Biogen said that it is evaluating next steps for tofersen (BIIB067) after acknowledging that the antisense drug missed its primary endpoint in a Phase III trial in people with superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS)—but showed what the principal investigator called encouraging multiple secondary and exploratory measures of biologic activity and clinical function.

Tofersen failed to meet the primary endpoint of the Phase III VALOR trial (NCT02623699), namely a statistically significant change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), as measured by a joint-rank analysis showing a difference of 1.2.

The clinical setback did not significantly hurt Biogen stock, which dipped about 1% in premarket trading as of 8:24 a.m. ET, to $278.50 from Friday’s close of $181.19.

“Investor expectations were very low to begin with heading into the data,” Michael Yee, analyst with Jefferies, wrote last night in a research note. “We don’t expect a meaningful impact on the stock as the current narrative remains on Aduhelm, reimbursement decisions in 2022, and cont’d progress on launch over the next few years.”

In June, Biogen won a controversial FDA approval for its Alzheimer’s disease drug Aduhelm (aducanumab-awva), albeit an approval conditioned on a new clinical trial that the agency hopes will resolve longstanding questions over the drug’s effectiveness.

Yee noted that in announcing second quarter results over the summer, it said it started a Phase III trial for tofersen in pre-symptomatic SOD1 carriers, “which seems consistent with VALOR’s findings suggesting earlier treatment may have a bigger effect.”

“We don’t believe investors would give much credit here given (1) data will be years away, (2) it’s difficult to treat ALS population, and (3) it’s a small market ~$200–300M peak sales (SOD1 is only ~1–2% of ALS),” Yee added. “Bottom line, the data likely does not support a BLA filing while the pre-symptomatic SOD1 data will be years away, so investor narrative will continue to center around Aduhelm in 2022.”

$1B Partnership Expansion

Biogen has licensed tofersen from Ionis Pharmaceuticals 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).

Ionis’ stock took a bigger hit on news of the tofersen results, falling 6% in premarket trading as of 8:43 a.m. ET, to $33 from Friday’s close of $35.10.

Biogen presented topline results for tofersen yesterday at the American Neurological Association (ANA) 2021 virtual meeting, being held through Tuesday.

In announcing those results yesterday, Biogen trumpeted what it called trends favoring tofersen in secondary and exploratory measures that included motor function, respiratory function, and quality of life.

According to Biogen, the change from baseline in total CSF SOD1 protein, a marker of target engagement, between tofersen and placebo patients stood at 38% for patients whose SOD1 ALS was faster progressing, and 26% for slower-progressing patients. The change from baseline in plasma neurofilament light chain (NfL), a potential marker of neuronal degeneration, between tofersen and placebo groups was measured at 67% for faster-progressing, and 48% for slower-progressing.

Among faster-progressing patients, those receiving tofersen showed improved respiratory function (Slow Vital Capacity (SVC); difference of 7.9 percent-predicted) and muscle strength (Hand-held dynamometer (HHD); difference of 0.02). Biogen added that additional trends favoring tofersen were seen across multiple exploratory patient-reported outcome measures of disease severity, quality of life, and fatigue. However, due to the low number of events over the 28-week period, a median time to event could not be estimated for survival analyses.

The VALOR trial enrolled 108 patients randomized to tofersen or placebo for 28 weeks at 2:1.

Data Strength Debated

“The results from the VALOR study are encouraging as they show reduction of SOD1 protein, reduction of neurofilament, a potential biomarker for neurodegenerative disease, and positive signals across multiple key endpoints including measures of important aspects of the daily lives of SOD1-ALS patients,” VALOR’s principal investigator Timothy Miller, MD, PhD, who is also ALS Center Director at Washington University School of Medicine, St. Louis, said yesterday in a Biogen statement.

However, Marc Goodman, Managing Director, Neuroscience, and a senior research analyst with SVB Leerink, raised a doubt about whether the results would be strong enough for tofersen to win a regulatory approval:

“These preliminary data may be supportive of some hints of efficacy; however, the study failed the well-understood ALS primary endpoint, and thus we don’t see how Biogen would be able to proceed with a filing with this data,” Goodman wrote in a research note last night.

Alfred Sandrock, Jr., MD, PhD, Head of Research and Development at Biogen, said the company will broaden early access to tofersen to all eligible SOD1-ALS patients through its already established expanded access program.

Biogen said most adverse events in both VALOR and OLE were mild to moderate in severity, including procedural pain, headache, pain in extremity, fall and back pain.

“The wait for new options has been long and difficult for the ALS community, and we welcome this important research advancement in this difficult to treat disease space,” Miller added.

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