Introduction
Epacadostat, developed by Incyte, is a selective IDO1 (indoleamine 2,3-dioxygenase 1) inhibitor that has been under intense scrutiny in the oncology field. Initially, it showed promise as a potential component of combination therapies, particularly when paired with PD-1 and PD-L1 inhibitors. However, recent developments have cast a shadow over its future.
Initial Promise and Clinical Trials
Epacadostat was part of the ECHO clinical trial program, designed to investigate its efficacy and safety in combination with various immunotherapies. The drug was being tested in multiple Phase 3 trials for various cancer types, including non-small cell lung cancer, urothelial cell cancer, head and neck cancer, renal cell carcinoma, and bladder cancer[4].
Key Trials and Findings
- The ECHO-202 trial, which combined epacadostat with KEYTRUDA (pembrolizumab), showed some promising results in patients with advanced melanoma. However, these findings were not sufficient to propel the drug forward in other indications[3].
- The ECHO-301 trial, a Phase 3 study investigating epacadostat in combination with KEYTRUDA for unresectable or metastatic melanoma, faced significant setbacks. The trial failed to meet its co-primary endpoint of overall survival, leading to a recommendation to stop the trial[4].
Setbacks and Scaling Back Development
In 2018, Incyte announced a substantial scaling back of epacadostat's development following the failure of a critical Phase 3 trial. This decision included discontinuing enrollment into six pivotal combination studies with Merck's KEYTRUDA and Bristol-Myers Squibb's Opdivo[1].
Impact on Clinical Collaborations
The failure of these trials significantly impacted Incyte's collaborations with major pharmaceutical companies. For instance, the planned Phase 3 study combining epacadostat with AstraZeneca's Imfinzi (durvalumab) for non-small cell lung cancer was not initiated[1].
Current Status and Future Directions
Despite the setbacks, Incyte has not entirely abandoned epacadostat. The company has shifted its focus to smaller, proof-of-concept trials where the biology and translational data are compelling.
Ongoing and Terminated Trials
- Some Phase 2 trials continue, such as the study combining epacadostat with pembrolizumab in patients with metastatic and/or locally advanced sarcoma, although the trial completion date has been extended[5].
- Other trials, like the Optimus study in neoadjuvant urothelial carcinoma, have been terminated due to business decisions rather than safety concerns[5].
Mechanism of Action and New Insights
Recent research has provided new insights into epacadostat's mechanism of action. It has been found that epacadostat stabilizes the apo-form of IDO1, which can still transduce a pro-tumorigenic pathway in certain cancer cells. This mechanism could explain the lack of effectiveness observed in clinical trials and may guide future immunotherapeutic strategies[5].
Market Projection
The market projection for epacadostat is uncertain and dimmed by the recent failures.
Industry Impact
The failure of epacadostat in key trials has raised questions about the future of IDO1 inhibitors as a class. While other IDO1 inhibitors like Bristol-Myers Squibb’s BMS-986205 and NewLink’s indoximod are still in development, the success of these drugs will be closely watched to determine if the issues with epacadostat are isolated or indicative of broader challenges with IDO1 inhibition[4].
Competitive Landscape
The oncology market, particularly the immunotherapy segment, is highly competitive. The failure of epacadostat has opened up opportunities for other drugs and combinations to fill the gap. PD-1 and PD-L1 inhibitors, such as KEYTRUDA and Opdivo, continue to dominate the market, and any new entrant will need to demonstrate significant advantages to gain traction[4].
Key Takeaways
- Clinical Trial Failures: Epacadostat's development has been significantly scaled back due to failures in pivotal Phase 3 trials.
- Shift to Proof-of-Concept Trials: Incyte is now focusing on smaller, proof-of-concept trials to explore epacadostat's potential.
- Mechanism of Action: New research suggests that epacadostat's stabilization of the apo-form of IDO1 may contribute to its lack of effectiveness.
- Market Uncertainty: The future of epacadostat and IDO1 inhibitors is uncertain, with significant competition from established immunotherapies.
FAQs
What was the initial promise of epacadostat in cancer treatment?
Epacadostat was initially promising as a selective IDO1 inhibitor, showing potential in combination with PD-1 and PD-L1 inhibitors to enhance cancer immunotherapy.
Why did Incyte scale back the development of epacadostat?
Incyte scaled back the development of epacadostat following the failure of a critical Phase 3 trial, which led to the discontinuation of enrollment in several pivotal studies.
What are the current ongoing trials for epacadostat?
Some ongoing trials include a Phase 2 study combining epacadostat with pembrolizumab in patients with metastatic and/or locally advanced sarcoma, although the trial completion date has been extended.
How does epacadostat's mechanism of action impact its effectiveness?
Recent research indicates that epacadostat stabilizes the apo-form of IDO1, which can still transduce a pro-tumorigenic pathway, potentially explaining its lack of effectiveness in clinical trials.
What is the market outlook for IDO1 inhibitors like epacadostat?
The market outlook is uncertain due to the failures of epacadostat and the competitive landscape dominated by established PD-1 and PD-L1 inhibitors.
Are there other IDO1 inhibitors in development?
Yes, other IDO1 inhibitors like Bristol-Myers Squibb’s BMS-986205 and NewLink’s indoximod are still in development, but their success will be closely watched to determine the broader viability of IDO1 inhibition.
Sources
- Biopharma Dive: "IDO drug development scaled back in wake of Incyte trial miss"[1]
- Incyte Investor Relations: "Progression-Free Survival Data from ECHO-202 Trial of Incyte's Epacadostat in Combination with KEYTRUDA® (pembrolizumab)"[3]
- Pharmaceutical Technology: "Incyte's clinical trial flop indicates an uncertain future for IDO inhibitors"[4]
- LARVOL VERI: "News - epacadostat (INCB024360)"[5]
