Blessed By Angels, GliaCure Tests New Alzheimer’s Approach In Humans

Xconomy Boston — 

Giant pharmaceutical companies have spent billions of dollars trying to crack Alzheimer’s disease, only to come up empty time after time. For small, cash-strapped biotechs, the challenge is even harder. Tufts University professor Philip Haydon is trying to make the improbable journey anyway.

Haydon has created GliaCure, a tiny startup run out of his Boston condominium, to go after a target often overlooked in drug development: microglial cells, one of the family of cells that provide the “glue” to hold together the brain’s hard-working neurons. And he’s about to find out if he’s on to something.

This week, GliaCure’s Alzheimer’s prospect, known by the name GC021109, began its first clinical trial. The drug candidate is the culmination of 20 years of work for Haydon, the chair of Tufts’ neuroscience department.

“I think what makes GliaCure unique is that they are a company built around that idea” of targeting microglia says James Hendrix, the director of global science initiatives at the nonprofit Alzheimer’s Association, and a medicinal chemist with almost two decades of experience in the pharmaceutical industry. “Now, [we’ll see] how far they’ll go.”

Like any effort to treat Alzheimer’s, GliaCure’s quest is fraught with risk. Haydon is trying to do what has not worked so far in many large clinical trials: make Alzheimer’s patients better by clearing out the telltale plaques, or clumps of misfolded amyloid-beta protein, from their brains.

After a first safety test in healthy volunteers, GliaCure will go after patients already showing serious signs of the disease, even though many in the field believe those patients are beyond help.

Haydon hopes a new approach can produce results. He aims to use a small molecule drug to target a specific receptor on microglia, one of the types of glial cells that that serve at least two purposes. They are the “glue” in the brain that holds neurons in place and connects them to one another as they fire the electrical and chemical signals responsible for our actions and feelings.

Microglia are also part of the brain’s specialized immune system. But when there’s inflammation in the brain, such as with Alzheimer’s, they don’t do a good job of clearing amyloid-beta plaques.

Haydon believes his drug might not only stimulate the microglia’s natural plaque clearing ability, but also cool off the inflammation that might be getting in their way.

“This two-pronged parallel action really sets us apart from what anyone else has tried,” says Haydon, GliaCure’s president, co-founder, and chief scientific officer.

Scientists still have a lot to learn about what’s really going wrong in the underlying biology of Alzheimer’s, which strips people of their ability to reason and remember. Many still believe that amyloid-beta plaques are a key to the Alzheimer’s mystery, but clearing those plaques from the brain hasn’t made patients better. Adding to the mystery, roughly 30 percent of people who develop plaques never develop Alzheimer’s at all.

The role of inflammation is also attracting more scrutiny, as it is in many diseases. Studies of non-steroidal anti-inflammatory drugs—aspirin, ibuprofen and the like—have uncovered a potential link between their use and lower Alzheimer’s risk, but there’s been no clinical proof.

It’s fertile ground, however. “The inflammation model is definitely on a lot of people’s radar,” says Ted Yednock, the former head of research at Elan Pharmaceuticals in South San Francisco, CA, and currently a consultant. “We’ll start to see more work emerge soon.” (Yednock is not affiliated with GliaCure and did not want to comment specifically on the company’s program.)

The only approved drugs on the market, donepezil (Aricept) and memantine (Namenda), are cognitive boosters that, at best, help delay the progression of the disease for some patients.

Because of the scientific uncertainty, Alzheimer’s drugs are extremely expensive to test and difficult to reliably measure. It’s hard for a tiny biotech to take a drug from idea to the FDA finish line; it’s probably impossible in Alzheimer’s. GliaCure is going to need a lot of help from institutional investors and a partnership with a pharmaceutical company should GC021109 show potential in human patients.

Still, GliaCure has had an intriguing head start. It’s one of the few biotech startups to draw an exorbitant amount of angel funding, about $8.5 million so far in two rounds. (the Halo Report put the median angel round size in 2013 for all angel rounds at about $600,000.)

Outside of its three-member executive team, the company has one full-time employee, Haydon’s wife Yolande (GliaCure’s business manager). The office is Haydon’s condominium, which overlooks the Boston harbor. While some of the science takes place at Haydon’s lab at Tufts, GliaCure outsources as much as possible to CROs.

“They say you can run a company out of your kitchen,” Haydon jokes. “It’s true.”

Then there’s GliaCure’s approach. Haydon says for many years, people have targeted glial cells in drug development in “haphazard” fashion. That’s partly because our understanding of their roles is relatively new. Until the early 1990s, there was no method to study glial cells, even though they account for 90 percent of the brain’s volume.

