The Friday Biotech Perspective #8
Genetic biomarkers steer progress in ALS
Amyotrophic lateral sclerosis (ALS) remains a mystery to researchers and the physicians tasked to treat the disease. Once diagnosed, ALS patients struggle to stay alive for five years. After the first symptoms appear, ALS progresses to quadriplegia and respiratory insufficiency within a few years.
Until the FDA approval of Amylyx Pharmaceuticals, Inc.’s (NASDAQ:AMLX) Relyvrio (sodium phenylbutyrate and taurursodiol) last year, there had not been a new drug approved to treat ALS in decades. The Relyvrio approval met with controversy, primarily because scientists and payers questioned the overall cost-benefit of the treatment. The controversy did not end after approvals in the US and Canada. In June 2023, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said clinical testing of Relyvrio did not “convincingly” demonstrate it slowed the worsening of ALS, signaling Relyvrio may not gain approval in Europe.
ALS researchers understand the disease progresses as motor neuron cells die. The two ingredients in Relyvrio appear to slow the pace of disease progression by reducing motor neuron cell death and inflammation. Several companies, however, are making progress by identifying more direct connections to ALS via gene mutations and biomarkers.
The FDA recently approved Qalsody (tofersen), a drug designed to treat ALS patients with a mutation in the SOD1 gene. Biogen, Inc. (NASDAQ:BIIB) and Ionis Pharmaceuticals, Inc. (NASDAQ:IONS) developed the drug. Toferson can only be sold to ALS patients with a SOD1 mutation that is confirmed by a lab test. The drug targets the mRNA produced from mutated SOD1 genes, thereby effectively reducing the synthesis of toxic SOD1 proteins that lead to the death of motor neuron cells.
Like Relyvrio, the approval of Qalsody represents a modest victory for ALS patients and their families. But other small companies and research efforts are tackling the disease through targeted ALS populations.
Wave Life Sciences (NASDAQ:WVE) developed its drug WVE-004 for ALS patients with C9orf72 gene mutations, a sub-group believed to account for 12% of the estimated 20,000 ALS patients in the US. Early data indicated WVE-004 reduced poly glycine-arginine repeat (polyGP) levels across all active treatment groups. PolyGP is a toxic protein produced by the C9orf72 gene mutation. In May, however, the company said WVE-004 did not show a clinical benefit when compared to the placebo group during phase Ib/IIa clinical trial.
COYA Therapeutics, Inc. (NASDAQ:COYA) fared better with its blood biomarker data study. COYA’s ALS drug, COYA 302, works to reduce inflammation by boosting the activity of regulatory T-cells, a type of anti-inflammatory immune cells also known as Tregs. The drug also simultaneously decreases the activity of pro-inflammatory immune cells. COYA Thera expects controlling neuroinflammation will act to “propagate neuronal injury in ALS,” according to investigators in the COYA 302 proof-of-concept (POC) trial. If COYA 302 promotes less neuronal injury, the disease will progress slower.
Throughout the POC trial for COYA 302, the company identified promising blood biomarkers which correlated to patient responsiveness to treatment with the drug. Last month, COYA Thera published confirmatory analyses of blood biomarker data from a cross sectional cohort of sporadic ALS patients (n=30) and healthy controls (n=10). The data revealed ALS patients demonstrated a strong correlation between a clinical response and levels of 4-HNE and inflammatory biomarkers monocyte chemoattractant protein-1 (CCL2) and interleukin (IL-18), validating the use of Treg-enhancing therapies, according to COYA Thera.
The biomarker data will inform COYA Thera which patients to recruit for future clinical trials. The company also is working with medical centers around the US who are conducting ALS studies.
While progress in ALS treatment certainly is not moving fast enough for patients and their families, the few recent sparks of understanding may improve treatment incrementally. Not surprisingly, the new approaches to ALS are being developed by smaller companies.