WuXi AppTec Content Team Editor
Tomorrow, the US FDA will convene an external panel of experts to discuss whether the clinical trial data of Amylyx’s investigational therapy AMX0035 in patients with amyotrophic lateral sclerosis (ALS) support its regulatory approval. This investigational therapy has received a lot of attention from the industry and the ALS patient community because there are currently only two FDA-approved therapies in the ALS disease area, and they do not significantly alter the course of the disease. For this 100% fatal disease, patients urgently need innovative treatment options.
When it comes to ALS, readers may have heard of the “Ice Bucket Challenge,” a fundraiser that once swept social media and sparked awareness of ALS (aka ALS) focus on. Famous physicist Professor Hawking once fought bravely against ALS for a long time. The motor neurons in the brain and spine of people with this disease continue to die, resulting in muscle weakness and paralysis, ranging from the inability to walk to the inability to speak, swallow, and breathe. People with ALS live an average of only four years after diagnosis.
Although ALS was discovered more than 150 years ago, its pathogenesis is still not fully elucidated. Gene mutations are associated with about 10% of patients, and environmental factors are also believed to play a role. important role. This adds to the challenge of developing targeted therapies because the pathogenesis is unclear.
▲Joshua Cohen (right) and Justin Clay (left) (Photo source: Amylyx official website)
Amylyx’s AMX0035 was born out of the thoughts of two college students, Joshua Cohen and Justin Klee, in their college dorm room. Their idea was that although scientists have not been able to identify the root cause of nerve cell death due to the complexity of the nervous system, Since nerve cell death is associated with the clinical progression of the disease, can they find a way to Delay the process of nerve cell death?
That’s how AMX0035 was born,it contains two ingredients – sodium phenylbutrate and taurursodiol. In neurodegenerative diseases, mitochondria and endoplasmic reticulum are often abnormal in nerve cells. Mitochondria are the “energy centers” of cells, while the endoplasmic reticulum is the “factory” for the production of various proteins. Disorders of these two types of organelles can lead to protein folding errors, abnormal energy metabolism and other problems, resulting in the death of nerve cells. Amylyx’s vision is to delay nerve cell death by improving the health of mitochondria and endoplasmic reticulum in cells with these two drugs. They have the advantage of being FDA-approved for other diseases and therefore have a proven safety profile. When Amylyx first started, the two co-founders were only 21 and 22 years old.
In a phase 2 clinical trial, patients treated with AMX0035 showed a reduction in mean scores compared with placebo after 24 weeks using the ALSFRS-R score, a composite measure of daily functioning in patients with ALS The magnitude is significantly reduced. The study has been published in the New England Journal of Medicine. “Even a two-point change in score can be a significant change in a patient’s daily life,” said Dr. Sabrina Paganoni of Massachusetts General Hospital, who led the clinical study. “The two-point difference Means the difference between being able to eat successfully and needing to use a feeding tube, or the difference between being able to walk and needing to use a wheelchair.”
Additionally, AMX0035 reduced the risk of death in patientsby 44% in a long-term follow-up study. Amylyx’s press release states that this is the first ALS therapy to simultaneously extend life and improve motor function in patients in a randomized, controlled clinical trial. Late last year, its new drug application was granted priority review status by the U.S. FDA. It is worth mentioning that Amylyx is already conducting a confirmatory phase 3 clinical trial, planning to test the effect of AMX0035 in 600 ALS patients, and the trial results are expected to be available in 2024.
In addition to AMX0035, according to incomplete statistics, there are more than 100 innovative therapies in the ALS R&D pipeline that have entered the clinical development stage. Several innovative therapies are expected to reach development milestones in 2022, including Biohaven Pharmaceuticals’ myeloperoxidase (MPO) inhibitor verdiperstat, which reduces microglial activation and reduces ALS Neuroinflammation in patients. CNMAU-8, developed by Clene Nanomedicine, is a gold nanocrystal suspension that has neuroprotective and remyelin-promoting effects. Prilenia Therapeutics’ S1R agonist pridopidine is also a dopamine D2 receptor antagonistagent. It has effects such as enhancing neuroprotection and neuroplasticity. These therapies are expected to receive Phase 2/3 clinical trial results this year.
In addition, Wave Life Sciences’ WVE-004 is an antisense oligonucleotide (ASO) therapy for the treatment of C9orf72-related ALS. Eledon Pharmaceuticals’ monoclonal antibody AT-1501 blocks CD40 ligand-mediated signaling, potentially improving muscle function and delaying disease progression. These therapies are expected to receive early clinical trial results this year.