The biggest clinical trial news of 2015 so far, arguably, was a report from Biogen Idec (NASDAQ: BIIB) about a drug meant to do something never done before: repair nerve damage in multiple sclerosis patients and possibly reverse the course of the disease.
The news was also quite ambiguous. In a Jan. 8 release, the company deemed the results “positive,” even though the trial, dubbed RENEW, didn’t prove statistically significant for the most important measure and showed no improvement in two other measures. The full data set is to be unveiled at an unspecified future medical conference, Biogen Idec said.
In other words, the results were not the clear-cut, move-this-drug-ahead-now kind that a company, its investors, and most importantly, patients in dire need of new treatments would like to see. Yet it provoked responses like this, from Ari Green, a neurologist at the University of California, San Francisco, who treats MS patients: “The progress they’ve made is an important step in right direction. Whether this specific agent is one with adequate efficacy and safety, we have no idea.”
That’s because this kind of nerve repair—called remyelination—has never been tried in humans before. Observers like Green were happy there were no safety problems and even a glimmer of positive effect in patients.
Biogen already has an industry-leading franchise of MS drugs such as interferon beta-1a (Avonex), natalizumab (Tysabri), and dimethyl fumarate (Tecfidera). They all help tamp down the immune system’s attack, but they don’t reverse existing damage to myelin, the fatty white protein that forms nerve sheaths and also constitutes about half the human brain.
Why the immune system identifies myelin as a pathogen and chews it up, no one knows. But Michael Gilman, the CEO of Padlock Therapeutics and a former Biogen research executive, says there are two schools of thought. One is that MS is an “outside-in” disease; the brain develops an immune response to a virus or infection that somehow goes into overdrive. The other theory is that it’s an “inside-out” disease; the primary defect or injury is in the brain, and the ensuing inflammation is a reaction to that injury.
Regardless of the reason, however, people with MS know the results: A nervous system that goes haywire, sometimes slowly, sometimes in bursts, causing all sorts of symptoms from numbness to vision loss to slurred speech and worsening motor coordination. It’s unpredictable, and it’s irreversible.
“People working in MS understand the paradigm shift of launching drugs that directly treat the damaged tissue,” said Tassie Collins, vice president of translational medicine at the Myelin Repair Foundation in Saratoga, CA, a nonprofit research group with its own R&D program. “That’s a biological paradigm shift.”
Collins sees a powerful one-two punch with current treatments. As those drugs keep the immune system in check, a myelin repair treatment would help the body rebuild the nerves.
Biogen’s test was the first to show something. The company’s R&D chief Doug Williams, whom Xconomy interviewed at the J.P. Morgan Healthcare Conference in San Francisco, said, “We’ve now demonstrated ‘proof of biology’—that we can get remyelination in man—which is something that’s never been demonstrated before.”
Major drug companies don’t often enter the middle stages of clinical development—the just-completed trial was Phase 2a—while learning on the fly about the biology of a disease. It’s a recipe for lots of time and money spent pursuing a very risky goal, which tends to make short-attention-span shareholders nervous. But that’s what Biogen is doing.
“In new areas, where we’re pioneering biology, part of it is accepting that you have to do basic work on the clinical side too,” said Williams, who joined Biogen four years ago.
With myelin repair, the risk and reward are both high. Biogen’s big bet is on a monoclonal antibody, dubbed BIIB-033, that blocks a protein called LINGO-1 and, in animal tests, both encourages remyelination and restores health.
In the Phase 2a data released earlier this month, Biogen tested BIIB-033 in patients with acute optic neuritis (AON), an attack on the optic nerve that is often the first acute symptom to afflict a MS patient. (UCSF’s Green says 25 to 30 percent of all first attacks of MS are AON, and that 80 percent of all MS patients at some point suffer an AON attack.)
Biogen’s idea was to get its anti-LINGO drug into patients soon after an acute attack to see if the optic nerve could recover. And here’s where the top-line data get tricky.
Biogen reported that in 34 percent of the people in the study, electric signals moved more freely through the nerve after treatment—a measurement of the nerve working better. But the study wasn’t designed to measure if their eyesight actually improved. Biogen said it didn’t, nor did damaged retinal nerve cells show any physical improvement.
Biogen pointed to the 34 percent—as did UCSF’s Green and others—as a positive sign. But there were plenty of caveats: That percentage did not include everyone who started the trial. Those “intent to treat” patients are the “gold standard,” said an MS specialist who advises the MRF. Not including them—and not saying how many of the trial dropouts were in the patient group taking the drug or those taking placebo—opens up a lot of questions.
“We need to see the data,” the MS specialist said, speaking on condition of anonymity.
The secondary endpoints—repairing the optic nerve cells and improving vision—weren’t the main goal of the study. But missing those endpoints badly, as the study did, was also instructive, said Williams. The delay between the acute optic neuritis attack and getting the drug into patients might explain why it had no functional effect. By the time they were treated, was it already too late?
All these questions and more illustrate why Biogen is on the cutting edge with its clinical program. No one really knows how to design a program, or what exactly to look for.
But more data points are on the way. Green, the UCSF neurologist, is also running a small Phase 2 remyelination trial in MS patients. It’s about the same size as Biogen’s optic neuritis trial, and data could be available later this year. “There’s a big difference between their trial and ours,” Green said. “We’re swinging for the fences.”
Green praised Biogen for being a pioneer—and disclosed that he provided advice to the company before the AON trial—but his trial is “more ambitious” because it’s testing chronic MS patients, not just ones with a recent optic neuritis attack. He’s skipping the intermediate step of Biogen’s trial and hunting for bigger answers.
As an academic, Green can afford more risk. He also has little invested in the drug being tested; it’s an over-the-counter antihistamine that he and UCSF professor Jonah Chan discovered through a screening tool Chan invented (and which is now under license to Roche).
The MRF has also tapped an off-patent drug, approved for hypertension 20 years ago, in a myelin repair trial it launched recently with the National Institutes of Health.
With so many unknowns in myelin repair, that trial and Green’s trial will no doubt inform Biogen’s clinical course. The learning-as-you-go approach even extends to a much larger Phase 2 trial, dubbed SYNERGY, that Biogen is currently conducting with BIIB-033 in more than 400 MS patients.
That trial is testing for improvement across a range of functions. Evidence of myelin repair probably won’t be enough. Will patients’ various motor skills and cognition actually improve? The data, which Williams said “we really need to see to figure out what the next step in the clinical trial process will look like,” won’t be ready until 2016.
Will Biogen learn enough to proceed into a large, expensive Phase 3 trial? Williams seems ready and willing to push the boundaries. Biogen can keep testing drugs, like those it has brought to market, that benefit MS patients whose symptoms wax and wane. “We can keep doing those studies ’til the cows come home,” said Williams. “We know how to do those really well, but that’s not where the need is.”
Ben Fidler contributed to this report
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