Novel SGLT1/2 Inhibitor Safe, Tolerable in NASH
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BOSTON — Patients with non-alcoholic steatohepatitis treated with licogliflozin experienced dose-dependent improvement in alanine aminotransferase levels and other measures, according to study results presented at the Liver Meeting 2019.
Licogliflozin (Novartis) is an inhibitor of sodium-glucose co-transporters 1 and 2 that limits the absorption of glucose from the gut and reabsorption from the kidney.
“Dual inhibition of SGLT1 and SGLT2 with this medication in the gut and kidneys led us to significant weight loss in previous studies and favorable changes in metabolic parameters in patients with type 2 diabetes and/or obesity,” Stephen A. Harrison, MD, medical director of Pinnacle Clinical Research in San Antonio, said in his presentation. “Using that as a backdrop, we wanted to evaluate the efficacy and safety of licogliflozin vs. placebo in patients with NASH over 12 weeks of treatment.”
Researchers conducted a randomized, double-blind, placebo-controlled trial comprising 110 patients with histologically confirmed or phenotypic NASH (defined as BMI 27 kg/m2 in non-Asians or 23 kg/m2 in Asians, ALT 50 in men or 35 in women and type 2 diabetes). They randomly assigned patients to receive either 150 mg or 30 mg of licogliflozin, or placebo for 12 weeks.
The primary outcome of the study was the effect of ALT concentration after 12 weeks. Investigators also assessed the improvement in body weight, liver fat content and aspartate aminotransferase. Seventy-seven patients completed treatment, including 18 who received placebo, 25 who received 30 mg licogliflozin and 34 who received 150 mg licogliflozin.
Patients in the 150 mg and 30 mg groups experienced a 27% and 19% placebo-adjusted reduction in serum ALT concentrations after 12 weeks of treatment, respectively. They also experienced a similar reduction in AST (30% and 23%) and improvement in glutathione S-transferases (32% and 26%).
Patients who received either dose of licogliflozin experienced a placebo-adjusted reduction in body weight of about 4% (P = .0001), and reductions in HbA1c (absolute change: 150 mg, 0.96% [P = .0001]; 30 mg, 0.81% [P = .001]).
Harrison said the drug was generally well-tolerated by patients with the most commonly reported adverse event being diarrhea. A similar number of patients in the 30 mg and placebo groups reported having diarrhea (38.9% vs. 40%), but it was more common in the 150 mg group (76.5%).
“Based on the findings that we’ve seen here, assuming that they hold up through the rest of the trial, it justifies further investigation in long-term studies and in combination with drugs with different mechanisms of action,” Harrison said. “A study called the ELIVATE study will evaluate the drug tropifexor with this medication in combination in patients with NASH and liver fibrosis and will help to define the role in the treatment of NASH.”
Reference:
Harrison SA, et al. Abstract L07. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.
Disclosures: Harrison reports consulting for 3v Bio, Akero, Altimmune, Axcella, Blade Therapeutics, Chronic Liver Disease Foundation, Cirius, CiVi Biopharma, Contravir, Corcept, Cymabay, Echosens, Foresite, Galmed, Genfit, Gilead, Hightide, HistoIndex, Innovate, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Novartis, Novo Nordisk, Perspectum, Poxel, Prometic and Viking.
Perspective
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Arthur McCullough, MD
This is an important study with a novel new drug that was performed by an excellent group of investigators. It’s particularly significant because patients with fatty liver disease also have comorbidities such as diabetes, so when treated this can help the fatty liver disease, as well.
This concept is crucial because it addresses this unique and unmet need to treat patients with non-alcoholic fatty liver disease, which affects 25% of the United States and a certain percentage of these patients will progress to end-stage liver disease.
The use of this drug is particularly novel as it inhibits both glucose absorption from the intestine and increases the renal excretion of glucose; the later also promotes weight loss. The only significant complication was diarrhea at the high dose, which was to be expected. It’s certainly a potentially exciting drug based on strong preliminary data.
Because this is a phase 2 trial, we shouldn’t jump into this too quickly, as many phase 2 trials never get to the clinical arena because of side effects or lack of efficacy. The primary outcome was a decrease in ALT and that was achieved over placebo with a higher dose, quite effectively.
There are enough data here to proceed to a phase 3 trial, where investigators will have to show histologic improvement on biopsy. Therefore, we should view this drug with a question mark until a phase 3 trial demonstrates a clinically meaningful endpoint. One also has to worry about off-target effects of any drug.
Of particular interest is the heart. I don’t know if to the manufacturer will seek FDA for approval as a treatment for NASH or as a treatment for diabetes and NASH. This is important because the FDA now requires new drugs for diabetes to demonstrate no cardiovascular risk and often require the drug to be evaluated in a study that looks at cardiovascular outcomes.
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