Committee favors EU approval of Qalsody for adults with SOD1-ALS

Decision, expected by June, could make therapy 1st in Europe for rare ALS form

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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An advisory committee of the European Medicines Agency (EMA) has recommended that Biogen’s Qalsody (tofersen) be approved in the European Union under exceptional circumstances to treat adults with amyotrophic lateral sclerosis (ALS) associated with SOD1 gene mutations.

The positive opinion from the Committee for Medicinal Products for Human Use, known as CHMP, is based on clinical and biomarker data from the Phase 1/2/3 VALOR clinical trial (NCT02623699), which altogether tested Qalsody in more than 175 patients. Overall, the treatment candidate led to a 60% reduction in blood levels of neurofilament light chain (NfL), a marker of nerve cell damage.

An approval under exceptional circumstances can be recommended for therapies with a positive risk-benefit, but where comprehensive data are unlikely to be obtained given the rarity of the disease. The recommendation now will be reviewed by the European Commission, with a decision expected between April and June.

If approved, Qalsody will become the first therapy authorized in the European Union to target a genetic cause of ALS.

“The CHMP’s positive opinion reinforces the impact Qalsody can have in SOD1-ALS and further demonstrates Biogen’s commitment to address the unmet needs of people living with ALS and neuromuscular diseases,” Priya Singhal, MD, Biogen’s head of development, said in a company press release.

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Qalsody approved in US in 2023, also for use in adults

In the U.S., Qalsody early last year was granted conditional approval to treat adults with SOD1-ALS. The U.S. Food and Drug Administration’s decision also marked the the first conditional approval of a treatment for this form of ALS in that country.

Per the medication’s label, injections are given monthly into the spinal canal, or intrathecally, following three initial doses given two weeks apart.

Experts welcomed the positive opinion from the CHMP.

“This is a significant milestone for the entire ALS community — for the first time we have a treatment that led to sustained reductions in neurofilament, a marker of [nerve cell] injury and neurodegeneration,” said Philip Van Damme, MD, PhD, professor of neurology and director of the Neuromuscular Reference Center at the University Hospital Leuven, in Belgium.

Mutations in the SOD1 gene are found in as many as 20% of people with familial ALS and up to 2% of people with sporadic ALS, where there’s no known family history of the disease. Such mutations result in a toxic form of the SOD1 protein, which is prone to form toxic clumps that accumulate and damage nerve cells.

This is a significant milestone for the entire ALS community — for the first time we have a treatment that led to sustained reductions in neurofilament, a marker of [nerve cell] injury and neurodegeneration.

To produce the SOD1 protein, SOD1‘s genetic code is used to form an intermediate molecule called messenger RNA, or mRNA. The mRNA then is shipped from the nucleus to the cell’s protein-making machinery, where it is used as a template for making SOD1.

Qalsody belongs to a class of therapies called antisense oligonucleotides (ASOs), and is designed to bind to SOD1‘s mRNA and promote its degradation. That allows it to halt the production of the mutated SOD1 protein. By doing so, the therapy is expected to reduce toxic SOD1 clumps, slow disease progression, and potentially extend survival in SOD1-ALS patients.

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Treatment found to slow ALS progression in VALOR study

The three-part VALOR study, started in 2016, investigated Qalsody in a total of 176 ALS patients carrying SOD1 mutations.

In its Phase 1/2 parts, the therapy — then still known as tofersen — was found to be generally safe and well tolerated when given in single or multiple ascending doses. It also was shown to have the ability to reduce SOD1 and NfL levels in the spinal fluid.

The Phase 3 part then enrolled 108 patients who were randomly assigned to receive eight intrathecal injections of Qalsody (100 mg), or a placebo, given over six months. The main goal of this part was to assess changes in functional disability among the 60 patients with rapidly progressing ALS, after 28 weeks, or about seven months.

While the trial failed to meet its goal, trends supporting Qalsody were observed in some secondary measures, including muscle strength, quality of life , and lung function. Also, the medication resulted in marked drops in blood NfL levels — by 60% compared with a placebo.

After completing VALOR, participants could enter an open-label extension study (NCT03070119), which is still ongoing, wherein all are receiving Qalsody for up to seven years.

One-year data including the Phase 3 trial and the extension study showed the treatment led to a significant and clinically meaningful slowing of ALS progression. Specifically, those who started on the medication in VALOR had a 6-point decline in ALS Functional Ratings Scale-Revised (ALSFRS-R) scores versus a 9.5-point decline for those who were initially on a placebo.

The most common side effects in Qalsody-treated patients included muscle and joint pain, fatigue, fever, and increased levels of white blood cells and proteins in the spinal fluid.

The therapy now is also being tested in the ATLAS Phase 3 trial (NCT04856982). That global study is evaluating whether Qalsody can delay the onset of ALS symptoms in patients with a SOD1 mutation who already show signs of neuronal damage, as defined by elevated NfL levels. It’s slated to run through 2027.

“We are proud to help pioneer the role of neurofilament in SOD1-ALS clinical trials and are deeply grateful to the people living with SOD1-ALS, their loved ones and study care teams for their dedication to furthering research for the ALS community,” Singhal said.