FDA Releases Briefing Docs for Upcoming Biogen/Ionis Tofersen Adcomm

 Biomarkers as a surrogate endpoint in ALS will go on trial March 22 as Biogen and Ionis’s tofersen faces the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee.

Tofersen, which Biogen licensed from long-time collaborator Ionis in 2018, is being developed to treat superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1) ALS.

A rare genetic form of the disease, few SOD1-ALS patients survive more than three years after diagnosis. It affects approximately 330 people in the U.S., according to Ionis.

Biogen is seeking accelerated approval of tofersen 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. They are increased in the blood and cerebrospinal fluid (CSF) when neurons or their axons have been damaged. An accepted marker of neurodegeneration, neurofilament has been gaining steam as a surrogate endpoint in neurodegenerative diseases.

FDA Briefing Documents

In guidance documents released Monday, the FDA raised concerns that were largely statistical in nature.

Key among these were:

• A regulatory review showed that the decline in both placebo and treatment groups was much less than expected, leading to what the FDA called a “greatly underpowered” study.
• The magnitude of the correlation between changes in neurofilament and changes on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALFRS-R) are “small in magnitude and may be influenced by potentially data-driven analysis choices."
• The Phase III VALOR trial did not provide evidence of an effect on clinical outcome, making it challenging to assess whether the drug's effect on the biomarker is reasonably likely to predict its effect on clinical outcome.

Despite this, the FDA appeared to be receptive to the idea of approving tofersen based on the existing data, even asking advisors to consider full approval for the drug and referring to regulatory flexibility. 

Given the extremely rare nature of SOD1-ALS, a second double-blind, placebo-controlled study in this population does not appear feasible, the FDA wrote. 

In its briefing documents, Biogen stated a Confirmatory Evidence Generation Plan could be based on the ATLAS study, which is currently enrolling. Data from this study are expected in 2027.

Biogen also intends to rely on real-world evidence, including natural history studies.

In a concluding paragraph, the FDA wrote that despite the notable limitations of the failed VALOR study, "The Division considers that the data may suggest a treatment effect of tofersen in SOD1-ALS."  

A Poor Statistical Plan

Tofersen flunked the VALOR trial in October 2021, missing the primary endpoint of improvement in disease activity from baseline as measured by the ALSFRS-R.

Angela Genge, M.D., chief medical officer at QurAlis, was the top recruiter for the tofersen program. Genge told BioSpace that the topline Phase III data did not meet clinical significance because of the ALSFRS-R. 

“It was the best that we had for a long time, but it has inherent issues with variability and a difference in certification…and administration of the scale,” she said.

Genge also pointed to how the study was powered, calling tofersen “a good drug with a poor statistical plan.” 

The primary endpoint for VALOR was the change from baseline to week 28 on the ALSFRS-R among faster-progressing patients. For this subgroup, the change from baseline was −6.98 with tofersen compared to −8.14 for the placebo group – a difference of 1.2 points that was not deemed statistically significant.

Genge said that the definition of a fast progressor changed between Phase I/II studies and the pivotal VALOR trial, leading to the placebo arm performing better than expected.

“When you take the full body of evidence, and you look at ALSFRS-R across all of the patients…and look at the other clinical outcome measures, it is obvious that this drug has a significant positive effect,” she said.

Merit Cudkowicz, M.D., chief of the Neurology Department at Massachusetts General Hospital, was the co-principal investigator on VALOR. She told BioSpace she is supportive of tofersen.

“The clinical effects follow neurofilament lowering and are of the type we have not seen previously in people with ALS,” she wrote in an e-mail.

Beyond Biomarkers

The New Drug Application for tofersen was not based on neurofilament alone. Integrated 12-month data from VALOR and an open-label extension (OLE) study showed that earlier initiation of the drug slowed the decline in clinical and respiratory function, strength and quality of life.

The benefit of earlier treatment was also reflected in the biomarkers, as patients in the early treatment group saw a 33% reduction in SOD1 protein compared to 21% in the delayed start (OLE) group. Similarly, the early-start group saw a 51% reduction in plasma neurofilament compared with 41% for OLE patients. 

When looking at outcomes of the normal progressors, particularly in the OLE, Genge said she has seen patients plateau.

“In clinic, this is what we're seeing. We are seeing patients not progress after five years.” 

Broader Implications

The guidance that emerges from Wednesday’s adcomm has implications beyond Biogen and Ionis.

QurAlis has a biomarker-driven strategy that combines an assay for stathmin-2 with neurofilament to provide evidence of target engagement. Encoded by the STMN2 gene, stathmin-2 is well-known for neural repair and axonal stability that is downregulated in nearly all people with ALS.

Genge said she could list ten clinical trials with robust biomarker plans relevant to their mechanism of action.

In March 2022, BrainStorm Cell Therapeutics presented new genetic data from the Phase III trial of its ALS candidate, NurOwn, that showed an association between possession of the UNC13A rs12608932 SNP risk allele and harmful effects of TDP-43.

TDP-43 has long been linked to ALS pathology.

Genge said the most important result from the tofersen program is neurofilament and using a biomarker to demonstrate valid disease modification before seeing the clinical benefit. 

“We've been waiting 30 years in ALS to have validated biomarkers that can show us efficacy and disease modification,” Genge said. “I really hope this is the beginning of a new era where biomarkers and precision medicine drive ALS therapeutics.”

In an e-mailed statement to BioSpace, Stephanie Fradette, PharmD, clinical development lead, Tofersen, and ALS portfolio head at Biogen, struck a similar tone:  

"Our hope is that the learnings from the tofersen program help move the field as a whole forward and increase the potential to have a biomarker in ALS." 

https://www.biospace.com/article/neurofilament-as-a-surrogate-endpoint-goes-on-trial-in-tofersen-adcomm/