🔎Don't sleep on obesity innovation.

Oral GLP-1 is now available. But drug development won't stop there. RNA-based weight loss drugs are the next frontier. They promise higher efficacy with better muscle retention.

TLDR Summary

• GLP-1 drugs are first and foremost appetite suppressants. They slow down the digestion process. The patient then voluntarily eats less and the resulting caloric deficit burns excess fat. That’s why they work for weight loss.

• Because they are so powerful and because the addressable market is so large, the pace of innovation in this space remains strong. Just recently for example, Novo Nordisk introduced oral semaglutide for weight loss which has the potential to accelerate adoption.

• The oral form makes the drug more convenient. It doesn’t solve one of the key challenges of GLP-1 drugs though. While losing weight via caloric deficit is effective, it can come with serious side effects. The body won’t necessarily just burn unwanted fat to address the caloric deficit. It might burn muscle or bone tissue if those are deemed less essential than fat deposits. Avoiding these side effects requires a disciplined approach to both nutrition and physical activity throughout GLP-1 treatment.

• Interestingly, a potential solution for this challenge is emerging from a corner of the Biotech industry that many people see with skepticism: RNA technology. Several companies are currently exploring whether RNA technology can be used to raise basal metabolism to complement a GLP-1 weight loss therapy. Patients then won’t only lose weight due a lower food intake, but also by burning more fat, even when they are not working out. Body fat would then literally dissipate as heat. So far, these drugs are still at clinical stage or approved for certain genetic disorders only. But the door may be opening to a much bigger story here.

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GLP-1s 1.0

By now, you are probably already familiar with how GLP-1s work. It has been a hot topic for several years. But if you are interested in understanding the scientific basics more thoroughly, I encourage you to read my original article from 2023.

Lilly, Novo and the quest for curing obesity (incl. Excel workbook)

Obesity drugs have continued to proliferate since I wrote that article. Many concerns about side effects have subsided. These drugs have continued to march into the mainstream. There are amazing weight loss stories everywhere, both in the media and likely also around you at work or among friends and family. We live during times where people love technological and pharmaceutical solutions to their problems. GLP-1s fit the zeitgeist perfectly.

Eli Lilly has emerged as the new top dog in the obesity drug space. Tirzepatide beats semaglutide on efficacy and Novo has disappointed in its trials on tolerability. That’s only the current score though. It will continue to be a cutthroat race for both to stay ahead and get further ahead. The industry is too highly sought after to stand still. To maintain their market position and justify their valuations, both companies need to reiterate their drugs regularly to move the efficacy/tolerability/safety/convenience frontier forward.

GLP-1s 2.0

Novo Nordisk landed a big win on convenience recently. On January 5, they announced that semaglutide (Wegovy) is now available for weight loss in oral form. Needless to say, popping a pill comes with a much lower barrier than jabbing yourself with a needle. And based on trial results, its efficacy is very similar to injectable semaglutide.

The average weight loss after 64 weeks was 14% vs. 15% after 68 weeks for the injectable version. It does require a daily pill vs. a weekly injection. But I believe that oral semaglutide has the potential to help Novo gain ground again and overall to accelerate GLP-1 adoption.

This innovation doesn’t address one of the central challenges of obesity drugs though. When you force your body into a caloric deficit, you lose weight because your body starts burning body tissue to address that deficit. You might want your body to burn fat exclusively. But your body will naturally choose the tissue it deems less relevant for survival. That’s what a caloric deficit is from a biological perspective: fight for survival.

If you live a sedentary life and if you have a bad diet, your body might choose to burn muscle or bone tissue instead of fat tissue. Therefore it’ss crucial that the GLP-1 therapy is complemented with a disciplined nutrition and physical activity regimen. And even then, risks for side effects remain.

Future iterations of obesity treatments have to improve along all four dimensions noted earlier: Efficacy, tolerability, safety and convenience.

It seems that an improvement of the safety frontier may come from an unexpected direction.

GLP-1s 3.0

Last week, I published my second edition of the Biotech Compendium which covered RNA therapeutics. And I must say I can’t think of a past Fallacy Alarm article that had a worse effort-to-effect ratio.

🔎Biotech Compendium: RNA therapeutics

Engagement on the article has been absolutely abysmal. I’m actually quite happy with how it turned out which is why I believe the problem is rather the topic itself, not my attempt to cover it. People don’t like RNA technology. And who can blame them after the crap we had to go through a few years ago?

I think it’s a mistake though to reject this technology for emotional reasons. RNA is a very promising technology. It might lift the entire Biotech industry to a new level. Respiratory vaccines are not the only application. And more importantly they are not the most ideal application. RNA technology has the potential to play a significant role in cancer therapy and in obesity, arguably the two most lucrative verticals in Biotech.

If you are curious about the mechanics of RNA technology, check out the article referenced above. Only briefly: One of the most important functions of our cells is to make proteins, some of them being exactly the proteins that are typically administered as externally manufactured Biotech drugs. RNA can be used as an instruction for our cells to make (more of) certain proteins, change the proteins made or avoid the production of certain proteins. This can be exploited for therapeutical purposes.

Several Biotech companies are doing exactly that right now with the idea to alter the production of proteins to manipulate the pace at which the body burns fat. If complemented with a GLP-1 drug, this can improve the preservation of body tissue that patients do not want to lose.

I have discussed the companies that are active in this space in more detail in the article above. To give you some tickers:

• Arrowhead ARWR 0.00%↑: Has a pipeline candidate that suppresses the production of a protein that slows down fat clearance in the blood. Without this protein present, fat will be removed faster from the bloodstream. It is then taken up by cells where it is more likely to be burned. Arrowhead recently announced encouraging interim clinical data on an RNAi-based obesity program which in combination with tirzepatide shows increased weight loss efficacy and improved muscle retention vs. using tirzepatide alone.

• Wave Life Sciences WVE 0.00%↑: Has an early stage candidate in the pipeline that suppresses the production of a protein that signals to the body to favor energy conservation and fat storage. Without this protein present the body shifts toward burning more energy and storing less fat.

• Ionis Pharmaceuticals IONS 0.00%↑ : Has a drug that suppresses the production of a protein that blocks fat clearance from the blood. It’s currently approved for a rare genetic disorder that causes severe hypertriglyceridemia (abnormally high fat concentration in the bloodstream).

• Dicerna Pharmaceuticals: Has a bunch of RNA-based drug candidates for cardiometabolic and liver diseases in their pipeline and got acquired by Novo Nordisk (!) four years ago.

Admittedly, none of these companies have moved into the obesity spotlight, yet. But don’t be surprised if that changes soon.

Sincerely,

Rene