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Investors are making a lot of money on obesity plays. Obesity is at epidemic proportions, so it's easy to see why obesity drugs including GLP-1 agonists have exploded in the marketplace. This class of drugs was originally designed to manage blood sugar levels in diabetics but was expanded to treat obesity, an even bigger market. JP Morgan analyst Richard Vosser estimated the global obesity drug market will reach $71 billion by 2032.

The first approval of Byetta was in 2005 but the market has since grown to include a bunch of diabetes drugs youve heard on TV ads like Trulicity, Victoza, Adlyxin, Ozempic, Rybelsus, and Mounjaro. Blockbuster drugs like Ozempic, now called Wegovy, and Mounjaro, now called Zepbound, were repurposed as obesity drugs.

This repurposing trend is a common theme in the biotech space. The only issue is that obesity has become a common theme, which ultimately makes it a crowded trade and harder to pick the winners and losers. Combination drugs like survodutide, retatrutide, and cagrisema are up-and-coming drugs in phase 3 development for obesity, but investing in these names means you are simply following the herd. Investing requires leading with an edge and some forethought. This article highlights pure-play drug developers in MASH likely to be the focus of investors looking for the next big thing in biotech.

Looking Beyond GLP-1 Inhibitors Toward the MASH Epidemic

Drug makers like Eli Lilly (NYSE: LLY) with their drug Mounjaro (tirzepatide) have already repurposed their drug once and are looking beyond diabetes and obesity, with their eyes set on and an even more lucrative market of metabolic dysfunction-associated steatohepatitis (MASH). LLY has promising interim clinical data showing 74% of overweight adults who took the higher dose of tirzepatide cleared MASH versus 12.6% in placebo. The first approval of a MASH drug on March 15, 2024 by Madrigal Pharmaceuticals (NASDAQ: MDGL) has ignited the sector with investors looking for the next big pure play.

Multiple MASH Targets

Metabolic dysfunction-associated steatohepatitis (MASH) is a complicated disease on the regulatory front. Approval criteria are a resolution of MASH symptoms via biopsy without a worsening of fibrosis. The disease formerly known as nonalcoholic steatohepatitis (NASH) is caused by a buildup of fat in the liver that leads to complications which include fibrosis (scarring of the liver), cirrhosis (severe scarring of the liver), and liver cancer. Once MASH progresses this far, liver transplantation is currently the only viable option. After MDGLs approval of Rezdiffera, investors have been flocking to other MASH names looking for a follow-on drug that either works in combination with Rezdiffera or one that is superior in safety and efficacy.

MASH Drug Targets

MASH has several druggable targets. The GLP-1 target is the mainstream approach because it also treats type 2 diabetes. Next in terms of a drug target is the fibroblast growth factor 21 (FGF21) which has a number of players in late-stage development. Galectin-3 is another target for MASH drugs as research has shown it is implicated in fibrotic and inflammatory feedback loops. There are also promising drugs that target the thyroid hormone receptor beta (THR). Breaking from the mainstream approaches is the A3 adenosine receptor (A3AR) which is highly expressed in inflammatory and cancer cells whereas low expression is found in normal body cells.

FGF21 Agonists

89Bio Inc. (NASDAQ: ETNB) is developing a lead molecule called pegozafermin which is a specifically engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21). It is similar in mechanism of action to Bristol Myers Squibbs (NYSE: BMY) drug pegbelfermin which was discontinued despite positive results which showed more than half the patients having NASH resolution at 16 weeks. FGF21 analogues are taken via subcutaneous injection. The targeting of the FGF21 pathway helps regulate metabolism and cellular process, especially in the liver fat tissue. Balancing out this metabolic pathway helps reduce liver fat, which can result in reduction in liver fibrosis (scarring) over time. The company has strong fibrosis data with favorable tolerability and dosing convenience. The long term data suggests there is a cumulative impact on patients taking background GLP-1 therapy. ETNBs phase 3 program in MASH could achieve accelerated approval using histology in non-cirrhotic (F2-F3) and cirrhotic (F4) patients although the FDA has acknowledged greater importance in clinical outcomes and not histology. They have clinical trials in both fibrosis and cirrhosis and expect to initiate their cirrhosis trial in Q2 2024. The company has almost $600 million in cash with a market cap of $875 million. The slight premium over cash, solid and consistent trial results, along with short and long-term catalysts make this an attractive setup for investors. This is the first on the top 6 list.

Akero Therapeutics (NASDAQ: AKRO) is also targeting MASH and MASH cirrhosis with an FGF21 agonist. Their drug is called efruxifermin and is commonly referred to as EFX. In their phase 2b MASH trial they showed a 65% reduction in liver fat content vs 11% in placebo which places them close to the front of the pack because it was done in only 12 weeks. Unfortunately, their phase 2b trial in MASH missed the endpoint for improvement in liver fibrosis at the 12-week time frame but showed 60% had MASH resolution after 36 weeks versus 26% in placebo. The company lost a lot of value on that readout but the statistics show a cleanly designed trial is likely to hit the regulatory endpoints. Guidance from an end-of-trial FDA meeting is forthcoming, but the timing is still uncertain and weighing on the stock price. While there is a lot of potential in this name, the uncertain timing of the regulatory pathway makes this ideal for the patient investor looking more for a NASH cirrhosis play. The company is well funded with over $550 million in cash and a $1.5 billion market cap.

