Biogen (BIIB) received mixed news from an FDA advisory committee Wednesday when it took up whether to recommend agency approval of the company’s tofersen, an RNA-targeting therapy that, if authorized, would be the first treatment to target a genetic cause of Amyotrophic Lateral Sclerosis (ALS).

But the positive and negative votes from the FDA’s Pe­riph­er­al and Cen­tral Ner­vous Sys­tem Drugs Ad­vi­so­ry Com­mit­tee may ultimately benefit Biogen and tofersen by paving the way for an accelerated approval of the ALS treatment that would require submitting additional clinical data to the agency.

Tofersen is an intrathecally delivered antisense oligoucleotide indicated for adults with ALS that is associated with a mutation in the superoxide dismutase 1 gene (SOD1-ALS). The therapy is designed to reduce SOD1 protein synthesis by targeting the degradation of SOD1 messenger RNA (mRNA).

By a unanimous 9–0 vote, the advisory committee or “adcomm” held that the evidence presented by Biogen supported the idea that a reduction of neurofilament light chain (NfL) in plasma, an indicator of neurodegeneration, was “reasonably likely” to predict clinical benefit for patients with SOD1-ALS.

However, the adcomm was more divided, generating only three “yes” votes, two abstentions, and five “no” votes on clinical data from results of a placebo-controlled study and a long-term extension study, with additional supporting results from the effects on relevant biomarkers—such as changes in NfL or reductions in SOD1 protein in cerebrospinal fluid (CSF) concentrations —did not provide “substantial” evidence that treatment with tofersen was effective in patients with SOD1-ALS.

The vote followed a rewording of the question during the adcomm meeting from “convincing evidence”—as well as a mix of clinical data that included tofersen missing its primary endpoint in the Phase III VALOR trial (NCT02623699) of statistically significant change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).

However, Biogen cited VALOR’s multiple encouraging secondary and exploratory measures of biologic activity and clinical function—including reduction of SOD1 protein and reduction of NfL. The company also cited 12-month results showing that individuals with SOD1-ALS who started tofersen earlier experienced a slower rate of decline in clinical and respiratory function, strength and quality of life.

The adcomm also reached a consensus that the overall benefit-risk assessment for tofersen in SOD1-ALS patients was favorable based on reviewing the totality of data. The FDA usually, but not always, follows the recommendations of its advisory committees.

“A major advance’”

“If approved, tofersen would potentially represent a major advance for people living with SOD1-ALS,” Priya Singhal, MD, MPH, executive vice president, head of development, and interim head of research and global safety and regulatory sciences at Biogen, said in a statement. “We thank the FDA for convening this important discussion.”

Biogen submitted its new drug application (NDA) for tofersen last year to the FDA, which accepted the filing in July 2022 under its accelerated approval pathway, and granted a priority review. That review was supposed to have culminated in a Prescription Drug User Fee Act (PDUFA) target decision date of January 25. But in January, the agency pushed back the PDUFA date three months, to April 25, after concluding that Biogen’s responses to information requests by the FDA constituted a “major amendment” requiring additional review time.

The mixed voting led several market watchers to predict that the FDA will ultimately approve Tofersen through its Accelerated Approval Program, since it allows for earlier approval of drugs that treat serious conditions, and fill what the agency deems an unmet medical need based on a surrogate endpoint. Under Accelerated Approval, Biogen would be required to conduct additional clinical studies to confirm an anticipated clinical benefit.

The reason: Because accelerated approval decisions are based on surrogate endpoints, they can be made by convincing the FDA that a drug in question is “reasonably likely to predict clinical benefit,” on which the adcomm sided with Biogen.

“We believe it should be granted accelerated approval by the PDUFA date of April 25,” Marc Goodman, senior managing director, neuroscience and a senior research analyst with SVB Securities, wrote Wednesday in a research note. Goodman retained SVB Securities’ 12-month price target of $310 and “Outperform” rating on Biogen shares. [SVB Securities was not among entities included in the recent Chapter 11 filing of its parent company SVB Financial Group, and SVB Securities operations have continued uninterrupted.]

