NASH contender CymaBay runs into trouble as mid-stage data disappoint
A snapshot of negative data from an ongoing 52-week mid-stage NASH study evaluating CymaBay Therapeutics’ lead drug has triggered alarm, after the experimental liver drug, seladelpar, performed worse than a placebo at a three-month readout.
Surprised and aghast, investors of the San Francisco-based biotech wasted little time in registering their disappointment. The company’s shares $CBAY plummeted about 44.5% to $6.16 in early Tuesday trading.
In the 181-patient trial, patients were either given placebo, seladelpar 10 mg, 20 mg, or 50 mg once daily. The main goal at the end of 12 weeks was to induce a statistically significant improvement in liver fat content. Patients given the placebo saw a reduction of 20.8% in liver fat, while those given the three escalating doses of seladelpar experienced smaller improvements: 10 mg (9.8%), 20 mg (14.2%) and 50 mg (13%).
Cymabay has previously said it expected to see a 20-30% relative — placebo-adjusted — change in liver fat at 12 weeks.
“While the reductions in liver fat were minimal, we remain encouraged by the significant improvements in biochemical markers of liver injury…” Pol Boudes, CymaBay’s chief medical officer, said in a statement.
The experimental drug’s 52-week biopsy readout is expected in mid-2020. Seladelpar belongs to a family of drugs that activate proteins called peroxisome proliferator-activated receptors (PPARs), which regulate gene expression. Existing evidence suggests that in the liver, PPAR agonists play a role in bile acid synthesis, inflammation, fibrosis and lipid metabolism.
“While there is still a 52-week follow-up, we believe that these 12-week results significantly lessen the competitive threat of seladelpar in NASH. Hence, by lessening the competitive threat, we believe these results should benefit Intercept, as OCA remains the only medication to show a benefit on fibrosis in a Phase 3 trial. While OCA has some issues of its own, we think it is notable that one of those is NOT a failed randomized, placebo controlled study,” Baird’s Brian Skorney wrote in a note.
Akin to CymaBay, French drug developers Genfit (set to report pivotal data in 2019) and Inventiva are working on their own PPAR agonists for NASH.
On Tuesday morning, shares of Genfit $GNFT — that recently made its Nasdaq debut — were also down about 15% at $20.37. The movement likely reflects investors taking the CymaBay data as evidence against the efficacy of Genfit’s elafibranor, Skorney noted. “We think this move is somewhat unjustified…the two medications were thought to have differentiated mechanisms of action, it seems that this may not be the case, as seladelpar’s data suggest that the medication does not reduce liver fat, which is similar to what we have seen from earlier trials of elafibranor.”
However, as a consequence of the new CymaBay data, the two PPAR agonists now look more similar than different, he said. “CymaBay may be at a significant disadvantage moving forward as we believe that even if PPAR agonism is successful in Genfit’s Phase 3 trial, without any clear signs of differentiation, CymaBay may have an uphill battle as they work to catch up to Genfit in NASH. If elafibranor fails in NASH, it would probably be predictive of the outcome of seladelpar in NASH. Either way, we think this makes the PPAR class, as a whole, look like a less significant competitive threat to OCA.”
Other major NASH contenders — Gilead $GILD (fail in Phase III) and Intercept $ICPT (mixed win in Phase III) — have disclosed the top line numbers of their late-stage trials. Intercept is poised to submit its marketing application later this year.