Galectin-3 Antagonists

Galectin Therapeutics (NASDAQ: GALT) has an adaptive design phase 2/3 study in NASH cirrhosis with an interim readout before year end 2024. Their intravenously administered galectin antagonist called belapectin showed complete prevention of esophageal varices in a phase 2 trial despite failing to meet their (now defunct) primary endpoints. Their pivotal trial used lessons learned from the phase 2 trial, utilizing a primary endpoint of prevention of esophageal varices. If the interim results confirm a complete or near complete prevention of varices like they did in their phase 2 trial, they would have a compelling argument for conditional approval, likely with another post-market confirmatory phase 3 trial. Almost 50% of patients that develop esophageal varices die within a year, and the varices are extremely costly to treat. So eliminating the significant and imminent threat of death is the compelling benefit.

The company is in solid financial shape with enough cash runway to complete their pivotal trial by 2025. They also have the backing of a billionaire investor who is also their Chairman of the Board. Additionally, their drug demonstrated promising results in cancer, psoriasis, and atopic dermatitis which could lead to a label expansion once they are approved. The market cap of the company is sitting around $225 million despite the near certainty of a positive interim trial readout within the next 8 months, which could translate into billions within that time frame.

The company is not alone in the space and has 2 other competitors with oral galectin-3 antagonists. Galecto Bioscience (NASDAQ: GLTO) announced they were scrapping their cancer drug, which had a 60% response rate after three months, to focus on NASH. GLTO had a failed trial in idiopathic pulmonary fibrosis because of their drugs poor tolerability, which has forced them to seek strategic alternatives with a focus on liver disease. As a result, their development timelines for MASH are in flux. Galectos small molecule approach to inhibiting intracellular galectin-3 is the likely culprit for their drugs poor tolerability and its more likely large molecules which target extracellular galectin-3 will succeed.

Bioxytran Inc. (OTCMKTS: BIXT) has the most technologically advanced oral galectin antagonist that completed phase 2 trials in standard risk COVID-19, but the company is underfunded and therefore moving forward cautiously. Both Bioxytran and Galectin Therapeutics are developing larger molecules compared with Galecto and both their drugs have been found to be safe as opposed to Galecto. Bioxytrans additional benefit is that their drug doesnt require intravenous administration. Their clinical trials in NASH or cancer are dependent upon them finding a partner or a couple million dollars to get a shot at a number of multibillion dollar opportunities. Management indicated that the quickest way to approval was a COVID-19 regulatory approval and then proceeding with the label expansion. While the company boasts impressive technology and experienced management, they dont have the resources to prove their technology for all these indications yet. It's for these reasons that the stock should remain high on peoples watch listsin case they get funding.

Thyroid Hormone Agonists

Viking Therapeutics (NASDAQ: VKTX) is the largest pure play MASH company measured by market capitalization with a number of molecules in phase 2 or 3 development. Their leading drug candidate, VK2809, is a THR agonist. They also have a dual agonist for both the GLP-1 hormone and glucose-dependent insulinotropic polypeptide (GIP), VK2735. Clinical trials for VK2735 have been highly successful making it a darling with a market cap of $7.56 which exceeds the market cap of MDGL that has an approved MASH drug that also targets THR .

Vikings VK2809 targets non-alcoholic steatohepatitis (NASH) and fatty liver. It aims to reduce liver fat, preventing inflammation, damage, and potential progression to cirrhosis. Clinical trial results for VK2809 include significant weight loss (up to 14.7% of baseline body weight) and improvements in liver fat content. Notably, 85% of VK2809 patients experienced a >30% decrease in liver fat by week 12, correlating with improved histology. At least 88% of participants lost at least 10% weight loss versus 4% for placebo. The company is also innovating for their next generation, orally administered NASH drug, which had positive phase 1 trial results.

Other Approaches

CanFite Biopharmas (NYSE: CANF) lead drug candidate, namodenoson, is an A3 adenosine receptor (A3AR) antagonist, but what makes them stand out from the crowd is their platform technology that has the ability to screen targets in both the inflammatory and tumor micro-environment. It is also the only drug in the MASH space that is taken orally once a day. Both inflammatory and cancerous cells are overexpressed with A3AR which makes them an ideal target in MASH and liver cancer. The company completed both phase 2 and 3 studies for other indications such as liver cancer, so the favorable safety profile is well established in hundreds of patients. MASH study results showed a linear reduction in weight over time, a reduction in liver fat measured by proton density fat fraction (PDFF) on magnetic resonance imaging, validation of blocking the A3AR receptor, and the liver protective effect of the drug manifested by a reduction in hepatic inflammation. The company has a favorable status with both the EMA and FDA which could lead to a conditional approval. Their platform technology includes other large-market disease indications including psoriasis, pancreatic cancer, liver cancer, and erectile dysfunction.

The company also has 6 major drug partners and the potential to earn $130 million on regulatory and sales milestones for their 2 pivotal phase 3 assets. With a compressed market cap of $10 million which is trading barely over their cash and the potential of regulatory approval within the next 1.5 years, it's easy to see how this biotech could translate into an extraordinary investment if it achieves regulatory approval. The company has a solid management team with a low burn rate which means they are less likely to dilute because their interests are aligned with shareholders. This rounds out the top 6 MASH companies with the best risk to reward ratio.

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View source version on newsdirect.com: https://newsdirect.com/news/6-stocks-positioned-to-soar-as-investors-focus-on-mash-411511691

AKRO, MDGL, VKTX, LLY

COMTEX_451219533/2655/2024-04-22T06:04:22