NASH drug passes phase 2 trial

SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.

Jim Kling/MDedge News

“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.

The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”

The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.

At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.

At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).

The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).

A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).

Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.

The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.

SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.

Jim Kling/MDedge News

“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.

The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”

The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.

At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.

At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).

The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).

A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).

Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.

The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.

SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.

Jim Kling/MDedge News

“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.

The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”

The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.

At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.

At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).

The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).

A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).

Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.

The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.