Today April 25th, the US Food and Drug Administration (FDA) has approved Qalsody, a new drug for the treatment of a rare genetic form of ALS (Amyotrophic Lateral Sclerosis) developed by the biotechnology companies Biogen (Cambridge, Massachusetts) and Ionis Pharmaceuticals (Carlsbad, California). This decision is made one month after the favorable consensus reached by an independent advisory board regarding the controversial results of a clinical trial.

ALS is a neurodegenerative disease characterized by a progressive muscular paralysis following slow destruction of motor neurons in the nervous system. This disease often starts in the legs or the hands and spreads to other parts of the body until patients end up needing assisted ventilation at the final stage. Average life expectancy of ALS patients is three to five years from symptoms onset.

After several weeks of uncertainty, the FDA has decided to approve Qalsody (known scientifically as Tofersen) for the treatment of ALS, a resolution made following a positive decision of a committee of nine independent advisers to evaluate the inconclusive results of the phase III clinical trial that tested the drug. With the FDA thumbing up, Qalsody becomes the first treatment to target a genetic cause of ALS and fuels the debate over the clinical use of neurological drugs that have been approved before the confirmation of conclusive benefits. For this reason, Biogen will have to provide clinical evidence from ongoing trials to keep Qalsody on the market.

An accelerated approval that brings hopes to patients

Last March, a panel of nine independent advisers created by the FDA promoted the official approval. After the evaluation of Tofersen in a phase III clinical trial, the advisory board voted against the effectiveness of the drug to slow the progression of the disease in ALS patients (5-to-3 vote with one abstention). However, they agreed unanimously that Tofersen reduces neurofilament light chain (NfL) in plasma, a biomarker for neuronal damage that might determine the effectiveness of the drug in future trials of longer duration.

Tofersen is not the first case of a drug whose acceptance has been accelerated by the FDA. In 2021, the American organization approved aducanumab, a drug also developed by Biogen for the treatment of Alzheimer disease that divided the neuroscience community due to the absence of enough clinical evidence demonstrating its benefits. Nevertheless, given the low number of patients affected by this rare form of ALS (approximately 330 patients in the USA) and the difficulty to run and replicate small clinical trials, it is possible that some upcoming drugs targeting rare diseases will have to drive in the “fast lane” to reach the green light.

What is Qalsody ?

Qalsody is the brand name of Tofersen, an “antisense” drug that targets superoxide dismutase 1 (SOD1), a protein that becomes toxic in patients and induces neuronal degeneration. Tofersen binds to the messenger RNA of SOD1 and promotes its degradation, slowing the production of the protein. Approximately 2% of ALS cases are associated with mutations in SOD1.

Tofersen was tested in the “VALOR” phase III clinical trial on 108 SOD1-ALS patients, who followed a six-months treatment with either placebo or the actual drug. At the end of the study, the patients filled a questionnaire to evaluate changes in physical function over time. The results, published last year in the New England Journal of Medicine (NEJM), showed that severity in subjects treated with Tofersen did not improve better than in placebo recipients. However, patients following the Tofersen treatment exhibited a reduction in both SOD1 and NfL in plasma, which could be used as a biomarker to predict the effect of the drug in longer trials. In addition, an extension study of the “VALOR” trial in which all patients were given Tofersen revealed that six months might have been too short to observe improvements. Longer trials may shed more light on the effect of this new drug and its potential benefit for SOD1-ALS patients.

Original sources

Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, et al. Trial of Antisense Oligonucleotide Tofersen for. N Engl J Med. 2022;387(12):1099-110.

News release of Biogen (First resolution)

News release of Biogen (Final decision)

News release of the FDA (Approval of Qalsody)