Early surprise phase III news from Biogen Inc. and Ionis Pharmaceuticals Inc. with nusinersen – which led to $75 million more in the latter's bank account – cranked up speculation regarding would-be rival Avexis Inc.'s AVXS-101 for spinal muscular atrophy (SMA). Biogen CEO George Scangos said "we, of course, will keep an eye on competition. But for now, we are focused on making this drug available to patients as quickly as we can."

Shares of Carlsbad, Calif.-based Ionis (NASDAQ:IONS) closed at $38.01, up $8.82, or 30.2 percent, Monday after the company and partner Biogen, of Cambridge, Mass., said the study known as ENDEAR met the primary endpoint pre-specified for the interim analysis. Biogen exercised its option to develop and commercialize nusinersen globally and paid Ionis a $75 million license fee. Regulatory filings are due in the months ahead. (See BioWorld Today, Aug. 4, 2014.)

Testing nusinersen in infantile-onset (consistent with type 1) SMA, the study found that infants getting the antisense oligonucleotide experienced a statistically significant improvement in the achievement of motor milestones compared to those who didn't, and the compound turned up an acceptable safety profile. ENDEAR was not expected to finish until the middle of next year, and Biogen said regulatory filings will happen in the months ahead.

Nusinersen is designed to alter the splicing of SMN2, a gene that is nearly identical to SMN1 (defective in SMA patients), to bring about more production of fully functional SMN protein. Phase II results were so satisfactory and proof-of-concept so clear that the companies went ahead with an interim peek, having added a co-primary functional/motor endpoint to the original survival endpoint to boost chances there.

Lynn Parshall, chief operating officer for Ionis, said the companies have "ongoing and very productive dialogue with both the European Union and U.S. regulatory agencies, and that has resulted in a change in the endpoint for the study," and she reiterated that "all of the analyses that we did favored the drug in the interim analysis. We will be talking more about this in detail at an upcoming medical meeting."

Leerink analyst Geoffrey Porges wanted to know during the conference call with company officials whether the primary endpoint has relevance for studies in the older children or type 2 disease.

Ionis CEO Stanley Crooke first provided a grim overview of SMA type 1. "The sad fact is that infants with SMA type 1 are at their very best at the first visit. After that, they decline rapidly and steadily," and "untreated infants never achieve a new motor milestone. So what was done in this study is all the infants that had been treated for at least six months were evaluated for their ability to do certain things that SMA infants are not expected to do like move their arms, kick their legs, grasp, sit up, have head control, which is actually a very difficult task for infants – to roll over, stand, walk. They are very discrete evaluations. And the differences between the treated infants and the control infants were highly statistically significant."

DATA FROM CHERISH TRIAL AHEAD

Regarding the ongoing childhood study, "endpoints are different because these children, some of them will have walked as toddlers and then progressively lose the ability to walk, so the majority of patients in the childhood study are not ambulatory," Crooke said. "For children who are not ambulatory, there are very specific measurements that have been perfected over the years by the physicians who care for these patients that are used to evaluate their motor strength. And we have not updated our phase II study in that patient population for some time, but we continue to see great things out of nusinersen and that patient population as well."

Chicago-based Avexis, which went public in February with an upsized IPO that priced 4.75 million common shares at $20 apiece – the midpoint of its intended range – to raise $95 million, has a pivotal trial with AVXS-101, an intravenous gene therapy for SMA type 1, set to begin in the first half of next year. The drug was granted breakthrough therapy designation last month, and open-label phase I data showed that all 15 patients were living more than 10.5 months, when natural history predicts 50 percent would have "experienced an event," Jefferies analyst Eun Yang pointed out), with median event-free survival of 14.9 months. Shares of Avexis (NASDAQ:AVXS) closed Monday at $35.60, down $2.03. (See BioWorld Today, Feb. 12, 2016.)

Piper Jaffray analyst Joshua Schimmer sounded circumspect, keeping his overweight rating and $35 price target on Ionis pending more clarity during the company's earnings call later this month. "With the Avexis gene therapy program delivering very strong early clinical results from a single center, the path forward for [that company] in the context of a nusinersen program which is rapidly moving toward commercialization is unclear," he wrote in a research report. "Given the strong results with AVXS-101, but what will likely be rapid adoption of nusinersen, it will be interesting to see if Avexis will be able to move forward without a randomized trial, and whether future analysis of the product will be in addition to nusinersen (or any next-generation Ionis antisense approaches) or instead of it."

Crooke addressed the next-generation possibilities, saying investors should think of "these studies as a beginning of evaluation of nusinersen. As everyone knows, the evaluation of breakthrough drugs continues long after they are commercialized, and I'm optimistic that Biogen over time will explore the dose frequency and all those sorts of things to optimize the performance. We do have new chemistries, and we continue to explore new chemistries, new mechanisms, new designs altogether, new designs in our neurological collaboration with Biogen. And so as we make those advances, one obvious place where they may be applied is in the follow-on for nusinersen. That's still at the very early discovery stage, so it really doesn't make any sense to predict when and if such an outcome would happen."

Meanwhile, Morningstar's Karen Andersen predicted approval for nusinersen in the first half of next year, ahead of schedule, and predicted a price "north of $100,000 annually" with sales that could surpass $2 billion per year. "Roughly 60 percent of the 30,000-35,000 patients with SMA are diagnosed with type 1 disease (the most severe form)," she noted in a report. Avexis stands "at least two years behind Biogen and Ionis in a best-case scenario for Avexis, assuming safety and efficacy data remain strong," she added.

The phase III trial called CHERISH is testing nusinersen in children with later-onset SMA, and top-line data are expected in the first half of next year, Laidlaw analyst Yale Jen said in a report. He added that, "going forward [with] nusinersen, Ionis could potentially receive up to $150 million in regulatory approval-based milestone payments, and we estimate the earlier one could be an up to $60 million payment for the initial approval(s)." Biogen's stock (NASDAQ:BIIB) closed Monday at $301.83, up $11.90.