Straight Dope on Medicine: MASH

Author

Scott Ganser
March 04, 2024

M*A*S*H, American television dramedy series that aired on CBS for 11 seasons (1972–83). It was based on the 1970 motion picture of the same name directed by Robert Altman. The show enjoyed excellent ratings and critical acclaim, with its final episode drawing the largest audience to date for a television episode.[i]

M*A*S*H followed the medical staff who cared for the wounded in a mobile army surgical hospital.

M*A*S*H had a distinctive anti-war message, something we could use more of today.

I watched this series, as a kid, frequently. It injected humor into the humorless Korean War. Robin Williams starred in a similar venture called “Good Morning Vietnam,” as if it were a vacation in Cabo. Something to be excited and cheerful about.

There is another MASH. This one is more medical, and it would make sense inserting it into a medical newsletter such as this.  MASH is metabolic dysfunction-associated steatohepatitis. Anytime you see “hepatitis,” you know we are talking about the liver. Being the topic du jour, what is all the hubbub?

Zealand Pharma announces Boehringer Ingelheim survodutide Phase 2 trial shows 83% of adults treated achieved groundbreaking results in liver disease due to MASH, with significant improvements in fibrosis[ii]

Metabolic dysfunction-associated steatohepatitis (MASH) is the more severe form of MASLD (Metabolic dysfunction-associated steatotic liver disease), is defined histologically by the presence of lobular inflammation and hepatocyte ballooning, and is associated with a greater risk of fibrosis progression.[iii]

MASLD has been estimated to affect 30% of the adult population worldwide, with its prevalence increasing from 22% to 37% from 1991 to 2019. The increasing prevalence of MASLD parallels the increasing prevalence of obesity and obesity-related diseases.\

Until now, with this development, all the other options for MASH sucked. That is the technical term for not being very good.

Synoptically speaking, there were a few takeaways from the intermediate phase trial:

  • Survodutide has potential to become best-in-class treatment for metabolic dysfunction-associated steatohepatitis (MASH)*, after meeting its primary and key secondary endpoint following 48 weeks of treatment versus placebo in a Phase 2 trial

  • Survodutide, a novel glucagon/GLP-1 receptor dual agonist, has demonstrated efficacy in people with obesity, and statistically significant results in MASH suggest the potential to lead to clinically meaningful benefits across the cardiovascular, renal, and metabolic spectrum

Before we really start getting into the science, how about some introductions?

About us

Zealand Pharma A/S is a biotechnology company focused on the discovery and development of peptide-based medicines. More than 10 drug candidates invented by Zealand have advanced into clinical development, of which two have reached the market and three candidates are in late-stage development. The company has development partnerships with a number of pharma companies as well as commercial partnerships for its marketed products.

Zealand was founded in 1998 and is headquartered in Copenhagen, Denmark, with a presence in the U.S., and employs around 250 people.[iv]

Zealand Pharma is not based in New Zealand, as it should be. No. No. No. No. No. Instead it is in Copenhagen.

They’ve been busy, busy, busy….

You might say they have been ZEALous.

Puns are allowed in medical newsletters. There is no prohibition.

Background

MASH is inflammation of the liver caused by the accumulation and storage of excess fat. The liver is an important organ in filtering our blood and providing fats and sugars for us to lead a healthy lifestyle every day. But it is at risk for certain conditions. MASH is one of them. Right now, about 6 million people in Australia have this condition.[v]

Copenhagen, Denmark, February 26, 2024 – Zealand Pharma A/S (Nasdaq: ZEAL) today announced that Boehringer Ingelheim has reported that up to 83.0% of adults treated with survodutide (BI 456906) achieved a statistically significant improvement of metabolic dysfunction-associated steatohepatitis (MASH) versus placebo (18.2%) in a Phase 2 trial [response difference: 64.8% (CI 51.1% - 78.6%), p-value (p<0.0001)]. The trial met its primary endpoint with survodutide reaching a biopsy-proven improvement in MASH after 48 weeks, without worsening of fibrosis stages F1, F2 and F3 (mild to moderate or advanced scarring). Survodutide also met all secondary endpoints, including a statistically significant improvement in liver fibrosis. Full data will be presented in the coming months.

"We are very excited by the positive topline Phase 2 trial results for survodutide in MASH announced today by Boehringer Ingelheim and we look forward to the planned disclosure of the full data at a scientific congress in the first half of this year," said David Kendall, MD, Chief Medical Officer of Zealand Pharma. "Furthermore, we are delighted with the announcement that Boehringer intends to move forward with further development in MASH as quickly as possible, as they progress with study recruitment in the ongoing Phase 3 clinical trial program for obesity."

The double-blind, placebo-controlled Phase 2 trial studied three doses of survodutide at 2.4 mg, 4.8 mg, and 6.0 mg. Top-line results demonstrated an improvement in MASH, at all doses explored in the trial. Treatment with survodutide did not show unexpected safety or tolerability issues, including at the higher dose of 6.0 mg.

About Survodutide (BI 456906)
Survodutide is a glucagon/GLP-1 receptor dual agonist with a novel mechanism of action that activates both the GLP-1 and glucagon receptors that are critical to controlling metabolic functions.

Survodutide was co-invented by Boehringer Ingelheim and Zealand Pharma. Boehringer is funding all activities and is exclusively responsible for clinical development. Survodutide has received U.S. FDA Fast Track Designation for the treatment of MASH and fibrosis. Survodutide is also being evaluated in five Phase 3 trials as part of the SYNCHRONIZE clinical program for people living with overweight and obesity. Further information is available on clinicaltrials.gov.

CCR2 – The Pfizer connection

As a researcher at Pfizer, I worked on a IgG4 monoclonal antibody designed to reduce/eliminate liver fibrosis and cirrhosis. I was working, but didn’t fit into “Pfizer’s business model.” Meaning they didn’t want to commit to it. It was stopped and started several times, and an effort was made to try to sell it off. But Pfizer wasn’t successful.

The accumulation of extracellular matrix (ECM) proteins in the liver leads to liver fibrosis and end-stage liver cirrhosis. C-C motif chemokine receptor 2 (CCR2) is an attractive target for treating liver fibrosis. However, limited investigations have been conducted to explore the mechanism by which CCR2 inhibition reduces ECM accumulation and liver fibrosis, which is the focus of this study. Liver injury and liver fibrosis were induced by carbon tetrachloride (CCl4) in wild-type mice and Ccr2 knockout (Ccr2-/-) mice.[vi]

In conclusion, this study depicts a novel mechanism by which CVC alleviates ECM accumulation in liver fibrosis by restoring the immune cell landscape. CVC can inhibit profibrotic gene transcription via inactivating the CCR2-STAT1/NFκB/ERK signaling pathways.

Currently, there is no specific drug for the treatment of hepatic fibrosis, and many drugs with anti-hepatic fibrosis effects are in the research and development stage. Recently, remarkable progress has been made in the research and development of anti-hepatic fibrosis drugs targeting different targets. We searched websites such as PubMed, ScienceDirect, and Home-ClinicalTrials.gov and found approximately 120 drugs with anti-fibrosis properties, some of which are in phase Ⅱ or Ⅲ clinical trials. Additionally, although these drugs are effective against hepatic fibrosis in animal models, most clinical trials have shown poor results, mainly because animal models do not capture the complexity of human hepatic fibrosis.[vii]