Sanofi SA said an investigational Bruton's tyrosine kinase (BTK) inhibitor it licensed from Principia Biopharma Inc. in 2017 significantly reduced disease activity associated with multiple sclerosis (MS) as measured by magnetic resonance imaging, meeting the trial's primary endpoint. The drug, SAR-442168 ('168), was well-tolerated with no new safety findings, Sanofi said. Next up are four phase III trials designed to investigate the drug's effects on MS relapse rates, disability progression and underlying CNS damage.
Having already earned $40 million up front and $55 million of a possible $765 million in milestone payments from Paris-based Sanofi for the asset, Principia next has an option to co-fund the phase III trials in return for additional potential gains. Principia’s shares (NASDAQ:PRNB) climbed 14.2% to $69.01 at the market's close, while Sanofi's U.S.-listed shares (NASDAQ:SNY) climbed 4.74% to close at $51.66.
The BTK inhibitor, created using Principia’s reversible, tailored covalency platform, could be the first B cell-targeted MS therapy to not only inhibit the peripheral immune system, but also cross the blood-brain barrier to suppress immune cells that have migrated into the brain. That could provide a critical new avenue for addressing key MS symptoms, Sanofi said.
The phase IIb trial was a randomized, double-blind, placebo-controlled, crossover study. Over 12 weeks of dose ranging, it evaluated '168 in patients with recurring MS. In one group, patients received one of four doses of '168 for the first 12 weeks, then crossed over to placebo for four weeks. The other group of patients received four weeks of placebo before crossing over to '168, providing data that were used to estimate a dose-response curve, thus minimizing exposure to placebo.
The study found that '168 showed a dose-response relationship in the reduction of new active gadolinium-enhancing T1-hyperintense brain lesions after 12 weeks of treatment. A dose-response curve for '168, in terms of reduction of brain MRI lesion activity, will be used for selection of the phase III dose.
Planning for phase III
Four phase III trials will investigate the effects of '168 on MS relapse rates, disability progression and underlying central nervous system damage. Two trials in relapsing MS, the most common form of the disease, as well as a separate trial in primary and secondary progressive MS, are planned to be initiated in the middle of this year.
Contemporary competitors in some of the indications include Ocrevus (ocrelizumab, Roche Holding AG), Mayzent (siponimod, Novartis AG) and the not-yet approved candidate ozanimod (Bristol-Myers Squibb Co.). Its NDA in relapsing forms of MS has a March 25 PDUFA date.
Erik Wallström, Sanofi's head of neurology development, told BioWorld that, despite there being multiple treatments for MS available, “there's still room to improve" by covering mechanisms of the disease in the brain that are partly responsible for disability progression. "That's most obvious in progressive MS," he said, where despite approaches to inhibit the immune-mediated effects of the diseases in the periphery, effects in the clinic have been relatively modest.
In the context of earlier stages of the disease, the ability of '168 to cross the blood-brain barrier presents a potential advantage, he said. There, it appears to suppress immune cells that have migrated into the brain and to modulate brain-resident microglia cells and macrophages that have been implicated in MS progression. "Of course, we need to prove with longer-term data that we can actually modulate these cells," he said, "but if we can do that, we're quite optimistic that we can provide extra benefit to patients.”
With more than 1.2 million MS patients in the U.S. and top EU markets alone, of which roughly a quarter have progressive forms of the disease, the magnitude of the medical need in MS is substantial, Sanofi's head of global R&D, John Reed, told investors during the company's fourth-quarter 2019 earnings call on Feb. 6.
Success of a new MS drug could also have a positive effect on Sanofi's bottom line. Its fourth-quarter 2019 MS sales decreased by 3% to €540 million (US$592.8 million), primarily due to a 42% decline in sales of Lemtrada (alemtuzumab) in the U.S. and Europe, reflecting increased global competition and an update to the EU label. In November 2019, the EMA recommend limiting its use to only highly active relapsing-remitting MS "due to reports of rare but serious side effects, including deaths." Fourth-quarter sales of another Sanofi MS drug, Aubagio (teriflunomide), increased 5.4% to €482 million, contributing to a full-year 2019 1.8% increase in Sanofi's MS sales to €2.16 billion.
A decision to make
Martin Babler, Principia’s president and CEO, told BioWorld that his South San Francisco-based company's deal with Sanofi is a clear out-license deal. But to ensure there'd be additional economic upside for Principia if the '168 program succeeds, his team built into the deal an option to co-fund Sanofi's phase III studies in return for better economics.
What lies ahead, he said, is "a financial strategy decision more than anything," hinging on the likely costs and returns of the program and how that fits into Principia's overall cash management strategy. "That decision is independent, in terms of timing, from how fast Sanofi moves into phase III," he added.
Before having to choose, Principia will get to see data from the phase IIb, the result of Sanofi's regulatory interactions with the FDA during an upcoming end-of-phase II meeting, and its plans for future development. "That's when we have to make the decision," Babler said.