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Hunting For Brain Plaques, Neurophage Turns to a Virus

Xconomy Boston — 

Scientists still have a lot to learn about what’s really going wrong, in the underlying biology, of patients with Alzheimer’s Disease and Parkinson’s Disease. That’s a big reason why it’s such a minefield for little biotech startups and big pharmaceutical companies to develop drugs in those areas. But it also provides room for some creative thinkers, and Cambridge, MA-based Neurophage Pharmaceuticals says it just might have an idea that can succeed where so many have failed.

Sometime next year, Neurophage will likely begin its first human clinical trial. Taking lessons learned from a virus found in bacteria, Neurophage has come up with a genetically-engineered protein drug that could attack these neurodegenerative diseases in a new way. The idea is that Neurophage’s fusion-protein molecule will soak up the excess plaques that accumulate in the brains of people with neurodegenerative diseases like Alzheimer’s and Parkinson’s. It’s the beginning of a long clinical journey for the 19-employee company that’ll take several years, and millions of dollars to complete. And given the preponderance of failures of drugs in the field, there’ll be no shortage of skeptics.

“It’s good that I started the company without any hair on my head,” jokes president, co-founder, and CEO Jonathan Solomon, of the myriad challenges the company will face.

Jonathan Solomon

Neurophage president and CEO Jonathan Solomon

Solomon co-founded Neurophage in 2007 out of Harvard Business School with another student, Hampus Hillerstrom (the company’s executive vice president and chief business officer). The company’s technology was originally licensed from Tel Aviv University and discovered by professor Beka Solomon. Her past discoveries in Alzheimer’s led to licensing deals with Wyeth and Elan. She’s also Solomon’s mother.

Solomon and Hillerstrom have since added a number of well-known names in the science and business world to their cause. Richard Fisher, formerly of Biogen Idec and GlycoFi, is Neurophage’s chief scientific officer. Vicki Sato, a professor of management practice at Harvard Business School, is on the company’s board, along with Kenneth Buckfire, the co-president and founder of investment bank Miller Buckfire. Board chairman John Dee steered the sales of Hypnion to Eli Lilly in 2007 and Link Medicine to AstraZeneca in 2012. Alnylam Pharmaceuticals CEO John Maraganore is an advisor, as is Michael Heartlein, the vice president of research of Shire’s human genetic therapies division.

While Neurophage is going after Alzheimer’s, the idea behind the company is more broad. The company is targeting diseases caused by protein misfolding. Proteins start out as a chain of amino acids, and they turn into functional proteins when they interact with one another, or “fold” into a three-dimensional structure. When they connect improperly, or “misfold,” they form proteins that are either inactive, or potentially toxic, and start to accumulate into plaques that the body has to get rid of.

Alzheimer’s, for example, is thought to arise from the buildup of certain types of plaques, or tangled proteins, in the brain. Researchers believe those plaques are formed by proteins like tau or amyloid beta that have folded incorrectly. Parkinson’s Disease, similarly, is thought to occur because of the accumulation of Lewy bodies, another protein folding error, inside nerve cells. Rare diseases like Huntington’s and Amyotrophic Lateral Sclerosis (a.k.a. Lou Gehrig’s Disease) are also on Neurophage’s radar.

In Alzheimer’s, many of the high-profile clinical failures have consisted of antibodies designed to latch onto one type of misfolded protein—tau, or amyloid beta, for instance. But because neurodegenerative disorders like Alzheimer’s, or even Parkinson’s, can include several types of misfolded proteins at once, Neurophage says it can succeed by using engineered fusion protein drugs that hit several of them at the same time.

“We’re the only company out there that can hit multiple misfolded proteins simultaneously,” Solomon says. “We’re looking for that process of how [the body] creates these aggregates, and that’s what we target. That’s where we’re unique.”

The idea to try this was essentially a fluke. Several years ago, Beka Solomon was running an experiment related to an antibody for Alzheimer’s. She wanted to find a way to reduce the side effects of the antibody, so she decided to put it on a filamentous bacteriophage called M13—a virus that targets bacteria—and give it to mice.

The results didn’t make any sense. Mice that got the virus with no drug attached to it were seeing a therapeutic effect. So she started putting the virus into test tubes with aggregates like beta amyloid and plaque-forming proteins associated with other neurodegenerative diseases. The phage was breaking them up too. The key was to figure out why.

The younger Solomon then teamed with Hillerstrom and decided to take on the problem. They licensed the IP surrounding the phage from Tel Aviv University, and formed Neurophage around it. They’ve since been able to secure three different venture rounds, raising a total of $35 million from Shire, Merieux Developpement, and private angel investors.

Using that cash, Neurophage’s scientists then studied the phage to figure out which parts of it were helping break up these plaques. They found that a tiny portion, some 0.1 percent of the mass, was in charge of the activity. Neurophage then took those pieces, built a fusion protein out of them called NPT002 with an in-house technology, and tested it in the petri dish just as it did with the virus. Neurophage found the same type of results in those experiments, and with animal models as well.

Even so, breaking up plaques in test tubes and animals is nothing compared to the exorbitant task of not only doing so in humans and proving it translates into a truly meaningful clinical benefit, but doing it safely. Neurophage plans to deliver the drug intravenously, through an injection once a month, and can look to the fact that fusion protein drugs like etanercept (Enbrel) are well established. And so far—in animal studies, of course—it’s been able to deliver NPT002 without seeing any big red flags for safety issues, like the compound sticking to organs it’s not supposed to, or homing in on different masses.

Still, it will take plenty of time, a lot of cash, and without question the help of a big pharmaceutical partner for Neurophage to get the ultimate proving ground of a huge Phase III clinical trial in either Alzheimer’s or Parkinson’s—the place where so many seemingly-promising drugs have failed.

So far, Neurophage has gotten some credible investors to back it, and has also been able to attract the interest of the Michael J. Fox Foundation, which has awarded the company two different grants to continue its research into breaking up Parkinson’s-related plaques. And Neurophage should complete another roughly $15 million Series D round—following the $6.4 million Series C round it announced in May—within the next couple months to get it to the point of submitting its first application to start clinical trials.

According to Solomon, Neurophage plans to begin its first clinical trial in the second half of 2015, through which it’ll likely use PET imaging to see if its drug candidate is reducing amyloid beta or tau in humans. Ideally, Neurophage would get a partner after Phase I trials that would help it run a big Phase II study in a large population like Parkinson’s or Alzheimer’s, while it handles a smaller study for a disease like Huntington’s, simultaneously, Solomon says. That’d allow the company to hedge its bet.

“If you’re fortunate, one of them you can move forward,” he says.