Star companies have fallen, microbial pharmaceutical in the end has no future?

There's no room for trial and error

If time must go back, the signs of this collapse of star companies in the field of microbial pharmaceuticals began to appear as early as 2019. In 2019, when global capital entered the market, Seres Therapeutics, a star micro-ecological pharmaceutical company, laid off 30% of its employees to refocus on the clinical advancement of its core pipeline. Later, with more and more pipelines entering the middle and late stages of clinical trials, the operating risks of microbial pharmaceutical companies are also greater.

In fact, simply combing the research and development investment and clinical achievements of the troubled microbiological drug companies in the past few years will find that behind the difficult promotion of clinical trials, the reasons are often very sad.

On the one hand, as a start-up company developing innovative biotechnology, microbial pharmaceutical companies lack experience in clinical trial strategies, and need a relatively loose space for trial and error, with failure in exchange for the possibility of success. Evelo Biosciences, which was disbanded in late November, is a case in point. In the interpretation of the outside world, several self-developed core pipeline EDP1867, EDP1815, EDP2393 clinical trials have failed, Evelo can not be sustained, can only be dissolved. But in fact, until the end, EDP1815 has maintained excellent safety and efficacy data for the treatment of psoriasis, and the long-term data of EDP2393 also beat the control group. In a sense, Evelo erred by giving limited mobility to the wrong indication.

On November 20, Evelo's board of directors filed its deregistration plan with the Securities and Exchange Commission, ending nearly 10 years of operations. In 2014, Flagship Pioneering launched Evelo, which focuses on developing oral microbiotics for the treatment of immune diseases, using drug formulations composed of a single microbial strain to up-regulate or down-regulate the function of immune pathways. In 2018, Evelo listed on the Nasdaq market, raising $85 million and reaching a market value of $2 billion at one point. Prior to this, a number of top institutions and enterprises such as Mayo Clinic, GV, Celgene participated in the investment, and Evelo became a very bright microbial pharmaceutical star enterprise.

The first Evelo to give up was EDP1867. In April 2022, a Phase I clinical trial of EDP1867 for the treatment of atopic dermatitis was declared a failure. In 15 patients who received a low dose of the drug EDP1867, there was no clear evidence of benefit after eight weeks and EDP1867 was put on hold.

As Evelo focused its efforts on EDP1815 and EDP2393, the strategy went off course. The most widely recognized view of EDP1815 is that it is less effective than placebo in treating atopic dermatitis. In February, a Phase II clinical trial of EDP1815 in atopic dermatitis failed to meet its primary endpoint. According to the trial results, the EASI-50 (i.e., 50% improvement in atopic dermatitis disease score) in the control group (placebo group) was 56%, while in the EDP1815 group, only 41%, 38% and 32% of patients in cohort 1, 2 and 3, respectively, achieved EASI-50 or above response at week 16, which was less effective than placebo.

The problem with Evelo's judgment at the time was that placebos were too effective. Unfortunately, after re-examination, in the clinical trial data published in April 2023, EDP1815's performance was still inferior to the placebo. In cohort 4, 37.9% of patients in the EDP1815 group achieved EASI-50 or above responses at week 16, compared with 44.7% in the placebo group.

Interestingly, EDP1815 has already performed well in an earlier phase II trial of psoriasis. According to Evelo's plan, they will advance the development of EDP1815 to treat a wide range of psoriasis patients with mild and moderate disease with few options. But for some reason, Evelo didn't focus on a Phase III clinical trial of EDP1815 for psoriasis. In the case of psoriasis, Evelo is actually betting on EDP2393. In March, Evelo received a delisting warning from Nasdaq. At the time, Evelo's CEO, Dr. Simba Gill, said that resources would be focused on EDP2939, the first drug candidate based on its next-generation extracellular vesicles platform.

Unfortunately, the data from the Phase II clinical trial of EDP2939 for psoriasis, released in October, are still not ideal. The primary endpoint of the study, the difference in the proportion of patients with a 50% improvement from baseline in the psoriasis Area and Severity Index (PASI) score (PASI-50 response) between EDP2939 and placebo after 16 weeks of daily treatment, was not realized. However, it is worth noting that this ratio varied from lower than placebo at week 16 (19.6% EDP2939 vs 25% placebo) to better than placebo at week 20 follow-up (33.9% EDP2939 vs 26.9% placebo). In other words, if the protocol had been properly designed, the clinical trial failure of EDP2939 might have been avoided.

At this time, Evelo tried to turn the engine around again, ready to abandon the EDP2939 and pick up the EDP1815. Dr. Simba Gill said, "While we are disappointed with the Phase II results of EDP2939, we continue to believe in the value of our Small intestine Axis (SINTAX) platform and our potential product, EDP1815." We previously reported positive efficacy and safety data in a phase 2 study in mild to moderate psoriasis with EDP1815. "Given the findings of this study, we are discontinuing development of EDP2939 and are reviewing potential strategic alternatives, including pursuing partnerships with EDP1815 and the SINTAX platform."