On November 9, 2017 Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL) reported its third quarter 2017 financial results and several clinical accomplishments that occurred during the third quarter including (Press release, Synta Pharmaceuticals, NOV 9, 2017, View Source [SID1234521906]):
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· the completion of patient enrollment in two Phase 2 clinical studies of MGL-3196, a liver-directed thyroid hormone receptor (THR) β-selective agonist, in patients with non-alcoholic steatohepatitis (NASH) and heterozygous familial hypercholesterolemia (HeFH), respectively;
· a second recommendation from the Drug Safety Monitoring Board (DSMB) that included a review of the data from both the NASH and HeFH Phase 2 clinical studies; and,
· the presentation of preclinical results at The Liver Meeting 2017, American Association for the Study of Liver Diseases (AASLD) demonstrating that MGL-3196 provides metabolic, anti-inflammatory and anti-fibrotic benefits in a long-term, high fat diet, mouse NASH model.
"With patient enrollment completed for the Phase 2 NASH and HeFH clinical studies we are on track to report top-line results for NASH late this year and HeFH early in 2018," said Paul Friedman, M.D., Chief Executive Officer of Madrigal. "Both indications have serious unmet patient needs and, based on both the preclinical and Phase I data that we have developed for MGL-3196, we believe our compound has the potential to be the first-and best-in-class THR β-selective agonist to safely and effectively meet these needs."
Rebecca Taub, M.D., Chief Medical Officer and Executive VP, Research & Development of Madrigal added, "Because safety is such an important requirement for patients with these diseases, we are encouraged by the latest recommendation from our DSMB to continue both the NASH and HeFH clinical trials with no modifications to either protocol. We look forward to the upcoming data readouts which, if positive, will enable us to initiate Phase 3 trials in 2018."
Clinical Program Summaries for MGL-3196
NASH
Non-alcoholic Steatohepatitis (NASH) is a common liver disease in the United States and worldwide, unrelated to alcohol use, that is characterized by a build-up of fat in the liver, inflammation, damage (ballooning) of hepatocytes and increasing fibrosis. Although people with NASH may feel well and often do not know they have the disease, NASH can lead to permanent damage, including cirrhosis and impaired liver function in a high percentage of NASH patients.
In October 2016, the first patient was treated in Madrigal’s Phase 2 trial of MGL-3196 for the treatment of NASH. The randomized, double-blind, placebo-controlled, multi-center study enrolled 125 patients 18
years of age and older with biopsy-confirmed NASH and more than 10% liver fat as confirmed by a magnetic resonance imaging-proton density fat fraction (MRI-PDFF).
In this trial, patients were randomized 2:1 to receive either MGL-3196 or placebo. The primary endpoint of the trial is the reduction of liver fat, assessed by MRI-PDFF at 12 weeks. Recent published data show a high correlation of reduction of liver fat measured by MRI-PDFF to NASH scoring on liver biopsy.
Efficacy will be confirmed at the end of the trial (36 weeks) by repeat MRI-PDFF and conventional liver biopsy to examine histological evidence for the resolution of NASH. Additional secondary endpoints include changes in clinically relevant biomarkers at 12 and 36 weeks, improvement in fibrosis by at least one stage, improvement of NASH, and safety and tolerability.
HeFH
Heterozygous familial hypercholesterolemia (HeFH), and a much rarer form called homozygous familial hypercholesterolemia (HoFH), are severe genetic dyslipidemias typically caused by inactivating mutations in the LDL receptor. Both forms of FH lead to early onset cardiovascular disease. HeFH, the most common dominantly inherited disease, is present in up to 1 in 200 people; the disease is found in higher frequencies in certain more genetically homogenous populations. Treatments exist for both HeFH and HoFH but many patients (as many as 40 percent of HeFH patients) are not able to reach their cholesterol (LDL-C) reduction goals on these therapies, reflecting the lifetime burden of cholesterol buildup in their bodies. Based on evidence of impressive LDL cholesterol lowering in Phase 1, and data suggesting that MGL-3196 has a mechanism of action that is different from and complementary to statins, Madrigal initiated a Phase 2 proof-of-concept trial in HeFH in February 2017. Patient recruitment for the study was completed in September 2017 and included 116 patients.
The 12-week, randomized, double-blind, placebo-controlled, multi-center study was expected to enroll up to 105 patients with HeFH randomized in a 2:1 ratio to receive either MGL-3196 or placebo, in addition to their current drug regimen (including high dose statins and ezetimibe). The primary endpoint of the study is reduction of LDL cholesterol, with secondary endpoints including reductions in triglycerides, Lp(a), and ApoB, as well as safety. Lp(a) is a severely atherogenic lipid particle, commonly elevated in familial hypercholesterolemia patients and poorly controlled by existing lipid lowering therapies. THR-β agonism is one of the few therapeutic approaches that can substantially lower Lp(a).
Financial Results for the Three Months and Nine Months Ended September 30, 2017
As of September 30, 2017, Madrigal had cash, cash equivalents and marketable securities of $62.1 million, compared to $40.5 million at December 31, 2016. The increase in cash and marketable securities resulted primarily from the net proceeds of $34.9 million from Madrigal’s private placement of equity in June 2017, and $3.4 million of net proceeds from issuances of common stock in the first quarter of 2017 pursuant to Madrigal’s at-the-market sales agreement, partially offset by cash used in operations of $16.4 million.
Operating expenses were $8.6 million and $23.2 million for the three month and nine month periods ended September 30, 2017, compared to $14.1 million and $17.5 million in the comparable prior year periods.
Research and development expenses for the three month and nine month periods ended September 30, 2017 were approximately $6.7 million and $17.9 million, respectively, as compared to $7.8 million and $10.4 million in the comparable prior year periods. The decrease for the comparable three month periods was due primarily to lower non-cash stock based compensation in 2017, partially offset by increased expenses for our Phase 2 clinical development programs for MGL-3196 in NASH and HeFH. The increase for the comparable nine month periods is primarily attributable to increased expenses for our Phase 2 clinical development programs for MGL-3196 in NASH and HeFH, partially offset by lower non-cash stock based compensation.
General and administrative expenses for the three month and nine month periods ended September 30, 2017 decreased to approximately $2.0 million and $5.3 million, respectively, as compared to $6.3 million and $7.1 million in the comparable prior year periods. These decreases are primarily attributable to one-time, merger related costs in the third quarter of 2016.
Interest income (expense), net, for the three month and nine month periods ended September 30, 2017 was $174 thousand and $342 thousand, respectively, as compared to $42 thousand and $(1.2) million for the comparable prior year periods. The decreases in interest expense in 2017 were due to the conversion of convertible debt to shares of common stock in connection with Madrigal’s merger, which closed on July 22, 2016.