Accelerated Approval Is US FDA Panel’s Preferred Path For Biogen/Ionis’s Tofersen In ALS
Executive Summary
Advisory committee unanimously concludes that the reduction in plasma neurofilament light chain concentration is reasonably likely to predict clinical benefit in SOD1-ALS, but majority of panelists say convincing evidence of efficacy to support regular approval has not been demonstrated.
The available evidence supports accelerated approval, but not regular approval, for Biogen, Inc. and Ionis Pharmaceuticals, Inc.’s Qalsody (tofersen) in a subgroup of patients with amyotrophic lateral sclerosis, a US Food and Drug Administration advisory committee said on 22 March.
The Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously that a reduction in plasma neurofilament light chain (NfL) concentration with tofersen is reasonably likely to predict clinical benefit in treatment of patients with ALS associated with a mutation in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS).
However, the panel voted 5-3, with one abstention, that placebo-controlled and open-label extension data, in addition to the biomarker data, are not sufficiently convincing to meet the substantial evidence of effectiveness threshold for regular approval.
In discussing whether NfL reduction is reasonably likely to predict clinical benefit, such that the evidence could support accelerated approval, panelists said data show that tofersen, an antisense oligonucleotide, unequivocally impacts the SOD1 protein and reduces plasma NfL concentration.
They also cited the totality of evidence, including from the literature and from the tofersen studies, that reduction in NfL leads to improved clinical outcomes, even though Biogen’s Phase III trial failed its primary clinical endpoint.
“I think a review of the 52-week data and comparing the early-start and later-start subjects was supportive that there’s a clinical benefit of the NfL reduction.” – Banner Alzheimer’s Institute’s Robert Alexander
“The VALOR study did not meet its prespecified clinical endpoints, so did not demonstrate efficacy,” said Liana Apostolova, chair of Alzheimer’s disease research at Indiana University. “However, we are adjudicating on the entirety of the data.”
She cited the data from the open-label extension, as well as data on a time-based relationship between the effect on the SOD1 protein and the subsequent downstream reduction in NfL, as well as the favorable trends for tofersen in terms of separation from the placebo group in VALOR and its open-label extension. “All of these data make me make the conclusion that we have sufficient data to advise that it is reasonably likely.”
“I thought there was sufficient evidence that NfL could be a reasonably likely surrogate,” said Robert Alexander, chief scientific officer of the Alzheimer’s Prevention Initiative at Banner Alzheimer’s Institute. “There was clear reductions of NfLs by tofersen both in the [cerebral spinal fluid] NfL and plasma NfL.”
Alexander acknowledged the concerns of the FDA statisticians, who said that while the data support an effect in NfL there were limitations to Biogen’s analyses and the company could not conclusively establish a causal relationship between tofersen effects on NfL and clinical outcomes in VALOR.
Nevertheless, “I think a review of the 52-week data and comparing the early-start and later-start subjects was supportive that there’s a clinical benefit of the NfL reduction,” Alexander said.
“It appears that NfL is bad for neurons and is tied with neuronal death, so if it’s lower the neuronal death should be lower,” said David Weisman, director of Abington Neurologic Associates’ Clinical Research Center.
Surrogate Marker Is Context Specific
The committee’s overwhelming vote on the reasonably likely standard would appear to clear the way for tofersen to become the first ALS drug cleared under accelerated approval by the 25 April user fee goal date.
However, Teresa Buracchio, acting director of the FDA’s Office of Neuroscience, made clear that the panel’s consideration of NfL reduction as reasonably likely to predict clinical benefit was specific to tofersen and SOD1-ALS.
“In this situation we are considering the NfL … as a surrogate marker in this specific population of the ALS-SOD1 population and in the setting of this therapy specifically,” Buracchio said. “If there was theoretically another therapy that came along targeting SOD1 mutation in ALS, we would look at that program separately on a case-by-case basis, and also the same for any other general ALS that was not specific to the SOD1 mutation.”
Amylyx Pharmaceuticals, Inc.’s Relyvrio (sodium phenylbutyrate/taurursodiol), the most recent ALS drug approved, did not demonstrate a positive effect on neurofilament heavy chain. (Also see "One Difference Between Amylyx’s ALS Drug And Aduhelm: A Biomarker Endpoint" - Pink Sheet, 30 Mar, 2022.)
No ‘Do-Over’ On VALOR
Although Biogen is seeking accelerated approval of tofersen on the basis of NfL reduction as a surrogate reasonably likely to predict clinical benefit, the FDA nevertheless sought panel input on whether the clinical data and other evidence was sufficient to support regular approval in light of the severity, rarity and unmet need in SOD1-ALS. (Also see "Biogen/Ionis’ Tofersen: US FDA Considering Both Accelerated And Regular Approval In ALS" - Pink Sheet, 20 Mar, 2023.)
While committee members were comfortable with the idea of accelerated approval, most were not willing to make the jump to regular approval based on the currently available evidence. Rather they believed more data were needed to confirm the drug’s clinical benefit, including data from the ongoing ATLAS trial in presymptomatic patients and longer-term survival follow-up in the VALOR open-label extension.
“I think that the field and the world should celebrate the data as the major milestone, the biomarker readout, the development, the signal of clinical effectiveness with a longer duration of the follow-up. But to adjudicate on the question of convincing data supporting efficacy, we need more data.” – Northwestern University’s Tanya Simuni
“I think that the field and the world should celebrate the data as the major milestone, the biomarker readout, the development, the signal of clinical effectiveness with a longer duration of the follow-up,” said Tanya Simuni, division head at the Parkinson’s Disease and Movement Disorders Center at Northwestern University. “But to adjudicate on the question of convincing data supporting efficacy, we need more data.”
Biogen has suggested that several limitations in the VALOR study’s design may have contributed to the miss on the primary clinical endpoint, including a 28-week duration period that likely was too short to detect a treatment effect given the proposed mechanism of action.
Alexander also agreed that the data do not meet the threshold of convincing evidence of efficacy. “You can speculate that maybe if the duration of the double-blind period had been longer or if NfL had been used as a covariate you might have seen a clearer signal, but that wasn’t done and there’s no real do-over here.”
Panel chairman Thomas Montine, chair of the pathology department at Stanford University, said the negative outcome in the placebo-controlled portion of VALOR weighed heavily on him when it came to determining whether the evidence for effectiveness was convincing.
‘Consequences of an Accelerated Approval’
On the other side of the vote, Weisman said he was persuaded that the drug works, and he raised reimbursement concerns about using the accelerated approval pathway that have followed in the neurology space since the FDA’s 2021 accelerated approval of Biogen’s Aduhelm (aducanumab-avwa) for Alzheimer’s disease.
“I think that the odds are extremely high that this drug works,” Weisman said. “I really worry about the consequences of an accelerated approval, maybe as a neurologist, where payers will not cover this drug and consider it experimental, which I think would be a big problem clinically.”
Michelle Mielke, chair of the Department of Epidemiology and Prevention at Wake Forest University, also believed the evidence was sufficient for regular approval.
“Certainly all of the data is not fully conclusive, but there are several aspects of the data that do suggest strong clinical evidence,” Mielke said. “My decision also weighed in the fact that this really is an unmet need and ALS is a very serious disease. So the fact that some people may be stalling in terms of their progression or possibly improving is very promising.”
During the open public hearing, the committee heard from 26 speakers, 22 of whom were patients, advocates, family members or health care professionals who favored approval. Many of these individuals spoke of the “intergenerational drama" and death resulting from the SOD1 mutation that has been passed down within families.
Many patients who testified said their conditions either stabilized or improved when they were taking tofersen as part of a clinical trial or through expanded access.