Agreed Sumant Kulkarni, a managing director and senior biotechnology analyst with Canaccord Genuity, also in a Wednesday research note: “Our bottom-line take on this AdCom[m] is that an accelerated approval for tofersen based on biomarker data is almost certain.

“We also got the sense that the FDA would even consider a full approval, which makes the upcoming action date that much more interesting,” Kulkarni added. He retained Canaccord Genuity’s $325 price target and “Buy” rating on Biogen shares.

10-Year, $1B-plus collaboration

Biogen has licensed tofersen from Ionis Pharmaceuticals (IONS) as part of a 10-year, $1 billion-plus expanded collaboration to develop more neurological drugs launched in 2018, six years after the companies began partnering to successfully develop the spinal muscular atrophy (SMA) treatment Spinraza® (nusinersen).

At the time, Biogen exercised an option to develop and commercialize the drug, previously called BIIB067 and originally IONIS-SOD1RX, in return for paying Ionis a one-time $35 million payment. Biogen also agreed to pay future post-licensing milestone payments of up to $55 million, and royalties in the low to mid-teen percentages on annual worldwide net sales.

Biogen incurred milestone payments to Ionis of $17 million last year, $10 million in 2021, and $28 million in 2020, the company disclosed in its Form 10-K annual report for 2022.

Eun K. Yang, PhD, an equity analyst with Jefferies, wrote in a Wednesday research note that while the “no” vote on the second question doesn’t appear to bode well for a short-term full approval, it’s a moot point based on insights from management at Ionis, which she said expects an accelerated approval of tofersen: “BIIB is not asking for full approval at this time.”

Investors responded to the FDA adcomm votes with enough stock buying to send Biogen shares up 1.5% on Thursday, from $261.22 to $265.17.

“We don’t see [Wednesday]’s AdCom as a stock-moving event,” Goodman continued, given the very small patient population identified for tofersen—between about 300 and 500 patients (approximately 330 in the U.S. alone and approximately 2% of the estimated 168,000 people with ALS worldwide, Biogen has estimated, citing a 2021 study)—as well as projections that the ALS treatment will generate ~$300 million in peak-year sales in the U.S.

Ionis shares saw no benefit from the FDA adcomm discussion on Tofersen. Instead, the shares fell 5% from $35.29 to $33.62.

“Interesting possibilities”

Kulkarni said the FDA staff briefing documents “throw up some interesting possibilities” for the developer of another ALS treatment—Clene (CLNN)’s lead candidate CNM-Au8®, a gold nanocrystal suspension being developed for ALS as well as Parkinson’s disease.

In October, Clene acknowledged data from the Healey ALS Platform Trial (NCT04414345  and NCT04297683) showing CnM-Au8 to have missed the study’s primary endpoint of adjusted slope of change in ALSFRS-R, and secondary endpoints of Combined Assessment of Function and Survival (CAFS) and slow vital capacity (SVC), all measured at 24 weeks. The trial was designed to assess CNM-Au8 and at least four other potential ALS treatments—zilucoplan (being developed by UCB), verdiperstat (Biohaven Pharmaceuticals, set to be acquired by Pfizer for $11.6 billion), pridopidine (Prilenia Therapeutics), and SLS-005 (also called trelahose injection; Seelos Therapeutics).

Clene has said it is continuing development of CnM-Au8, based on data from Healey that also showed positive results for a secondary survival endpoint for the 30 mg dose—namely a >90% reduction in the risk of death or death equivalent (permanently assisted ventilation) and risk of death alone at 24 weeks.

“We eagerly await biomarker data on CnM-Au8 (specifically NfL), and survival data,” Kulkarni wrote Monday in a research note.

If approved, tofersen would also be the second ALS treatment to gain FDA authorization in less than a year.

