Biogen Idec Announces Plans to Buy Nav1.7 Program
On January 11, pharmaceutical giant Biogen Idec announced that it would acquire Convergence Pharmaceuticals, a small UK company that has developed a compound aimed at alleviating neuropathic pain by blocking Nav1.7 sodium channels. The deal could be seen as a vote of confidence for the small-molecule drug; the company has reported positive outcomes in early clinical trials of the compound.
The Nav1.7 channel is a key regulator of excitability in pain-sensing neurons, and over the past decade, research has linked the SCN9A gene that encodes Nav1.7 to human pain disorders. People with congenital insensitivity to pain (CIP) bear a mutation in SCN9A that inactivates Nav1.7 and completely stops them from experiencing pain. Conversely, gain-of-function mutations have been identified in rare pain disorders such as inherited erythromelalgia (EM) and more common forms of painful peripheral neuropathy (see PRF related news story). Based on the genetic evidence, pharmaceutical companies painted a bull’s-eye on the ion channel as a target for new medications aimed at neuropathic pain.
“Once that target was identified, it’s not surprising that nearly every drug company in the world tried to aim for it,” said Stephen McMahon, director of the London Pain Consortium and professor at King’s College London, UK, who is not involved with any pharmaceutical company. But selectivity has been an issue, as researchers have sought ways to quiet Nav1.7 sodium channels specifically to target pain-sensing neurons without affecting other, related sodium channels in the brain or the heart. “There has been a huge attempt to make selective drugs for Nav1.7,” McMahon told PRF.
The acquisition comes on the heels of positive data from two Phase 2 clinical trials of the Convergence compound CNV1014802. The compound is a novel, relatively selective and state-dependent inhibitor of Nav1.7.
In a June 2014 press release, Convergence reported a successful Phase 2 trial of CNV1014802 for patients with trigeminal neuralgia, a neuropathic pain condition that features episodes of extreme pain in the face. Convergence used a novel trial design involving a 21-day open-label phase, followed by a randomized, placebo-controlled phase for responders (Zakrzewskaet al., 2013). Of the 67 subjects recruited, 44 completed the open-label phase and 31 met criteria to be randomized for the double-blind placebo-controlled phase. Patients who received CNV1014802 saw a 2.3-unit decrease in the numeric rating scale of pain—a 55 percent decrease in pain severity compared to 18 percent for placebo—and a 60 percent reduction on average in the number of painful paroxysms they experienced compared to a 12 percent reduction in the placebo group.
A second press release in September reported modest yet positive results of what Convergence called a “proof-of-concept study” of CNV1014802 in 81 patients with sciatica. Across all subjects, CNV1014802 reduced pain by about half a point on the 11-point pain scale, but about 60 percent of subjects who took CNV1014802 alone—without other medications—saw pain reduction closer to a full point on the scale compared to placebo. The drug was well tolerated with no major side effects reported in either study.
“I am very enthusiastic to see some successes,” McMahon said of the reports.
Other companies are also testing Nav1.7 inhibitors in clinical trials, though none has yet publicized positive results. Pfizer has completed Phase 2 trials of their compound PF05089771 for osteoarthritis, post-operative dental pain, and inherited EM. Xenon is collaborating with Genentech to develop an oral, selective Nav1.7 inhibitor. In a separate collaboration with Teva, Xenon is also developing a less selective, topically applied sodium channel inhibitor; trials are in the works for TV-45070 for osteoarthritis, post-herpetic neuralgia, and EM. (For details, see Bagal et al., 2014; Sun et al., 2014.)
The Convergence compound has several distinguishing features. It crosses the blood-brain barrier. In an effort to cut down on potential nonselective effects, McMahon said, “most drug companies have been making Nav1.7 blockers that are not brain penetrant but restricted to the periphery.”
Another distinguishing mark of CNV1014802 is that it works as a state-dependent blocker of Nav1.7, only inhibiting active channels. “It might target angry nociceptors rather than quiet ones, preserving normal functions of the nociceptive system,” McMahon postulated.
In 2013, the Convergence compound was granted orphan drug status for treatment of trigeminal neuralgia by the US Food and Drug Administration. That designation incentivizes development of drugs aimed at rare conditions by providing support and funding. Xenon and Teva’s topical compound also has FDA orphan drug status for EM.
Convergence operated as a private, venture-backed company since its 2010 spin-off from GlaxoSmithKline when that company halted its pain program. Scientists at Convergence will continue to operate under chief scientific officer Simon Tate from their Cambridge, UK, facility.
“Convergence has pioneered some of the most innovative science in pain management,” said Douglas Williams, executive vice president of research and development at Biogen Idec, Cambridge, Massachusetts, US, in a press release. The addition of Convergence, including its pipeline of candidates, “will provide a strong foundation upon which to expand our neuropathic pain portfolio.”
Stephen Waxman of Yale University Medical School, New Haven, US, and the Veterans Affairs Connecticut Healthcare System, West Haven, US, told PRF in an email, I am confident that, via Nav1.7 blockade, we will ultimately have a novel class of medications which provide much more relief from pain, with minimal central side effects and no addictive potential.” Waxman is collaborating with Convergence to test its compounds against patient-derived Nav1.7 variants, but has no financial stake in the company.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.
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