On October 17, Biogen announced that its anticipated antisense oligonucleotide therapy, Tofersen, failed to achieve its primary efficacy endpoint in the Phase III VALOR study (NCT02623699) for amyotrophic lateral sclerosis (ALS). Tofersen inhibits the production of mutant superoxide dismutase 1 (SOD1) protein, which is linked to toxic effects on the motor neurons in the disease. Although Tofersen is being studied for a limited sub-group of ALS disease caused by SOD1 mutations, accounting for only 2% of the total ALS population, this news is hugely disappointing as the drug was believed to be the next breakthrough therapy for this subset of patients.

Key opinion leaders (KOLs) previously interviewed by GlobalData stated that despite targeting a small population of ALS patients, Tofersen could pave the way for the increased development of precision medicine approaches that offer disease-modifying benefits for specific genetic subsets of ALS disease. Tofersen’s mechanism of action was highly regarded by KOLs, but some had concerns about the drug’s ability to replicate positive results from earlier trials in larger Phase III trials, a fear which has since played out. This setback will likely hinder Biogen’s planned filing for FDA approval in the ALS market. However, it is possible the company may take a similar approach as it did with its Alzheimer’s disease asset, Aduhelm (aducanumab), and still pursue an accelerated approval using some modestly encouraging data from the secondary endpoints of the trial.

Topline results from the Phase III VALOR study demonstrated that after 28 weeks of therapy, patients did not demonstrate statistically significant improvements in the primary endpoint assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) compared to placebo. However, Biogen insists that the company will not close the door entirely on its ALS programme considering multiple positive secondary and exploratory endpoints, including the reduction of neurofilament (NF), a biomarker correlated with neurodegeneration, as well as SOD1 protein levels. Additionally, the combined data from VALOR and the ongoing open-label extension portion of the study suggested that Tofersen showed signs of slowing disease progression, particularly in patients who started treatment early.

Despite the disappointing news, a glimpse of hope remains for Tofersen and ALS patients with SOD1 mutations. Firstly, as mentioned previously, it is possible that Biogen may still pursue FDA approval based on secondary endpoint data. Additionally, patients may be able to receive the treatment prior to approval via an ongoing early access programme. Finally, as an early therapeutic intervention within the pre-symptomatic stage of ALS is thought to massively impact therapy outcomes, Biogen is currently exploring the efficacy of Tofersen in delaying disease onset in the Phase III ATLAS trial (NCT04856982). Although a promising direction for Tofersen, recruiting the right patients will remain a significant challenge, due to the rarity of the disease and the limited subset of target patients.

Tofersen is the second high-profile pipeline asset to fail a Phase III trial for ALS this year, following the failure of Orphazyme’s arimoclomol in May 2021. These failures capture the historical struggle to develop disease-modifying treatments for this rare disease. The high failure rate in ALS clinical trials may be attributed to the disease’s unclear etiology and lack of specific biomarkers. Currently, the only treatment options available for ALS are Rilutek (riluzole) and Radicava (edaravone), neither of which can stop or significantly slow the progression of the disease. Therefore, significant opportunities remain for pharmaceutical companies to address.

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