Dozens of gene mutations associated with amyotrophic lateral sclerosis have been identified. Drug developers have homed in on a trio of genes.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative, fatal disease affecting motor neurons that control voluntary muscle movement. Initial symptoms can include muscle cramping, twitching, stiffness or weakness. As the disease worsens, people with ALS typically experience difficulties with speech, chewing and swallowing. In advanced ALS, there is muscle atrophy and paralysis. The average survival is 3 to 5 years after diagnosis, with respiratory failure being the most common cause of death.
Although ALS is rare, about 5,600 people in the United States receive a diagnosis each year, and more than 30,000 Americans are living with ALS. Most cases of ALS are considered sporadic, meaning there is no known risk factor or family history of the disease. But a sizable minority of cases — between 5% and 10%— fitintoa family pattern.
The cause of ALS is not fully understood. However, researchers know certain gene mutations are responsible for approximately two-thirds of the familial ALS cases and 10% of sporadic cases. ALS has no cure; treatment focuses on managing symptoms and prolonging survival.
In 2017, the FDA approved Radicava (edaravone), making it the first new drug approved specifically to treat ALS since Rilutek (riluzole) was introduced in 1995. In September 2022, the FDA approved Relyvrio (sodium phenylbutyrate and taurursodiol) as an ALS treatment. Developed by Amylyx Pharmaceuticals, based in Cambridge, Massachusetts, Relyvrio is designed to slow or prevent neuronal death by simultaneously blocking cellular death pathways in both the mitochondria and endoplasmic reticulum of motor neurons.
The FDA’s green light was based on results from the CENTAUR phase 2 trial, published in the New England Journal of Medicine in 2020. Study results showed that Relyvrio significantly slowed decline in function after six months compared with placebo and prolonged survival by about 6 1⁄2 months. Although the FDA granted the drug approval based on phase 2 trial data, Amylyx is continuing the PHOENIX phase 3 trial. That study is designed to enroll 600 participants and is intended to evaluate the drug’s safety and efficacy in slowing functional decline and improving survival over 12 months. Preliminary results are expected to be reported later this year.
Gene therapy pipeline
In 1993, researchers discovered that a mutation in the SOD1 gene is responsible for some cases of familial ALS. Since then, at least
a dozen other gene mutations associated with ALS have been discovered. Researchers now believe that about 25% to 40% of familial ALS is caused by a mutation in the C9orf72 gene. An additional 12% to 20% of familial ALS cases and 1% to 2% of sporadic cases are due to a defect in the SOD1 gene. A mutation in the FUS gene is the most common cause of juvenile-onset ALS. Research in ALS gene-targeted therapy that could potentially correct genetic mutations is underway.
Biogen in front
Biogen, headquartered in Cambridge, Massachusetts, in partnership with Ionis Pharmaceuticals in suburban San Diego, is leading the way in gene therapy for ALS.
The company has completed the phase 3 VALOR trial investigating the use of tofersen, an antisense oligonucleotide, in patients with ALS and SOD1 mutations. The SOD1 gene encodes the production of the protein superoxide dismutase 1 (SOD1), which helps eliminate toxins from the brain. In people with ALS related to the SOD1 gene, defective SOD1 proteins fail to clear toxins and instead aggregate in motor neurons and cause nervous system damage.
Tofersen uses antisense oligonucleotide technology to block cells from reading messenger RNA (mRNA) instructions to make defective SOD1 proteins. Results from the VALOR trial were published in the New England Journal of Medicine and presented at the annual meeting of the American Neurological Association in October 2021.
The VALOR study enrolled 72 participants who were randomized to receive an intrathecal injection (into the cerebrospinal fluid) of tofersen or a placebo. After completing the trial, participants had the option to continue treatment through the ongoing open-label extension study.
The VALOR trial did not meet its primary end point of slowing functional decline at week 28. Some secondary end points were reached, including reduced SOD1 protein levels in the cerebrospinal fluid and a reduction in plasma concentration of neurofilament light chain, a marker of neuron degeneration. Further analysis from the VALOR and open-label extension study showed that individuals who started tofersen earlier had slower functional decline than those who received placebo.
Biogen announced in July 2022 that the FDA had accepted a new drug application for tofersen based on the VALOR trial results. The agency is expected to announce whether it has approved the drug later this month. Meanwhile, Biogen is continuing the phase 3 open-label ATLAS study to evaluate the drug’s ability to delay ALS onset in pre-symptomatic individuals with an SOD1 gene mutation. Tofersen is available through an early access program for patients with SOD1 ALS.
Named for a patient
Ionis Pharmaceuticals is recruiting participants 12 and older with ALS and confirmed FUS gene mutation for a phase 3 trial. The FUS gene encodes the production of FUS proteins, which help repair DNA damage. In people with FUS gene mutations, defective proteins are made. They accumulate in the brain and spinal cord and lead to neurotoxicity. ALS associated with FUS gene mutation typically affects younger individuals and tends to progress quickly.
Ionis’ drug, ION363, is also called jacifusen and is named after Jaci Hermstad, an Iowa woman who received a diagnosis of FUS-ALS when she was 25, eight years after her twin sister, Alex, died from the disease. Neil Schneider, M.D., Ph.D., director of the Eleanor and Lou Gehrig ALS Center at Columbia University worked to find a treatment specifically for Hermstad and later collaborated with Ionis to further develop the drug. Jaci Hermstad died in 2020.
Like tofersen, ION363 is an antisense oligonucleotide that blocks FUS mRNA instructions for FUS protein production to potentially slow or prevent disease progression. The treatment is in a phase 3 trial led by Schneider. The first part of the trial will randomize participants to receive ION363 or placebo for 29 weeks. The second part will be an open-label study in which all participants will receive the investigational treatment for 73 weeks. The trial’s primary outcome is the change in the rate of functional decline from day 1 to day 225. Results are not expected to be reported until June 2025.
The third target
Alector, a San Francisco-based biotech company, in collaboration with GlaxoSmithKline, is developing a potential first-in-class agent targeting C9orf72 gene mutations. Research has shown that decreased levels of the protein progranulin and C9orf72 gene mutations are linked to abnormal aggregation of the TAR DNA-binding protein 43 (TDP-43) in brain cells, which is thought to lead to nerve cell death. The vast majority (95%) of people with ALS have abnormal TDP-43 protein aggregation.
AL001 is a human monoclonal antibody designed to increase progranulin levels, thus preventing TDP-43 clump formations. The candidate is in a phase 2 trial enrolling participants with ALS and confirmed C9orf72 mutation. The trial will evaluate the safety and tolerability of AL001 as well as the concentration of progranulin in participants’ plasma and cerebrospinal fluid. Results are anticipated in February 2023.
Rosanna Sutherby, Pharm.D., is an independent medical writer and community pharmacist in High Point, North Carolina, and a regular contributor to Managed Healthcare Executive ®.