Selonsertib is an investigational small molecule drug designed to address conditions characterized by inflammation and tissue scarring. It belongs to a class of compounds known as apoptosis signal-regulating kinase 1 (ASK1) inhibitors. This compound has been explored as a potential treatment for various diseases where oxidative stress contributes to disease progression.
How Selonsertib Works
Selonsertib functions by inhibiting apoptosis signal-regulating kinase 1 (ASK1), a protein that plays a role in cellular responses to stress. ASK1 is a type of enzyme called a kinase, and it is involved in signaling pathways that can lead to inflammation, programmed cell death (apoptosis), and the formation of fibrous tissue, known as fibrosis.
When the body experiences oxidative stress, ASK1 can become overactive, contributing to disease processes. By blocking ASK1, selonsertib aims to disrupt these harmful signaling pathways. This inhibition can potentially reduce inflammation, prevent excessive cell death, and limit the accumulation of scar tissue, thereby mitigating disease progression.
Selonsertib achieves its inhibitory effect by competing with adenosine triphosphate (ATP) in the catalytic domain of the ASK1 enzyme. This competition prevents ASK1 from functioning properly, thereby suppressing its downstream signaling, which includes pathways like p38 and c-Jun N-terminal kinase (JNK). This action is thought to contribute to its anti-fibrotic and anti-inflammatory properties.
Conditions Selonsertib Addresses
Selonsertib has been investigated for its potential to treat several medical conditions, particularly those involving fibrosis and inflammation. A primary focus of its research has been nonalcoholic steatohepatitis (NASH), a progressive liver disease characterized by fat accumulation, inflammation, and scarring of the liver. NASH can lead to severe liver damage, including cirrhosis and liver failure.
For NASH, selonsertib was explored because ASK1 is overactivated in liver injury and contributes to fibrosis progression. The drug was thought to potentially reduce hepatic steatosis (fatty liver), inflammation, and fibrosis in patients.
Beyond NASH, selonsertib has also been evaluated for its effects in other fibrotic diseases. This includes conditions like diabetic nephropathy, which involves kidney fibrosis, and acute liver failure (ALF). In models of ALF, selonsertib showed promise in protecting against liver injury.
The rationale for investigating selonsertib in these diverse conditions stems from ASK1’s common role in promoting inflammation and fibrosis in response to oxidative stress.
Current Research and Status
Gilead Sciences developed selonsertib, which progressed through Phase 2 and Phase 3 clinical trials.
In Phase 2 trials for NASH, selonsertib showed promising anti-fibrotic activity, with patients improving in fibrosis stage and other liver injury measures after 24 weeks. However, results from the larger Phase 3 clinical trials, STELLAR-3 and STELLAR-4, were not as favorable.
The STELLAR-3 trial (patients with bridging fibrosis F3 due to NASH) did not meet its primary endpoint of fibrosis improvement at week 48. Similarly, the STELLAR-4 study (patients with compensated cirrhosis F4 due to NASH) also failed to meet its primary endpoint. In both Phase 3 trials, the proportion of patients achieving the primary endpoint was similar between selonsertib and placebo groups. As a result, selonsertib is no longer under active development as a monotherapy for NASH.
Potential Side Effects
In clinical trials for selonsertib, adverse event rates and types were generally similar between selonsertib and placebo groups. This suggests the drug was well-tolerated.
While specific common side effects are not extensively detailed, the overall safety profile was consistent with prior studies. Serious adverse events were monitored, but no notable serious side effects differed significantly from the placebo group in Phase 3 trial results. The focus of reported outcomes primarily centered on the drug’s efficacy, with safety being assessed and found comparable to placebo.