Tapping UCSF Invention, Roche and Versant Dive Into Myelin Repair
When mice chew through the insulation that protects a house’s wires, an electrician can repair the wires. People with multiple sclerosis, whose immune systems malfunction and attack the insulation of their own neural wires, don’t have that option. Helping them could be a very big deal in MS care.
Swiss drug giant Roche, tapping into an unorthodox business model created by a San Francisco venture group, wants to find treatments to help. Roche and Versant Ventures have created the oddly named Inception 5—we’ll explain the name later—to house a promising new way to look for multiple sclerosis drugs, a high-throughput screen developed at the University of California, San Francisco.
Roche will contribute its vast libraries of compounds to test in the UCSF assay, and a seasoned team of drug discovery scientists in the employ of Versant’s Inception group will also try to design new compounds.
Repairing the neural insulation is called remyelination. Myelin is the substance that makes up the sheaths, and it’s also what the immune system mistakes for a pathogen. The attack leaves holes in the myelin, and like a house with faulty wiring, the patient’s nervous system starts to short-circuit, leading to a wide and unpredictable range of neurological symptoms.
While drug makers have produced improvements with drugs that tamp down the immune system’s attack, nothing is available to reverse the actual myelin damage. (Two monoclonal antibody therapies, one from Biogen Idec (NASDAQ: BIIB) of Cambridge, MA, and another from Acorda Therapeutics (NASDAQ: ACOR) of Ardsley, NY, are in the clinic.)
The UCSF assay, created by neurology professor Jonah Chan (pictured above), is an innovative way to get at a thorny problem: It’s really hard to build tests that demonstrate remyelination. Neurons, the cells that need to be remyelinated, are finicky to grow in the lab. Also a problem: oligodendrocytes, the cells that produce myelin, don’t wrap their myelin around the axons of neurons in an easily measurable way. (Axons are the branching arms of neurons that transmit electrical signals.)
There are other reasons, too, but Chan created a work-around: Build tiny silica cones that encourage oligodendrocytes to wrap their myelin cleanly. In other words, he built axons from pure glass. And when those silica cones (which Chan calls “micropillars”) are lined up in a testing plate, their cone shape allows measurement of the myelin thickness as it wraps around. Imagine reading the myelin as if it were the rings in the cross-section of a tree.
“Jonah’s done a great job,” said Jay Tung, chief research officer of the Myelin Repair Foundation in Saratoga, CA, which has worked with Chan in the past. “We are ecstatic about pharma, academics, startups, anyone moving the field forward. This is exactly what we want to see.”
“My view is that the missing link for finding candidate therapies for myelin repair has been the lack of a platform for efficient high-throughput screening of agents,” said Timothy Coetzee, chief research officer at the National Multiple Sclerosis Society in New York. The nonprofit funded much of Chan’s work that went into the micropillars. “The complexities of co-culture systems just don’t lend themselves to HTS. Jonah’s technology fills that critical gap.”
With the screening platform, researchers can test how thousands of drugs spur oligodendrocytes to produce myelin. That’s exactly what Inception 5 plans to do.
The group is part of a Versant initiative to keep its own drug-discovery team in-house at a company called Inception Sciences, led by a group of scientists who, at the Merck-Frosst labs in Montreal, had a string of successes including the painkiller rofecoxib (Vioxx)—later withdrawn from the market for safety concerns—and the asthma drug montekulast (Singulair). One of those scientists, Peppi Prasit, and Versant teamed up to create Amira Pharmaceuticals, which they sold in 2011 for $475 million.
Prasit and Versant managing director Brad Bolzon (right) immediately pivoted to launch Inception Sciences, which describes itself as a “small-molecule pharmaceutical incubator.” It is wholly owned by Versant and has two labs, one in San Diego, another in Vancouver. A third is about to open as well.
Instead of turning Inception Sciences into a sprawling biopharma, Versant uses a few million dollars at a time to fund Inception spin-offs that it partners with outside drug companies. (Hence the Inception 5 name; there are four other spinoffs, with more soon to be announced, according to Bolzon.) With Inception 5, Roche is paying for the research and has the option to buy the company outright once the Inception team files an IND, which is industry shorthand for asking the Food and Drug Administration permission to test a drug in humans.
Chan told Xconomy his work had drawn a lot of industry interest, but meeting the Inception scientists at their San Diego facility last year “hooked him.” Two people in particular, the medicinal chemist Brian Stearns and the biologist Daniel Lorrain, were “very impressive,” said Chan. “They’re so focused on developing products and new drugs. It made perfect sense.”
Chan also liked the idea of a third party like Inception between his work and Roche, which previously had asked him directly to screen their compounds in his lab. “That wasn’t appealing,” he said. “I didn’t want to be a service provider for companies.”
Instead, Chan and his students can get back to basic research and leave the screening work to others. “I’m just a lab rat,” he said. “It’s up to the drug hunters to take the next steps.”
Chan and his fellow UCSF neurology professor Ari Green, also an MD who treats multiple sclerosis patients, are among Inception 5’s founders and have an undisclosed equity stake. (Versant is the main owner, and Inception’s employees also take equity in each spinout.)
Even as the micropillar screen goes over to Inception 5, Green is overseeing a 50-person trial at UCSF with a drug he and Chan found with the screen. Like much of the work surrounding myelin repair, Green is taking a creative tack to measure the drug’s effect. The trial measures the speed at which light shone in a patient’s eye is converted into a signal in the brain. Myelin damage to the optic nerve slows that conversion. Patients whose speed improves during the trial might be experiencing myelin repair.
Data could be ready by the end of the year, but the trial isn’t meant to get a new drug on the market. They’re testing an off-patent, over-the-counter antihistamine, and its drowsy effect on patients rule out its potential as an MS drug. “Fatigue is the number-one issue for MS patients,” said Green. “But if this trial goes well, we’ll pursue funding for a large scale clinical trial, because even if it doesn’t lead to development of a therapeutic, it’ll help advance the field.”
It’s a field full of unknowns. As promising as Chan’s micropillars are, they’re synthetic. They only approximate how myelin would wrap around real axons, and they lack the complicating factor of inflammation in the micro-environment. Tung of the MRF says his group has an “intense focus” to move toward a high-throughput screen without using a synthetic material. Inception 5 will work on next-generation assays, too, says Green.
If Roche pulls the trigger and buys Inception 5, it will take the micropillar screen with it, which doesn’t sit well with Tim Coetzee of the NMSS. “If this platform technology got walled off from rest of the world, I’d be worried,” said Coetzee. “This is about MS, but we’re also starting to see defects in myelin in Alzheimer’s, ALS, and other diseases. It’s not as profound right now as MS, but there are other places this technology could have relevance.”