On October 17, Biogen announced that its expected antisense oligonucleotide treatment, Tofersen, did not reach its primary 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 associated with toxic effects on the motor neurons in the disease. Although Tofersen is being studied for a limited subset of ALS disease caused by SOD1 mutations, which account for only 2% of the total ALS population, this news is hugely disappointing, as the drug is thought to be the next groundbreaking treatment for this subset. of patients.
Key opinion leaders (COPDs), who have previously been interviewed by GlobalData, stated that despite the fact that Tofersen was aimed at a small population of ALS patients, Tofersen could pave the way for the increased development of precision medical approaches that offers disease-modifying benefits for specific genetic subgroups of ALS disease. Tofersen’s mechanism of action was highly respected by COPDs, but some had concerns about the drug’s ability to replicate positive results from previous trials in larger phase III trials, a fear that has since unfolded. This setback is likely to hinder Biogen’s planned application for FDA approval in the ALS market. However, it is possible that the company may take a similar approach as it did with its Alzheimer’s disease agent, 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 showed that patients after 28 weeks of treatment did not show 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 completely for its ALS program given several positive secondary and exploratory endpoints, including reduction of neurofilament (NF), a biomarker correlated with neurodegeneration, and SOD1 protein levels. In addition, the combined data from VALOR and the ongoing open-label extension section of the study indicated that Tofersen showed evidence of slower disease progression, especially in patients starting treatment early.
Despite the disappointing news, there is still a glimmer of hope for Tofersen and ALS patients with SOD1 mutations. First, as previously mentioned, it is possible that Biogen may still pursue FDA approval based on secondary endpoint data. In addition, patients may be able to receive treatment prior to approval through an ongoing early access program. Finally, as an early therapeutic intervention within the presymptomatic stage of ALS is thought to have a massive impact on treatment outcomes, Biogen is currently investigating the effect of Tofersen in delaying disease onset in the Phase III ATLAS study (NCT04856982). Although it is a promising direction for Tofersen, recruiting the right patients will continue to be a significant challenge due to the rarity of the disease and the limited subgroup of target patients.
Tofersen is the second high-profile pipeline asset to fail in a Phase III trial of ALS this year, following the failure of Orphazyme’s arimoclomol in May 2021. These errors capture the historic battle to develop disease-modifying treatments for this rare disease. The high error rate in ALS clinical trials can be attributed to the unclear etiology of the disease and the lack of specific biomarkers. Currently, the only available treatment options for ALS are Rilutek (riluzole) and Radicava (edaravon), none of which can stop or significantly slow the progression of the disease. Therefore, there are still significant opportunities for pharmaceutical companies to address.