Pila Pharma AB has announced promising preclinical results for its lead candidate, XEN-D0501, a TRPV1 antagonist, in reducing abdominal aorta aneurysm growth in mice. The study, conducted by Professor Dick Wagsater's Research Group at Uppsala University, Sweden, demonstrated a robust decrease in aorta dilatation of more than 50% compared to placebo. This finding establishes a preclinical proof-of-concept for XEN-D0501's potential in treating cardiovascular diseases. The company is preparing for a Phase 2a clinical trial (PP-CT03) to further evaluate the drug's safety and efficacy in humans.
XEN-D0501: A TRPV1 Antagonist
XEN-D0501 is a selective, synthetic, and potent small molecule TRPV1 antagonist in-licensed by Pila Pharma in 2016. TRPV1, or transient receptor potential vanilloid 1, is a receptor primarily expressed in sensory nerve fibers and is involved in detecting noxious stimuli, including heat and chemical irritants. Modulation of TRPV1 has potential applications in treating pain disorders, inflammation, and cardiovascular diseases. While TRPV1 agonists have been studied for obesity management, XEN-D0501 takes an antagonist approach.
Preclinical Evidence
The recent preclinical study aimed to assess the potential of XEN-D0501 to decrease abdominal aneurysm growth in mice. The headline results indicated that XEN-D0501 almost completely inhibited aneurysm development in the preclinical model, achieving the study's primary goal. These data are pending a confirmatory study and will be submitted for publication in a scientific journal.
Clinical Trial History and Future Plans
Pila Pharma has already completed two Phase 2a clinical trials (PP-CT01 and PP-CT02) with XEN-D0501. These trials demonstrated that the drug is well-tolerated in people living with obesity and type 2 diabetes. Notably, PP-CT02 showed that XEN-D0501 (administered as 4 mg twice daily for 28 days) significantly enhanced the endogenous insulin response to oral glucose compared to placebo. Furthermore, the trial observed a statistically significant reduction in ANP, a cardiovascular biomarker for heart failure.
In 2023, Pila Pharma reported excellent tolerability of XEN-D0501 following 13 weeks of administration at high doses in two animal species. This positive safety profile allows XEN-D0501 to progress into longer clinical trials. Currently, the company is preparing a scientific advice request regarding the study design for the next clinical Phase 2a trial, PP-CT03, which will be followed by a clinical trial submission in the UK. The objective of PP-CT03 is to identify the maximum tolerable dose of XEN-D0501 in people living with obesity and type 2 diabetes and to evaluate its safety profile following 3 months of chronic treatment. The study will also assess the drug's potential efficacy in reducing body weight.
Cautious Optimism
While XEN-D0501 has garnered attention and investor interest, some experts urge caution, emphasizing that the drug is still in early development. John B. Dixon, PhD, professor at Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Australia, stated, "There is simply no quality human data to say anything about the possibilities for this pathway." Vincenzo Di Marzo, PhD, director of the Joint International Research Unit for the Chemical and Biomolecular Study of the Microbiome in Metabolic Health and Nutrition, also noted that the company data are promising but preliminary.
Pila Pharma is now planning a 3-month dose-escalation study in people with obesity and diabetes. Dorte X. Gram, PhD, founder of Pila Pharma, expressed optimism, stating, "If these studies show that the molecule is as efficacious and safe as we think it is, then it would make life a lot better for a lot of people because it is a tablet, not an injectable."
The company is also exploring the potential of XEN-D0501 for treating cardiovascular diseases, particularly abdominal aortic aneurysms, and as a potential nonopioid painkiller.
