Madrigal Pharmaceuticals (MDGL) is poised to make history this week, if as expected the FDA approves its lead pipeline candidate resmetirom as a treatment for adults with metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis by the agency’s target action date of March 14.
That expectation has been shown by investors, who sent Madrigal’s shares soaring 49% over the past month, to $255.32 at the close of trading Friday (March 8) from $171.37 on February 8.
Madrigal’s February 8 closing price marked a nearly four-month low that came on the day the company published positive Phase III data from its pivotal MAESTRO-NASH trial (NCT03900429) assessing resmetirom in The New England Journal of Medicine (NEJM). The data showed that both evaluated doses of resmetirom (80 mg and 100 mg) were superior to placebo with respect to nonalcoholic steatohepatitis (NASH) resolution and improvement in liver fibrosis by at least one stage.
MAESTRO-NASH results showed that 25.9% of the 322 patients in the 80 mg resmetirom group and 29.9% of the 323 patients in the 100 mg resmetirom group achieved NASH resolution with no worsening of fibrosis, compared with 9.7% of the 321 patients randomized to placebo.
Also, 24.2% of the patients in the 80 mg resmetirom group and 25.9% of those in the 100 mg resmetirom group achieved fibrosis improvement by at least one stage with no worsening of Non Alcoholic Fatty Liver Disease [NAFLD] activity score, vs. 14.2% of placebo patients. Low-density lipoprotein cholesterol levels from baseline to week 24 shrunk -13.6% in the 80 mg resmetirom group and -16.3% in the 100 mg resmetirom group, vs. 0.1% for placebo.
“Data for the first 1,050 patients from the MAESTRO-NASH trial, together with data from completed resmetirom trials, support the potential for resmetirom to provide benefit to patients with NASH and liver fibrosis,” MAESTRO-NASH researchers concluded. They were led by corresponding author Stephen A. Harrison, MD, lead principal investigator of the MAESTRO studies. Harrison is founder and chairman of Pinnacle Clinical Research and Summit Clinical Research, both in San Antonio, TX.
Resmetirom is a once daily oral, liver-directed thyroid hormone receptor (THR) β-selective agonist designed to treat underlying causes of NASH in the liver, while improving multiple atherogenic lipid profiles.
MAESTRO-NASH evaluated two dosages of resmetirom compared to placebo in a 52-week serial liver biopsy Phase III study in which a total 1,759 patients had been enrolled as of February 20, the date of the most recent update posted on ClinicalTrials.gov.
Editorial draws fire
Unfortunately for Madrigal, investors gravitated not to the positive data, but to an accompanying editorial written by Kenneth Cusi, MD, chief of the division of endocrinology, diabetes & metabolism in the department of medicine at the University of Florida.
In the editorial, Cusi acknowledged that the results from MAESTRO-NASH were “encouraging to the field.” But Cusi recommended that patients taking resmetirom be monitored for their thyroid levels based on concerns about the long-term effects of hormonal changes tied to the drug—such as the 17–21% decrease seen in free thyroxine (T4) levels in blood, since too much or too little T4 can indicate thyroid disease.
Cusi also raised questions about how Madrigal plans to price resmetirom: “The large number of persons needing treatment will open a debate about treatment access and about how to best monitor treatment response and when to discontinue resmetirom in patients who do not have a response in order to avoid futile long-term therapy.”
At least one analyst took issue with Cusi’s findings.
“We don’t think [the] recommendation is appropriate,” Akash Tewari, an equity research analyst with Jefferies, wrote Friday in a research note, adding: “We think the NEJM editorial is likely noise.”
Tewari offered four reasons for disagreeing with Cusi and asserting that the hormonal changes he cited were “clinically insignificant”:
- Following resmetirom treatment, the free T4 level at week 52 was still within the normal range of 0.7–1.9 ng/dL. A similar level of free T4 decrease had been reported in Phase II studies.
- Hypothyroidism patients made up ~12–14% of patients enrolled at baseline: “They would likely have been excluded from the trial if there’s concern on hypothyroidism.”
- No thyroid-stimulating hormone (TSH) elevation was reported. TSH elevation would have been expected to accompany a decrease in free T4.
- Monitoring has been recommended for drugs when patients develop hypothyroidism in studies. “That said, no such AE [adverse event] has been reported for resmetirom (note: we already have data out to 52 weeks [plus] the drug has been tested in other trials as well).”
Data from MAESTRO-NASH forms part of the basis of Madrigal’s new drug application (NDA) for resmetirom, as well as data from a second Phase III trial assessing the drug in in NAFLD patients, MAESTRO-NAFLD-1 (NCT04197479) and an open-label extension study, MAESTRO-NAFLD-OLE (NCT04951219).
“Well-Positioned”
“We think MDGL is well-positioned within NASH, given resmetirom’s attractive oral dosing and clean safety profile,” Tewari concluded. “As such, we model peak sales of ~$2.9B for resmetirom in NASH across U.S. + E.U.”
Two other analysts share Tewari’s enthusiasm for resmetirom.
“We would be strong buyers going into the potential approval,” Edward Nash, a managing director and senior biotechnology analyst with Canaccord Genuity, wrote Thursday in a research note. Nash raised his firm’s 12-month price target nearly 1%, from $336 to $338, and maintained its “Buy” rating on Madrigal stock.
David Lebowitz, a senior research analyst with Citigroup focused on biotechnology, initiated coverage of Madrigal with a “Buy” rating and a price target of $382.
