Validating SER-014, a TRPV1 antagonist, to treat endometriosis

Validating SER-014, a TRPV1 antagonist, to treat endometriosis Summary Endometriosis is a chronic inflammatory condition that affects ~10% of women and often results in debilitating pain. The disease is characterized by lesions consisting of endometrium-like tissue infiltrated with inflammatory cells, nerves, etc. In addition to local pain and irritation, lesions often lead to peripheral sensitization, including TRPV1 upregulation. The disease is most commonly treated with NSAIDs, with hormonal manipulation (steroid hormones and GNRH receptor modulators), and with surgery to remove lesions. Approximately 30% of patients are not effectively treated by any of these options and endometriosis-associated pain is an important driver of opioid use in women. There are no guidelines for the use of opioids in gynecologic pain, and endometriosis patients can find themselves dependent upon opioids without substantial symptom relief. Endometriosis increases the likelihood of chronic opioid use, opioid dependence/abuse, and opioid overdose. Serentrix LLC is a biotech company invested in the development of new, non-addictive therapies for pain. Our lead compound, SER-014 (previously called PHE377 that we acquired from PharmEste), is a transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor antagonist that has been tested in Phase 1 trials in healthy human subjects. Because TRPV1 is a key channel that mediates pain and inflammation in endometriosis, our goal is to develop SER-014 as a novel small molecule TRPV1 antagonist for the treatment of endometriosis as detailed below in our aims. Serentrix is collaborating with Dr. Michael Rogers at Children’s Hospital at Harvard Medical School, an expert in endometriosis research, who has developed and validated a best-in-class mouse model of disease, and Dr. Megan Falsetta at the University of Rochester Medical Center, an expert in genitopelvic pain research with extensive experience in the measurement of calcium signaling. Together, we will test SER-014 in this validated endometriosis model and confirm that it’s mode of action is specific to inhibiting the response to TRPV1 agonists (e.g., capsaicin), while not dysregulating thermal responses. SER-014, unlike many failed TRPV1 antagonists does not cause hyperthermia in animals or humans; we will show this is due to its mechanistic specificity. Aim1: Measure the efficacy of SER-014 against endometriosis-associated pain and lesion size in a validated mouse model. This will demonstrate the extent to which blood levels achieved by safe doses of SER- 014 can alleviate pain and reduce lesions. In alignment with this HEAL initaitive RFA, we will confirm its efficacy as a novel, safe, non-addictive treatment for endometriosis, a lifelong condition that destroys quality of life. Aim 2: Confirm the molecular mechanism through which SER-014 impedes TRPV1 activity without inducing hyperthermia. This will ascertain that SER-014 is ready to be tested in human studies and is devoid of side effects that were commonly associated with other TRPV1 receptor antagonists. Since SER-014 has already been tested in a Phase 1 clinical trial, our goal is to generate evidence sufficient to derisk a Phase 2 clinical trial seeking evidence of efficacy in endometriosis.