way too early to credit him with improving the odds for Alzheimer’s drug development. Wait until we see if EnVivo’s alpha-7 works, he said.  “The proof of the pudding,” he went on, “is in the eating.”

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