CymaBay Therapeutics, Inc. announced 12-week topline results from an ongoing 52-week Phase 2b dose-ranging, paired liver biopsy study of seladelpar for the treatment of nonalcoholic steatohepatitis (NASH). Seladelpar is a potent and selective peroxisome proliferator-activated receptor delta (PPARδ) agonist currently in development for NASH and primary biliary cholangitis (PBC).
The double-blind, placebo-controlled study randomized 181 subjects with biopsy-confirmed NASH and a liver fat content (LFC) greater than 10% to receive either placebo or seladelpar 10 mg, 20 mg, or 50 mg once-daily. The enrolled subjects had established NASH with a mean NAFLD Activity Score of 5.2 at baseline, with 83% of subjects having stage 2 or stage 3 fibrosis. Other key baseline characteristics include a mean LFC by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) of 21% as well as elevated mean ALT and AST levels of 62 U/L and 46 U/L, respectively. Approximately half of the subjects enrolled had a diagnosis of type 2 diabetes. The primary endpoint was the relative change in LFC from baseline to 12 weeks. The study remains blinded and will continue to 52 weeks with assessments including a liver biopsy, non-invasive imaging evaluations, and biomarker assessments of inflammation and fibrosis.
Reductions in LFC as measured by MRI-PDFF at week 12 are highlighted in the table below. Treatment with seladelpar resulted in minimal reductions in liver fat that were not significant when compared to placebo.
|
Placebo (n=26) |
Seladelpar 10 mg (n=50) |
Seladelpar 20 mg (n=47) |
Seladelpar 50 mg (n=48) |
||
| Relative Change in LFC from Baseline (LS Mean, SE) | -20.8% (5.6) | -9.8% (4.2) p=0.087 |
-14.2% (4.3) p=0.32 |
-13.0% (4.3) p=0.23 |
|
| Proportion of Subjects with ≥ 30% Relative Reduction in LFC | 30.8% |
24.0% p=0.66 |
25.5% p=0.47 |
18.8% p=0.23 |
|
|
Absolute Change in LFC from Baseline (LS Mean, SE) |
-4.7% (1.1) |
-2.6% (0.9) p=0.10 |
-3.3% (0.9) p=0.28 |
-2.7% (0.9) p=0.14 |
|
| Proportion of Subjects with ≥ 5% Absolute Reduction in LFC | 34.6% | 30.0% p=0.41 |
38.3% p=0.48 |
25.0% p=0.049 |
|
mITT = modified intent-to-treat population; LFC = Liver Fat Content LS Mean = Least-Square mean; p-values relative to placebo
Treatment with seladelpar resulted in robust and clinically meaningful reductions in markers associated with liver injury as highlighted in the table below. Alanine aminotransferase (ALT) declined up to 37.5% or 32 U/L in 12 weeks. These reductions in ALT are significantly greater than the 17 U/L threshold that has been correlated with histologic improvement in NASH. Gamma glutamyl transferase (GGT) also decreased significantly, suggesting a reduction in hepatocellular oxidative stress. Significant reductions in alkaline phosphatase (AP) at 12 weeks were observed, supportive of a decrease in hepatocellular bile acids. The marked changes in these liver enzymes collectively suggest the potential to impact ballooning and lobular inflammation, the two key components of NASH resolution.
| Relative Change from Baseline to Week 12 (LS Mean, SE) |
Placebo (n=27) |
Seladelpar 10 mg (n=53) |
Seladelpar 20 mg (n=51) |
Seladelpar 50 mg (n=50) |
| ALT | -8.9% (5.1) p=0.08 |
-22.9% (3.8) p<0.0001 |
-32.0% (4.0) p<0.0001 |
-37.5% (4.0) p<0.0001 |
| AST | -12.9% (5.8) p=0.03 |
-11.6% (4.4) p=0.009 |
-15.2% (4.5) p=0.001 |
-17.3% (4.5) p=0.0002 |
| GGT | -4.5% (4.3) p=0.3 |
-28.2% (3.2) p<0.0001 |
-37.6% (3.3) p<0.0001 |
-43.1% (3.4) p<0.0001 |
| AP | 4.4% (2.9) p=0.12 |
-19.1% (2.1) p<0.0001 |
-25.1% (2.2) p<0.0001 |
-33.4% (2.2) p<0.0001 |
ALT, AST, GGT, AP from safety population; p-values relative baseline
Dr. Stephen Harrison, MD, Medical Director of Pinnacle Clinical Research, founder of Summit Clinical Research and principal coordinating investigator of the seladelpar Phase 2b NASH Study, commented, “NASH is a complex, multifactorial disease that can lead to liver injury and fibrosis. These data demonstrated a notable decrease in biochemical markers of liver injury despite lack of overall improvement in liver fat. The dose response relationship in serum ALT reduction is very encouraging and supports the potential histopathologic benefit of seladelpar in patients with NASH. We are looking forward to the 52-week histology results.”
Professor Mary Rinella, MD, Department of Gastroenterology and Hepatology, Northwestern University, stated, “It is encouraging to see the impressive decrease in ALT and GGT consistent with a reduction in hepatic inflammation and possibly oxidative stress. The magnitude of reduction in ALT exceeds thresholds shown in recent publications to correlate with histologic improvements in the context of NASH.”
Treatment with seladelpar also resulted in reductions in low-density lipoprotein cholesterol (LDL-C) and triglycerides. At 12 weeks, the median percent changes in LDL-C were 7.8, -7.5, -8.4, and -14.4 in the placebo, seladelpar 10, 20, and 50 mg groups, respectively. The median percent change in triglycerides were 14.4, -9.1, -4.0, and -10.0 in the placebo, seladelpar 10, 20, and 50 mg groups, respectively. There were no significant changes in high-density lipoprotein cholesterol. High sensitivity C-reactive protein (hs-CRP), a key marker of inflammation and cardiovascular risk, decreased by a greater magnitude in seladelpar-treated subjects, with median percent changes were -3.1, -16.7, -20.7, and -22.6 in the placebo, seladelpar 10, 20, and 50 mg groups, respectively.
Seladelpar demonstrated a favorable safety and tolerability profile at all doses evaluated in this study. The most common (>5%) treatment emergent adverse events included nausea, constipation, dizziness, headache, gastroesophageal reflux disease and upper abdominal pain. The majority of treatment emergent adverse events were mild to moderate in severity and deemed unrelated to study drug. There were two serious adverse events that occurred after randomization through week 12, neither of which were deemed to be related to study drug.
Dr. Pol Boudes, MD, Chief Medical Officer of CymaBay Therapeutics, added, “While the reductions in liver fat were minimal, we remain encouraged by the significant improvements in biochemical markers of liver injury that we observed at week 12. The 52-week liver biopsy data will allow us to understand whether the improvement in liver injury markers will translate into histological improvement. The observed improvement in markers of liver injury are consistent with the observed effects of seladelpar in PBC and further support the potential for seladelpar to improve liver health.”