Lessons from a prior obesity company: what Zafgen taught me about development risk

In late 2005 I founded my first company, an obesity drug developer called Zafgen. This was still long before the highly weight-negative GLP-1 drugs like Ozempic became available. No truly effective drugs for obesity were available at the time, and those that were (like sibutramine and orlistat) had their own challenges with safety and side effects that limited their success. The need for new agents for people struggling with obesity was obvious.

My 2 co-founders and I identified a pair of intriguing, related anti-obesity approaches that were still in academic labs, and licensed them for development. With seed funding we determined that one of those technologies might have promise for testing in patients. It was represented by a well-known anti-parasitic compound made by a fungus, and it seemed to have excellent effects in a widely used mouse model of obesity. The theory behind its action was that the smallest blood vessels, at the very end of the vascular tree, in fat tissue were unstable (as they are normally able to be resorbed easily with weight loss or rebuilt with weight gain) and that the compound would cause those blood vessels to be “pruned”, leading to weight loss. It was not a lot to go on, but the weight loss we observed in mice was undeniable and highly significant.

One of our investors identified a molecule that had previously been tested outside the US in patients with advanced cancers. This compound appeared to be safe in those subjects (but was not effective for use in cancer), and it had the same molecular target as the fungal compound we had tested in mice. Despite having an unusual chemical structure for a drug, it was licensed by Zafgen for development, becoming a product candidate known as beloranib.

Several years, rounds of financing, and clinical trials later, as well as an IPO in 2014, beloranib showed remarkable efficacy in obesity in humans, specifically in a very difficult to treat condition known as Prader-Willi Syndrome (PWS). Individuals with PWS have an insatiable hunger beginning in early childhood that invariably leads to obesity, which is often quite severe. There were no marketed drugs available for them and their families, and the initial studies gave Zafgen and the PWS community hope. However, in late-stage development, when patient numbers are increased to try to confirm safety and efficacy, a small number of patients developed clots in the lower extremities and lungs, and – in the worst possible outcome, 2 patients died. Despite continuing support from the Prader-Willi community, this was the beginning of a spiral that the company was never able to get out of.

For me, the lessons of Zafgen are three-fold:

1. Safety is paramount. This is, of course, the case with all drug development, but it is even more so in obesity, which is not an immediately life-threatening condition. Chronic obesity does lead to a great deal of morbidity and mortality, but the guiding principle of medicine, dating all the way back to Ancient Greece, is “First, do no harm”. The side effects and potential safety issues that are acceptable in a drug depend on their use: for example, some potential safety issues are acceptable in new drugs for patients with what would otherwise be terminal cancers. However, for obesity, drug safety must be of the highest order and the number one concern. The molecule that was licensed by investors into Zafgen and became beloranib had been in development for cancer, where the efficacy and safety calculation is very different than for obesity. Development of a brand new molecule from the ground up, with different chemistry, may have been a better choice.

This is one area where Energesis’ lead program stands out: it is a combination of 2 previously-approved drugs, both of which have long track records of safety in millions of patients. Both components of EGS-2632 have established safety records at their approved doses, and are being used together at only a fraction of their approved dosages. We firmly believe this will reduce both safety risk as well as overall development risk, although naturally the safety of the combination itself still has to be established in human studies.

Preclinical Disclaimer: Energesis’ programs, including EGS-2632, are currently in preclinical development. They have been evaluated only in laboratory and animal models and have not yet been tested in humans. They are not approved by any regulatory authority, and preclinical results may not predict human safety or efficacy.

2. Understanding mechanism of action (MoA) is critical. Technically, approval of a drug requires demonstration of efficacy and safety. It does not require an understanding of how the drug works. However, knowing the MoA helps build confidence in the efficacy and safety from an early stage, and makes obtaining resources to support development easier. At Zafgen, the MoA of beloranib was never clear, and that is still true to this day. Intriguing questions that remain unanswered are: How does beloranib cause weight loss? Where is the energy (from fat) going? We will likely never know the full story.

In contrast, the biology of brown fat is well-understood. There is a large body of scientific evidence showing that increasing brown fat mass in animal models of obesity leads to increased energy expenditure, improvements in blood glucose, cholesterol, body weight, and fat mass. Many of these outcomes have been shown in humans as well by using chronic cold exposure (which creates more brown fat). Our lead candidates are designed to make additional brown fat cells and thereby increase energy expenditure. We also know the molecular targets of our candidates, and those targets are addressed by already-approved drugs. We view this as a favorable starting point for safety.

3. Striking a balance between stakeholders is a challenge. The truth in small companies is that investors can have outsized influence on development decisions, including investors without long tenures in the pharmaceutical industry. The decision to license beloranib – an existing compound already with phase I safety data, was made to save time and money, not because it was necessarily the best molecule for development for obesity. While many chemists I know would have reservations about the particular chemistry of beloranib (which contains a reactive group called an epoxy), the investors at Zafgen ruled the day on this decision.

With this in mind, at Energesis we have strived to advance our science as far as possible before bringing on large investors. We have succeeded in this through nearly a dozen peer-reviewed grants from the National Institutes of Health, the Department of Defense, and the state of Massachusetts, as well as a small amount of private funding from friends & family. This approach has allowed us to go where the science leads us, and do what we believe is best for patients.

Overall, drug development is a risky business. However, my experience with Zafgen reinforced what is most important – strive to create something that can help patients struggling with obesity and improve public health, and make patients and their safety priority #1.