Liver toxicity looked to have killed Cymabay’s seladelpar last year, but last month an investigation cleared the PPAR agonist of wrongdoing and the US FDA allowed trials to restart. Today the company followed with encouraging results from a phase III trial in primary biliary cholangitis that was stopped with the clinical hold, and spelled out plans to move into another pivotal study early next year.
Thus another former Nash play pivots to PBC. Genfit did the same earlier this year after elafibranor, another PPAR agonist, crashed out in phase III (Genfit’s predictable liver disease failure sets up a cirrhosis pivot, May 12, 2020). PBC is a rare disease so the market potential is much smaller than Nash, and with several companies now focused on this space, the competition is hotting up.
Intercept is already on the market with Ocaliva and after the FDA refused to approve the drug in Nash it seems that it too will be relying on PBC for sales for the foreseeable future. In this autoimmune condition the bile ducts are progressively destroyed, leading to liver cirrhosis.
Ocaliva is far from a perfect treatment option for PBC, however. As well as a black box warning for liver failure, it can also cause severe pruritus in between 19-23% of patients, according to its US label. The disease itself already causes around two-thirds of people to suffer from itching.
As such, developers like Cymabay and Genfit have a relatively low bar to beat in terms of safety, and clinical results suggest that they have a good chance of doing so, perhaps on efficacy as well. There are always caveats to cross-trial comparisons but at the very least on pruritus they could offer better options, as both have reported improvements on patient itching scores in phase II.
In the Enhance trial, which Cymabay detailed today, seladelpar demonstrated a significant improvement on a self-reported pruritis scale at the higher dose tested, which executives said would probably be taken into phase III. They also suggested that pruritus would also be made a key secondary endpoint in a pivotal study, with the goal of getting a label claim for itch reduction.
This would be a major point of differentiation from Ocaliva. On biomarker measures seladelpar also seems to stack up well: the primary endpoint used in PBC has traditionally been a composite of three measures, however impact on ALP is also considered an important marker.
|A cross-trial comparison of PBC rivals|
|Seladelpar, phase III Enhance trial, results at 3 months|
|5mg (n=56)||10mg (n=55)||Placebo (n=56)|
|Primary composite endpoint||57%||78%||12.50%|
|ALP mean change||-36%||-44%||-3.70%|
|Elafibranor in PBC: results at 12 weeks from phase II (n=45)|
|Composite secondary endpoint||67%||79%||6.70%|
|ALP mean change||-48%||-41%||3%|
|Ocaliva in PBC, results at 12 months|
|10mg (n=73)||Titration 5-10mg (n=70)||Placebo n=73|
|Primary composite endpoint||48%||46%||10%|
|Note: Composite endpoints comprised of: ALP less than 1.67-times ULN, Decrease in ALP of at least 15%, Total bilirubin less than or equal to ULN. Source: Company statements, US drug label for Ocaliva.|
A major point to remember when looking at the Enhance trial is that the results presented were from a modified intent-to-treat group. This is because the trial was stopped early due to the clinical hold, and as such many patients had not been followed for the initially intended length of time.
As such, these signals of efficacy need to be repeated in a second phase III. Although enthusiastic sellside analysts raised the prospect of a filing on the back of these results and the subsequent trial becoming a post-marketing requirement, this seems highly unlikely. Cymabay executives rightly talked this down, pointing to the absence of 12 months of safety data, and a drug already on the market.
They also said that Nash was no longer a focus, unless a partner could be found, another prudent move. But with Genfit saying it wants to start its PBC trial this year, Cymabay needs to keep up the pace. Investors should probably brace themselves for a cash call.
This story has been corrected to make clear that Enhance was a phase III trial.