While neurons fire electrical signals back and forth, glial cells are electrically silent. Because of that, it was hard for researchers to understand what they do or their impact on brain function. Eventually, technologies such as genetically-engineered mice and the fluorescent chemical sensors invented by Nobel laureate Roger Tsien made possible the study of glial cells: astrocytes, oligodendrocytes, and microglia.

“[Microglia and astrocytes] have come in and out of favor the last 20 years,” says Irene Griswold-Penner, who as senior director of neurobiology at iPierian used models of glial cells and neurons—“brains in a dish”—to test the company’s antibody treatments for neurodegenerative diseases (now in the hands of Bristol-Myers Squibb).

“There would be some tiny bit of data that suggest a role for either some target in microglia or astrocytes in the neurodegenerative diseases, and then people just wouldn’t make headway.”

But there is now a growing body of scientific literature examining their role in brain function, and a greater understanding of the roles of the different types of glial cells.

Haydon made glial cells the focus of his research more than two decades ago, after a fluky experiment he ran in 1992 showed they released chemicals, rather than just being essentially inactive.

But the idea for his company came out of a lecture he attended in 2008. He heard someone say that if you stimulate a certain receptor on a microglial cell, it kickstarts phagocytosis. Think of that as the brain’s garbage men clearing out the trash around them by digesting it. Haydon surmised he could use a drug to do that in Alzheimer’s patients, since, he says, microglia cells surround beta-amyloid (the misfolded protein that forms plaques). But they don’t digest beta-amyloid correctly once the disease takes hold, perhaps because they are hampered by inflammation.

The drug is a small molecule that stimulates a receptor on microglia called P2Y6. Haydon says the drug appears to work in two ways: triggering phagocytosis and tamping down the release of an inflammatory cytokine, IL-12.

“The thinking is we’re taking the foot off the brake by removing inflammation, and at the same time we’re pushing our foot down on the gas to stimulate directly the clearance of amyloid beta,” Haydon says.

After early experiments in mice at Tufts that showed clearance of plaques Haydon developed some intellectual property and set up GliaCure in 2011 with the help of some “friends and previous business colleagues.” (He wouldn’t name them, only referring to his main benefactors as “wealthy individuals” who are “incredibly supportive of the program.”)

Other GliaCure officials are Rudy Schreiber, a former Evotec, Roche, and Sepracor executive, who is VP of translational research and development, and CFO Alan Barber, who is also president of financial management firm Prestar Group. GliaCure’s board includes Walter Dewey (a portfolio manager at Reinhart Partners), Michael Szulczewski (president of Prairie Technologies, acquired by Bruker in 2013) and Joe Zakrzewski (recently the CEO of Amarin).

Given just clearing out plaques on its own hasn’t been enough in clinical trials so far—high-profile antibody drugs like bapineuzumab and solanezumab did so, but didn’t improve patients’ lives—Haydon is hoping that two-pronged strategy will have different results.

Haydon claims his candidate, in an in vivo model, both reduced plaques and improved memory formation. He’s not aware of anyone else trying GliaCure’s specific approach on Alzheimer’s, but like any other untested mechanisms, it’s got its share of questions. For example, the drug disrupts the function of the P2Y6 receptor, which can be found on many other cells throughout the body, not just microglia.

“This receptor is one of the adenosine receptors, and pharmas have been trying to target the adenosine receptors for years,” says Griswold-Penner. “But you have to have such a clean inhibitor against the particular homologue that you’re interested in. You can have effects on the heart, all sorts of side effects, because there are so many adenosine receptors that affect every vital function in the body.”

Haydon notes specifically P2Y6’s presence on circulating T cells, a key component of the immune system. But his concerns have been allayed so far in animal studies, where the drug has proven “very safe” even after delivering a maximum dose—far higher than would be needed for a therapeutic response.

Then again, as Haydon acknowledges, “a [mouse] model is a model.”

Human studies are a different story. And potential side effects aside, even recruiting the right patients for those studies is a massive undertaking, because it’s still unclear when the right time is to treat an Alzheimer’s patient. Many drugs have been doomed by treating the disease too late in the process to make a real impact.

That’s yet another bridge GliaCure will have to cross eventually, and a major reason why the company plans to hedge its bets. It’ll test the drug’s anti-inflammatory/phagocytosis dual mechanism in other diseases like psoriasis and Parkinson’s, and plans to develop other glia cell-targeting candidates as fast-acting anti-depressants or sleep therapeutics as well.

To do that, however, GliaCure is going to have hire some full-timers and a CEO, raise a bunch of money, and presumably, move out of that condo.

“We are totally cognizant of the fact that it’s going to cost a lot of money, and we’ve got to find groups with deep pockets,” Haydon says. “The science is exciting. We’ve got to just make sure we can drive it forward.”