Biogen’s New Drug Application for first treatment of rare form of neurological disease accepted by FDA

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A drug to target a rare genetic form of a neurological disease that affects the nerve cells, leading to the loss of everyday functions, could be the first of its kind available if approved.

The US Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) from Massachusetts-based Biogen Inc. for tofersen, an investigational drug for superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS).

Amytrophic lateral sclerosis (ALS) can cause loss of voluntary muscle movement including chewing, walking and talking – and is uniformly fatal.

SOD1-ALS is a rare genetic form of ALS that affects approximately 330 people in the US which is progressive and if approved, tofersen would be the first treatment to target a genetic cause of ALS.

The application has been granted priority review and given a Prescription Drug User Fee Act action date of January 25, 2023.

Life expectancy

The FDA has noted that it is currently planning to hold an Advisory Committee meeting for this application, on a yet-to-be determined date. The average life expectancy for people with ALS is three to five years from time of symptom onset. There is currently no treatment targeted for SOD1-ALS.2  

Priya Singhal head of global safety and regulatory sciences at Biogen, said: “The available data show that tofersen has the potential to make a meaningful difference for people with SOD1-ALS. Pursuing the FDA’s accelerated approval pathway offers the potential to make tofersen available to people living with this fatal, neurodegenerative disease as quickly as possible. If approved, tofersen will be the first treatment to target a genetic cause of ALS and we hope this will pave the way for further advances in this relentless disease.”

Biogen is seeking approval of tofersen under the FDA’s accelerated approval pathway, based on the use of neurofilament as a surrogate biomarker that is reasonably likely to predict clinical benefit. Neurofilaments are normal proteins found in healthy neurons, that are increased in blood and cerebrospinal fluid when damage has been done to neurons or their axons and are a marker of neurodegeneration. 

In ALS, higher levels of neurofilaments have been found to predict more rapid decline in clinical function and shortened survival. Tofersen study results suggest reductions in neurofilament preceded and predicted slowing of decline in measures of clinical and respiratory function, strength, and quality of life. Biogen is committed to ongoing data generation and finalizing the confirmatory data package with the FDA.

Healthy volunteers

The tofersen NDA included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the Phase 3 VALOR study, and the open label extension (OLE) study. Also included are the most current 12-month integrated results from VALOR and the OLE study, recently presented at the European Network to Cure ALS (ENCALS) annual meeting.

In previous reports in October 2021, VALOR, a six-month Phase 3 randomized study, did not meet the primary endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. However, trends of reduced disease progression across multiple secondary and exploratory endpoints were observed. The 12-month integrated data showed that earlier initiation of tofersen led to sustained reductions in neurofilament, a marker of neurodegeneration and slowed decline across multiple efficacy endpoints.

Timothy Miller, principal investigator of VALOR at Washington University ALS Center, said: “The 12-month results showed 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. These are critical measures for people living with this devastating disease. For people in my clinic living with SOD1-ALS, tofersen may meaningfully slow the rapid progression of their disease and the impact it has on their lives.”

Pain in extremities

In the 12-month data, the most common adverse events (AEs) in participants receiving tofersen in VALOR and the OLE study were headache, procedural pain, fall, back pain and pain in extremities. Most AEs in both VALOR and the OLE were mild to moderate in severity. Serious neurologic events including myelitis, radiculitis, aseptic meningitis, and papilledema, were reported in 6.7 percent of participants receiving tofersen in VALOR and its OLE.

During the FDA review period Biogen will maintain its early access program for tofersen, now with participants in over a dozen countries.

Tofersen is an antisense drug being evaluated for the potential treatment of SOD1-ALS. It binds to SOD1 mRNA, allowing for its degradation by RNase-H in an effort to reduce synthesis of SOD1 protein production.

This will come as positive news for the company as last month, (June) it said it was forced to end an observational trial of Alzheimer’s drug, Aduhelm, after a ruling by US federal insurance program, Medicare. Biogen said the coverage decision by Medicare forced it to abandon the trial of the drug after enrolling just 29 participants.

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