Ionis and Biogen Stop Development of ALS Drug After Trial Failure

Rare Daily Staff

Ionis Pharmaceuticals and Biogen said they were stopping development of BIIB105, an experimental antisense oligonucleotide for the treatment of the rare, neurodevelopmental condition amyotrophic lateral sclerosis, based on data from the phase 1/2 ALSpire study.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder that affects motor neurons, the nerve cells in the brain and spinal cord that control voluntary muscle movement and breathing. As motor neurons degenerate and die, they stop sending messages to the muscles, which causes the muscles to weaken, start to twitch, and waste away. Eventually, in people with ALS, the brain loses its ability to initiate and control voluntary movements such as walking, talking, chewing and other functions, as well as breathing.

BIIB105 was designed to reduce expression of ataxin-2 (ATXN2) protein and demonstrated statistically significant cerebrospinal fluid (CSF) ATXN2 protein reductions in the study. However, over the 6-month placebo-controlled period, treatment with BIIB105 did not result in a reduction in levels of plasma neurofilament light chain (NfL), a marker of neurodegeneration and neuronal damage. Additionally, BIIB105 did not demonstrate an impact on clinical outcome measures of function, breathing and strength.

“While BIIB105 lowered ATXN2 protein, it did not reduce neurofilament, which gives us confidence that BIIB105 did not slow the disease process,” said Stephanie Fradette, head of the Neuromuscular Development Unit at Biogen.

Longer-term biomarker and efficacy data from the open-label-extension were similar to those seen during the 6-month placebo-controlled treatment period, with sustained reductions in ATXN2 but no impact on NfL or clinical outcome measures over 40+ weeks of follow up. No evidence of benefit was observed in any subgroup evaluated, including those participants with a Poly-CAG expansion in the ATXN2 gene.

The phase 1/2 study was a randomized, placebo-controlled, dose-escalating trial to evaluate BIIB105 administered intrathecally to adults with ALS. Participants were randomized to receive BIIB105 or placebo (3:1 or 2:1 ratio) for 3 to 6 months. Participants who completed the placebo-controlled period were eligible to enroll in the open-label extension.

During the 6-month placebo-controlled portion of the study, the most common adverse events in BIIB105 treated participants were procedural pain, headache and fall. Adverse events leading to study discontinuation were higher in the BIIB105 group (8.3 percent) compared with the placebo group (3.6 percent).

Analyses of data from the study are ongoing to further understanding of the underlying disease process and effects of BIIB105. The companies will present the BIIB105 phase 1/2 data at the upcoming European Network to Cure ALS meeting in Stockholm, Sweden in June.

Ionis continues to advance its phase 3 ulefnersen program for people with the genetic form of the disease known as FUS-ALS. Biogen also markets Qalsody for SOD1-ALS, the first treatment to target a genetic cause of ALS, which was discovered by Ionis.

Photo: Stephanie Fradette, head of the Neuromuscular Development Unit at Biogen.