Behind the Drug: Tofersen (Qalsody) for ALS

While most amyotrophic lateral sclerosis (ALS) cases are sporadic, meaning no known family history or genetic cause exists, around 10% are genetic. About 2% of those are caused by a superoxide dismutase 1 (SOD1) gene mutation. That equates to fewer than 500 out of the estimated 31,000 Americans currently living with ALS.

And yet, SOD1-associated ALS (SOD1-ALS) is the only type of ALS that has an approved therapy targeting the cause of the disease. Tofersen, marketed by Biogen under the brand name Qalsody, won U.S. Food and Drug Administration (FDA) approval in April 2023.

The story behind how Qalsody went from a concept in a lab to an approved therapy on the market shows that drugs for rare diseases and small patient populations can have a path forward.

What is tofersen (Qalsody)?

Scientists believe the SOD1 mutation causes cells to produce a defective form of the SOD1 protein that damages motor neurons.

Qalsody is a type of drug known as an It is administered in intrathecal (in the spine) doses and usually requires a maintenance dose every 28 days.

“It’s the first time a drug that targets the root cause of any type of ALS is available,” says Sharon Hesterlee, PhD, Chief Research Officer at MDA.

This milestone did not come about suddenly but was years in the making. “The timeline on tofersen goes back 30 years,” Dr. Hesterlee says.

1990s: Background work

MDA, which has spent more than $176 million on ALS research since the 1950s, helped finance the research of Robert H. Brown Jr, DPhil, MD, who discovered the SOD1 gene in 1993. The following year, Teepu Siddique, MD, developed the first ALS mouse model with MDA funding.

“Some background work had to happen,” Dr. Hesterlee says. “We needed to understand what mutation was involved. A mouse model needed to be made. That laid the groundwork for the drug development that came later.”

The drug compound that became Qalsody emerged in the early 2000s. Preclinical studies began in April 2004, where it was tested in multiple animal models of disease in Don Cleveland’s lab at the University of California, San Diego. In 2007, Timothy Miller, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri, launched the  . MDA contributed more than $1 million to support toxicology studies and a phase 1 trial of a therapy developed by Ionis Pharmaceuticals over five years.

2010s: Clinical trials

In 2011, MDA awarded funds to James Berry, MD, MPH, of Massachusetts General Hospital to conduct a phase 1/2 trial to assess the safety and efficacy of the Ionis therapy and build upon the prior study. Finally, in 2018, Biogen exercised its option to acquire the Ionis compound and develop a second-generation version of the SOD1 therapy, which was named tofersen.

In the 2022 VALOR open-label extension study, tofersen reduced SOD1 levels by 35% compared to 2% with placebo in cerebrospinal fluid. The 2022 ATLAS study is also used to assess presymptomatic ALS patients and serves as the confirmatory trial for the accelerated approval of tofersen, which the FDA approved in April 2023. The drug costs around $100,000 per year.

Real-world impact

Qalsody has made a real difference in the lives of many people with SOD1-ALS. Blaine Dangel, 40, of New York City, is one of them.

In 2014, she developed a faintly painful limp while walking around the city. As her limp worsened over the next few years, the software developer consulted a series of orthopedic specialists and neurologists, but nobody could find the cause. Finally, a specialist recommended reconstructive surgery for flat feet. After a second opinion confirmed that suggestion, Blaine got the surgery and spent a full year off her feet.

“I never fully recovered, and at that point, my mom, who had progressive neurological disease for the last 15 or 20 years, also started talking about surgery,” she says.

Realizing that their conditions might be related, Blaine’s mom got genetic testing and learned she has SOD1-ALS, which is known to be passed down in an autosomal dominant inheritance pattern. Blaine soon received the same diagnosis as her mother.

After her diagnosis, Blaine signed up to participate in the Families Project, a research study for asymptomatic carriers of SOD1-ALS at New York’s Columbia University. She learned that she was showing symptoms of the disease that she hadn’t recognized, and within a month, she was allowed into the expanded access program (EAP) for tofersen, which was not yet FDA-approved.

“The path of diagnosis is scary for a lot of people, but because I went so quickly from being diagnosed to having a treatment option, there was never a long period of time where nothing was available,” Blaine says.

Her doctor warned her that the experimental drug might halt or slow her progression but was not likely to restore lost strength. Yet, about three months after starting on tofersen, Blaine did start seeing some progress.

“I was doing physical therapy at the time and was also measuring my strength and calf size,” she says. “It was growing, and the amount of exercise I was able to do was increasing.”

Unfortunately, after a year and a half on tofersen, Blaine got meningitis following her last lumbar puncture, and her doctors recommended discontinuing the drug. But she’s grateful for the time on the drug when her disease did not progress and even improved. “Tofersen reset the clock for me,” she says. “It bought me time to live, and it brought me hope about the other drugs out there in trials right now — not just for SOD1 but for everyone with ALS.”

While numbers of people taking Qalsody have not yet been reported, studies estimate that a little over 300 people in the U.S. live with SOD1-ALS. In addition, Europe received approval for Qalsody in May 2024, and Biogen reported that 330 people with confirmed SOD1-ALS received Qalsody across 18 European countries through their early access program. In alignment with new European Academy of Neurology (EAN) guidelines, patients with a confirmed genetic diagnosis should be offered Qalsody as a first line of treatment.

Improvements in ALS patients taking Qalsody have been observed, but are mostly reported anecdotally. Based on clinical trials, earlier initiation of Qalsody has been associated with slower declines in functional measures (ALSFRS-R) and muscle strength.