Article | March 29, 2024

Small Startup Going For A Big Play In Obesity

Source: Life Science Leader
wayne koberstein

By Wayne Koberstein, Executive Editor, Life Science Leader
Follow Me On Twitter @WayneKoberstein

Alessandro Toniolo
Alessandro Toniolo

Resalis Enters the Widening Space of Weight Loss

Discovery and accident are two words married at the hip. If you’re in the business of discovery, you should prepare for the fortunate accident, the kind that shows a pathway to something new and beneficial, one that takes you away from your original goal entirely and guides you thereafter toward a brand new destination. It was serendipity that brought a new direction to Resalis Therapeutics, echoing the rapidly expanding space it subsequently entered — developing new drugs for obesity and related liver diseases.

Complementary Spaces

The two areas, obesity and liver disease, are intertwined because of the liver’s role in the body’s metabolism of fat into energy. But when the liver cannot keep up and excess fat accumulates, its storage expands into other areas such as the abdomen, where it typically causes health problems, often including diabetes.

All of the new obesity drugs are essentially accidental discoveries arising from diabetes research, such as Novo Nordisk’s recognition that its diabetes drug, semaglutide (Ozempic), was achieving weight loss in diabetes patients. Sensing opportunity, companies with similar drugs aimed at reducing weight soon piled on, and more than several of them struck pay dirt, including Novo Nordisk with semaglutide (branded Wegovy for weight loss) and Eli Lilly with tirzepatide (Zepbound), as well as others still in development. Moreover, the activity encouraged companies targeting additional disease mechanisms in obesity.

Large companies have initially led the charge into the obesity space. No startup can equal the financial power of a top-tier pharma, yet history teaches that large pharmas tend to forfeit follow-on innovation to their tiny biopharma relatives. If the make-hay-while-the-sun-shines pricing of the first approved obesity drugs is an indicator, the obesity-drug boom will play out predictably.

Alessandro Toniolo, CEO of Resalis, is a scientist with a Ph.D. in chemistry and 10 years of experience in academic research. Yet in time he grew dissatisfied with theoretical approaches to chemistry and decided to make a significant career jump, earning a Master’s degree in business and landing his first job in pharma, “So I could match my background with science and numbers with business.” Starting in marketing at Eli Lilly, he worked at a string of companies, and his responsibilities in the commercial area grew to encompass strategic marketing, finally drawing his attention to biotech as an investor. For the past four years, he put his own money into bio startups and ultimately moved back to his native Italy, where he joined a small investors group, the Italian Angels for Growth, before coming to Resalis in October 2022.

Resalis began to emerge around 2015 from the research of Riccardo Panella, who was a post-doc fellow in oncology at the Harvard Medical School when he began working in a group pursuing “super oncogenic microRNAs” (miRNAs), a type of non-coding RNA (ncRNA) that can modulate messenger RNAs (mRNAs). A single miRNA can regulate multiple mRNAs, modulating entire pathways simultaneously.

In this case, observation overruled theory. A particular miRNA of interest, miR-22, failed the oncology experiment, but it appeared to boost obesity greatly in already obese mice quickly gaining weight on a high-fat diet. When Panella produced a miR-22-knockout mouse model, the knockout mice did not gain weight, even when he challenged them with high-fat diets. That meant mice over-expressing miR-22 would have the tendency to become obese despite their food intake. Conversely, for mice, and also potentially for humans, with normal or low levels of miR-22, even overeating would not confer obesity with all of its consequences.

It is truly interesting that serendipity is involved in the Resalis origin story just as it has been among the much larger companies now targeting obesity. “Everyone in Riccardo’s lab was aware of the miR-22 phenomenon, but no one except him thought it was the kind of material a company could work on. Sometimes, you may have to be the only one in an entire lab that matches observation with action, because no one else does.”

Panella, who became the company’s chief scientific officer and cofounder, initiated a collaboration with Professor Sakari Kauppinen, now the chief technology officer and cofounder of Resalis. Kauppinen is the Director of the Center for RNA Medicine at Aalborg University in Copenhagen and a worldwide expert in miRNA that are chemically modified with locked nucleic acids (LNAs), giving them a highly stable structure and resistance to enzymatic digestion. The research group around Panella and Kauppinen built a library of about 80 LNA-modified compounds to block miR-22 and selected the most promising candidates.

So far, the few obesity drugs seemingly headed for the market all share a common purpose: controlling appetite. Resalis’ drug has no effect on appetite. Instead, by blocking miR-22, they reduce the accumulation of fat. One pathway blocks the accumulation. Another pathway increases the transformation of white fat tissue (energy-storing) into brown adipose tissue (energy-releasing) fat. A third pathway boosts the total number of mitochondria throughout the body. The third pathway, Toniolo says, “has implications for multiple degenerative diseases, but we are at the beginning of the exploration of this field.”

Triple Trials

Resalis is not just a relatively small company, it is a small company entering a potentially big space, though of course the obesity market potential will expand only in keeping with how well the products in it perform. But that is true of any company, in any market. For Resalis and its peers in this space, small size carries some big challenges.

Number one is company funding, made steeper by the new approach Resalis is introducing as well as the sheer size of the risk and the stakes for a company of its size. Toniolo spent his entire first year assembling a Series A round of only €10 Million. That amount will comfortably cover early clinical trials once underway, but if the company must fund its next Phase 2 trial alone, he will need to raise at least the same amount again.

Toniolo believes the second major challenge for Resalis is bringing needed expertise in house —something also linked to funding. “In the U.S., you have much bigger investments that allow companies to form a super expert team. You have the ability to build a big team with the right expertise. In other regions, investors tend to be more risk-oriented sometimes and cautious. So, we need to put money into other activities besides salaries. We must rely on external advisors, and that introduces some inefficiency. Expertise is thus a potential issue that should be managed correctly.”

When Toniolo started reaching out to Big Pharma, he purposely sought advice, not money. “My first meetings with them were to say, ‘This is what I have. What kind of data would you like to see? What’s your strategy for the asset you would bring into clinical development? What would you want to achieve?’ We reached a different perspective together because we had built a mutual relationship, as well as credibility on our side.”

Lesson: If your company makes a similar move into a burgeoning space such as obesity, build relationships with investors before putting your hand out for investment. What you’ll learn from them may be pure gold.