Tofersen, an investigational antisense drug developed to treat amyotrophic lateral sclerosis (ALS) associated with a mutation in the SOD1 gene (SOD1-ALS), may have clinical benefit, FDA reviewers indicated in ahead of an advisory committee meeting.
On , the Peripheral and Central Nervous System Drugs Advisory Committee will vote on whether evidence supporting a reduction in plasma neurofilament light chain (NfL) -- a neurodegeneration biomarker proposed by drug developer Biogen as a surrogate endpoint for accelerated approval of tofersen -- is reasonably likely to predict clinical benefit in SOD1-ALS.
The committee will also weigh in on whether clinical data from the placebo-controlled and its study provide convincing evidence of tofersen's effectiveness in SOD1-ALS to consider full approval of the drug.
In VALOR, tofersen led to greater reductions in SOD1 protein in cerebrospinal fluid and plasma NfL but did not slow decline on the ALS Functional Rating Scale-Revised (ALSFRS-R) at 28 weeks in a subgroup of patients with fast-progressing SOD1-ALS.
Data from the open-label extension, however, suggested that long-term use of tofersen may have benefits. Of 95 study participants who entered the open-label extension -- some of whom were originally assigned to placebo (the delayed-start cohort) -- the change in the ALSFRS-R score at 52 weeks was -6.0 points for early starters and -9.5 points for delayed starters (difference 3.5 points, 95% CI 0.4-6.7). Differences favoring early-start tofersen also emerged for secondary endpoints.
"This is a situation where there is a negative clinical study that failed to show a statistically significant treatment effect in the prespecified primary analysis population," reviewers for the FDA's Division of Neurology and Office of Neuroscience wrote.
"The study, as designed, was markedly underpowered and thus limited in its ability to detect a difference if there was a drug effect; however, there are available data from that study that indicate target engagement of the therapy and a reduction in a biomarker that has been shown to be correlated with disease progression and prognosis in patients with ALS," they continued.
"Despite the notable limitations of a failed study and the many post hoc exploratory analyses that were conducted after [the VALOR trial], the Division considers that the data may suggest a treatment effect of tofersen in SOD1-ALS," they added.
The literature about NfL in ALS has evolved since the VALOR study was designed, the FDA reviewers noted. NfL's suitability as a surrogate endpoint will depend on several factors, including mechanistic evidence that tofersen reduces SOD1 protein, evidence showing NfL's value in predicting ALS disease progression and survival, and correlations between lower NfL and slower decline in clinical outcomes like the ALSFRS-R.
"In this setting of a very rare, life-threatening disease with significant unmet need, it is appropriate to exercise regulatory flexibility in applying the statutory standards for establishing effectiveness," the FDA reviewers wrote.
The main safety signal in the tofersen development program was a potential risk of serious neurologic adverse events, which may be related to tofersen's intrathecal administration, including myelitis, radiculitis, aseptic meningitis, papilledema, and elevated intracranial pressure.
"Given the serious and life-threatening nature of ALS, these risks do not appear to preclude approval and risk can be adequately mitigated through a description in labeling," the FDA reviewers noted.
Tofersen mediates the degradation of SOD1 messenger RNA to reduce SOD1 protein synthesis. Around 2% of ALS cases are caused by mutations in SOD1.
Tofersen is also being studied in the , which is assessing whether the drug can delay clinical onset of ALS in presymptomatic patients with a SOD1 genetic mutation and biomarker evidence of disease activity.
The FDA is scheduled to make its final decision about tofersen by . The agency often follows the advice of its advisory committees, but isn't required to do so.