Biogen and Ionis Discontinue ALS Program After Phase 1 Study Results Show No Clinical Benefit

Rare Daily Staff

Biogen and Ionis Pharmaceuticals said they are discontinuing the clinical program for the antisense oligonucleotide for C9orf72-associated amyotrophic lateral sclerosis because it did not show clinical benefit in a phase 1 study of BIIB078 (IONIS-C9Rx), an investigational antisense oligonucleotide (ASO) for people with C9orf72-associated amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is a rare and fatal condition that affects motor neurons (a type of nerve cell that controls voluntary movements) in the brain and spinal cord. When the nerve cells die, the brain can no longer initiate and control muscle movement, which results in severe disability, paralysis and eventually death.

People with ALS may lose the ability to speak, eat, move and breathe. The rate of progression between individuals is variable and the natural history generally reflects progressive worsening over time until death occurs. The average life expectancy from symptom onset is between two and five years. Currently approved medications may slow disease progression, but ALS management is mostly supportive, palliative and symptom based.

The phase 1 study was a randomized, placebo-controlled, dose-escalating trial to evaluate BIIB078 (IONIS-C9Rx) administered intrathecally to adults (n=106) with C9orf72-associated ALS. Within each of the six study treatment cohorts, participants were randomized to receive BIIB078 or placebo (3:1 ratio). The primary objective of the study was to assess safety and tolerability. Secondary efficacy endpoints included ALS Functional Rating Scale–Revised, Slow Vital Capacity, Hand-Held Dynamometry, and the Iowa Oral Pressure Instrument.

In the phase 1 study, BIIB078 was generally well-tolerated. The adverse events were mostly mild to moderate in severity and occurred at a similar rate across BIIB078 and placebo groups. The most common adverse events were fall, procedural pain, and headache.

BIIB078 did not meet any secondary efficacy endpoints and it did not demonstrate clinical benefit. In the dose cohorts up to 60 mg there were no consistent differences between the BIIB078 group and the placebo group. Participants in the BIIB078 90 mg dose cohort trended toward a greater decline than those in the placebo group across secondary endpoints. Based on these results, the BIIB078 clinical development program will be discontinued, including its ongoing open-label extension study.

“While these were not the results we were hoping for, they are clear and will inform future research across our broad pipeline of investigational ALS therapies,” said Toby Ferguson, vice president and head of the Neuromuscular Development unit at Biogen. “We remain focused on pioneering new treatments that will positively impact people living with this debilitating disease.”

“C9orf72-associated ALS is a complex genetic form of ALS and there are multiple mechanisms by which the scientific community believes the C9orf72 gene causes disease. We designed BIIB078 to test the prevailing hypothesis that the mechanisms of disease for C9orf72-associated ALS were caused by toxicity associated with the repeat containing RNA and corresponding dipeptides. Unfortunately, this phase 1 study did not support the hypothesis, suggesting that the disease mechanism is much more complex. While these results do not support further development of BIIB078, we anticipate they will provide valuable learnings that lead to a deeper understanding of this form of ALS,” said C. Frank Bennett, executive vice president, chief scientific officer and franchise leader for Neurological Programs at Ionis.

The companies will present the BIIB078 phase 1 data at a future scientific forum.

Photo: C. Frank Bennett, executive vice president, chief scientific officer and franchise leader for Neurological Programs at Ionis