ALS Nexus 2026: Experimental therapy shows early promise in SOD1-ALS
Trial data show decreases in key protein, decline in markers of nerve cell damage
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- ALN-SOD is an experimental RNA-based therapy targeting SOD1-ALS, a genetic subtype of ALS.
- Early Phase 1b/2 trial data show treatment reduces SOD1 protein levels and lowers markers of nerve cell damage.
- The therapy was generally well-tolerated and offers a promising alternative requiring less frequent dosing than existing options.
ALN-SOD, an experimental RNA-based therapy being developed for a genetic subtype of amyotrophic lateral sclerosis (ALS) called SOD1-ALS, showed an “encouraging” safety profile and preliminary signs of potential efficacy, according to early results from a Phase 1b/2 study.
Biomarker data from participants in the first-in-human Phase 1b/2 GOALS study (NCT06351592) showed decreases in a protein that forms abnormal aggregates in SOD1-ALS that are believed to contribute to the progressive nerve degeneration seen in people with the disease. Markers of nerve cell damage also declined with treatment, which was generally well-tolerated.
Findings from the Phase 1b/2 study were presented by Oren Levy, MD, PhD, senior medical director of Regeneron Pharmaceuticals, during an oral presentation at the ALS Nexus conference, held earlier this week in Orlando, Florida, and online. The presentation is titled “ALN-SOD: An siRNA targeting SOD1 for the treatment of SOD1-ALS.” Regeneron is developing ALN-SOD for SOD1-ALS in collaboration with Alnylam Pharmaceuticals.
“The trial continues to progress,” Levy said during the presentation. “We’re following those patients and recruiting more patients so that we can better understand the drug.”
ALN-SOD aims to reduce SOD1 protein production
ALS is a neurological disorder that affects nerve cells involved in the control of muscle movements. Although its underlying causes are often unclear, some people with ALS have genetic mutations that are known disease drivers.
Mutations in the SOD1 gene cause SOD1-ALS, one of the more common genetic subtypes of ALS. Researchers believe these mutations lead to problems with the shape of the SOD1 protein, causing it to start forming toxic aggregates that kill nerve cells over time.
Currently, the main treatment option for SOD1-ALS is Qalsody (tofersen), a medication that gained accelerated approval in the U.S. This RNA-based therapy is administered through an injection into the spinal canal (intrathecal injection) and uses genetic molecules called antisense oligonucleotides to reduce the amount of SOD1 protein being produced.
However, Qalsody’s monthly dosing schedule and associated risk of neuroinflammation may be drawbacks for some people with SOD1-ALS.
ALN-SOD uses a different type of genetic molecule, called small interfering RNA or siRNA, to reduce SOD1 protein production.
“Once the siRNA gets into cells, it can basically hop on [the] pathway that the cell uses as part of its everyday business to modulate and regulate expression of different proteins,” Levy said.
Analysis shows decrease in protein levels
In addition to requiring less frequent dosing and being associated with a lower risk of neuroinflammation, ALN-SOD could potentially offer stronger clinical benefit than Qalsody, according to Levy.
Preclinical studies in nonhuman primates showed that a single intrathecal dose of the therapy led to substantial, lasting decreases in SOD1 messenger RNA (mRNA) levels in the brain and spinal cord. SOD1 protein levels also decreased in the animals’ cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord. Of note, mRNA is the molecule that cells normally use as a template for protein production.
Based on these findings, the developers designed the GOALS study, which involves several small groups of participants receiving intrathecal doses of ALN-SOD every six months. If one group tolerates the therapy well, the next group receives a slightly higher dose.
These degrees of NfL reduction are really not something that you would see in the natural history of disease. [This finding is] strongly encouraging and indicative that we’re having an effect on neuronal damage.
To date, the trial has involved three groups, with three participants each. Participants in the first group started at a low dose, and then received an intermediate dose for their second and third doses of ALN-SOD. Those in group two have received two intermediate doses thus far, and those in group three have received one higher dose. Dosing will continue for up to four years.
CSF analysis conducted 12 weeks after the first ALN-SOD dose showed a decrease in SOD1 levels. Participants in group one, who had received the lowest dose, had a 19% decrease. In comparison, the highest-dose group had a more substantial 42% decrease in SOD1 levels.
Additionally, CSF levels of neurofilament light chain (NfL), a marker of nerve damage, decreased by at least 50% in all three groups at week 16.
“These degrees of NfL reduction are really not something that you would see in the natural history of disease,” Levy said, adding that the finding is “strongly encouraging and indicative that we’re having an effect on neuronal damage.”
Regeneron investigating siRNA-based therapies for other diseases
Researchers also assessed changes in clinical status. Scores on the ALS Functional Rating Scale-Revised, which evaluates the functional decline associated with ALS progression, remained relatively stable. So did slow vital capacity, a measure of respiratory function.
“It’s [a] very small number of patients, very early days, but again we’re seeing very little decline over time,” Levy said, adding that these observations are “very encouraging.”
Levy also said that “thus far, the safety profile looks encouraging.”
Most side effects were mild and resolved without treatment. However, four participants experienced serious side effects — two had serious complications related to intrathecal injection, one had a ruptured hemorrhoid that caused bleeding in the gastrointestinal tract, and one developed pneumonia. None of these were directly related to ALN-SOD, however.
Safety data also supported the researchers’ hypothesis that ALN-SOD may pose a lower risk of neuroinflammation compared with Qalsody. Although there were some spikes in inflammatory markers immediately after dosing, these resolved quickly.
As the GOALS trial continues, Regeneron is also investigating similar siRNA-based therapies for other diseases that cause nervous system damage.
“We’re now trying to use this [siRNA] platform to address multiple neurodegenerative diseases that are due to accumulation or buildup of toxic [protein] aggregates,” Levy said.
Note: The ALS News Today team is providing virtual coverage of the ALS Nexus Conference Aug. 23-26. Go here to see the latest stories from the conference.
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