The first, Amylyx (AMLX)’s Relyvrio® (sodium phenylbutyrate and taurursodiol), is indicated for ALS in adults. Relyvrio won approval after the FDA’s Pe­riph­er­al and Cen­tral Ner­vous Sys­tem Drugs Ad­vi­so­ry Com­mit­tee held an unusual second hearing where it reversed an earlier recommendation against the drug. The about-face, which came at the urging of ALS patient groups, sparked some renewed investor interest in Amylyx last summer that faded with FDA approval last September.

The approval of Relyvrio has begun to pay off for Amylyx, which generated $22.2 million last year in net product revenue—including sales in the U.S. and Canada, where the drug was approved in June 2022 under the name Albrioza™. The European Medicines Agency is reviewing Amylyx’s marketing authorization application for the drug under its original name of AMX0035.

Relyvrio is one of three ALS treatments approved by the FDA. The others are:

  • Riluzole, a glutamate release inhibitor sold as a generic as well as under the brand names Rilutek®  (tablet; Covis Pharma), ‎Tiglutik (oral suspension; ITF Pharma, a subsidiary of Italfarmaco); and Exservan™ (oral firm; Mitsubishi Tanabe Pharma America).
  • Edaravone, an antioxidant also marketed by Mitsubishi Tanabe Pharma America as both Radicava®  (injection) and Radicava ORS®  (oral suspension).

Leaders and Laggards

  • Altimmune (ALT) shares nosedived 55% on Tuesday, from $10.92 to $4.95, after the company reported results that disappointed investors from an interim analysis of 160 participants in the Phase II MOMENTUM trial (NCT05295875) assessing the once-weekly candidate pemvidutide in patients with obesity or who are overweight. Altimmune called the MOMENTUM trial successful based on a mean weight loss of 10.7% (9.7% when adjusted for placebo patients) at the study’s high dose of 2.4 mg at Week 24. The weight loss “is kind of right at the border of what investors thought was going to be acceptable. So it’s not enough for some, it’s just barely enough for others,” Jonathan Wolleben, equity research analyst, biotechnology and biopharmaceuticals with JMP Securties, told Reuters.
  • Pear Therapeutics (PEAR) shares yo-yo’ed earlier this week, tumbling 46% on Monday from 39 cents to 21 cents, then bouncing back 60% Tuesday to 33.5 cents. The roller-coaster trading followed the company’s announcement Friday after the close of trading that the prescription digital therapeutics (PDT) developer had begun exploring strategic alternatives that include “an acquisition, company sale, merger, divestiture of assets, licensing, or other strategic transactions and/or seeking additional financing.” Pear set no timetable for a decision, but warned that if it could not complete a transaction, “it may be required to seek a reorganization, liquidation or other restructuring.”
  • Quince Therapeutics (QNCX) shares rocketed 71% on Tuesday, to $1.44, after Echo Lake Capital made an unsolicited offer to acquire the company, which in-licenses and acquires clinical-stage assets targeting debilitating and rare diseases. Echo Lake has offered $1.60 a share, a 90% premium to Monday’s closing price of 84 cents a share. Echo Lake noted that Quince’s stock price has cratered 95% since its IPO in 2019 and plunged 70% since last year when it acquired NOV004, designed for accelerated fracture repair in patients with bone fractures and osteogenesis imperfecta. Quince plans to out-license NOV004 after shelling out $15 million last year for the precision bone growth molecule. Quince said it was evaluating the proposal.
  • Zura Bio (ZURA) shares more than quadrupled, zooming 314% from $7.24 to an even $30 on Wednesday, after the company completed a $215 million special purpose acquisition company (SPAC) merger with “blank check” company JATT Acquisition. The combined company is expected to receive gross cash proceeds of up to $189 million from the deal. Zura is advancing a single product, the interleukin-7 receptor subunit alpha (IL7Rα) inhibitor ZB-168 for alopecia areata and other inflammatory diseases. The company is based in London, with its workforce in both the U.K. and the U.S.
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