“NASH has historically proven to be a challenging space for drug development, but resmetirom provides a compelling risk-benefit for patients,” Lebowitz wrote Wednesday in a research note.
Madrigal CEO Bill Sibold said in a statement that additional data on resmetirom was forthcoming, namely two ongoing outcomes trials that he said carried the potential to confirm clinical benefit and expand the eligible patient population for resmetirom to include patients with more advanced disease.
“We intend to build on our leadership position in NASH drug development,” Sibold vowed. “The unprecedented efficacy and safety results from the pivotal MAESTRO-NASH Phase III trial provide Madrigal with a unique opportunity to establish resmetirom as the foundational therapy for NASH with significant fibrosis and transform care for patients who currently have no approved treatment options.”
For Novo Nordisk, a new all-time high
The good times, and good clinical news, roll on for Novo Nordisk (NVO), which saw its stock reach a new all-time high of DKK 919.60 ($134.92) on Thursday after the company presented positive albeit early clinical data at an investor event about a new weight loss drug that is envisioned to generate blockbuster sales once the company loses patent protection for semaglutide.
Semaglutide is the glucagon-like peptide 1 (GLP-1) drug marketed by Novo Nordisk in two indications that have generated blockbuster sales of over $1 billion—in obesity as Wegovy®, and in type 2 diabetes as Ozempic®.
The new drug, amycretin (NN9487), is a once-daily oral therapy designed to act as a co-agonist of both the GLP-1 and amylin receptors. In a Phase I trial (NCT05369390) that has enrolled 144 obese or overweight patients, amycretin led to a 13.1% weight reduction after 12 weeks compared with placebo in a subgroup of 16 patients treated with an unspecified dose of the drug, according to data presented at Novo Nordisk’s Capital Markets Day 2024 (CMD24).
Novo Nordisk acknowledged the endpoint of body weight change was “exploratory” and thus did not hold statistical significance.
But speaking with CNBC on Friday, Novo Nordisk CEO Lars Fruergaard Jørgensen said the results were nonetheless noteworthy. One reason he cited was because the extent of weight loss was more than double the 6% of 12-week weight loss shown in patients treated with Wegovy during clinical studies leading up to its approval.
Another reason cited by Jørgensen: Amycretin is an oral drug, compared with Wegovy and Ozempic, both of which are injectable.
“We believe in the future there’ll be different segments of anti-obesity treatments, with different patients having different preferences,” Jørgensen told CNBC. “Some will prefer an injectable and we really believe that once we can take a pill, it’s a very convenient offering.”
Amycretin is a long way from being commercialized; the drug is on track for a Phase II study expected to start in the second half of this year and end in early 2026.
However, Novo Nordisk couldn’t keep the momentum going on Friday. Shares dipped nearly 2% to DKK 905 ($132.81), as investors opted for profit-taking.
Yet Novo Nordisk’s shares have still climbed 30% since the start of 2024, when the price stood at DKK 697.10 (102.31) at the close of trading January 2. Over the past 12 months, Novo Nordisk stock has rocketed 82%, from DKK 497.25 ($72.98) on March 8, 2023.
Leaders and laggards
- Amylyx Pharmaceuticals (AMLX) shares cratered 82% on Friday, from $18.97 to $3.36, on speculation about the future of its marketed adult amyotrophic lateral sclerosis (ALS) therapy Relyvrio® (sodium phenylbutyrate and taurursodiol) after the company acknowledged the drug failed the Phase III PHOENIX trial (NCT05021536), designed to confirm the safety and efficacy of Relyvrio in 664 adults with ALS. PHOENIX missed its primary endpoint of reaching statistical significance measured by change from baseline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at Week 48, and did not achieve statistical significance in secondary endpoints. Amylyx said it will share plans within eight weeks for Relyvrio, which could include voluntarily withdrawing the drug from the market. Relyvrio won approval in 2022 as the first ALS drug approved by the FDA in five years.
- Elevation Oncology (ELEV) is the fastest-growing stock so far this year, catapulting 625% from $0.63 on January 2 to $4.57 on Friday—yet down 9% from $5.01 on March 1. The antibody-drug conjugate (ADC) cancer therapy developer began its latest surge February 26 with a 13% jump from $2.56 to $2.90, four days after announcing it had expanded its ongoing Phase I trial (NCT05980416) of lead pipeline candidate EO-3021, a therapy for adults with solid tumors, into Japan given its high prevalence of gastric cancer. “This will allow us to potentially address a significant unmet need for new gastric cancer therapies outside of the U.S., while also enabling us to characterize the safety and efficacy profile of our anti-Claudin 18.2 agent in a diverse patient population,” president and CEO Joseph Ferra stated on Wednesday. Elevation said it plans to provide an update from the study in mid-2024 and report additional data in the first half of 2025.
- Immuron (IMRN) shares nearly tripled, zooming 176% on Thursday from $1.65 to $4.55 after the company announced it would discuss a Phase III registration strategy with the FDA for its lead pipeline candidate Travelan® (IMM-124E) following positive interim topline results achieved in a Phase II trial (NCT05933525). Data from 60 patients who completed the inpatient challenge portion of the study showed Travelan to have reduced Enterotoxigenic Escherichia coli (ETEC)-induced moderate to severe diarrhea by 36.4% compared to patients randomized to placebo. Protective efficacy of once daily dosing was shown to be approximately 50% as effective as the current recommended 3x daily dosing regimen—a “strong result,” said Immuron, given the lower than expected attack rate. Travelan also showed 66.7% protective efficacy against ETEC induced severe diarrhea compared to placebo patients.
