FDA Issues CRL to Vanda Pharmaceuticals’ Tradipitant for Gastroparesis Symptoms

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Credit: US Food and Drug Administration

The US Food and Drug Administration (FDA) has declined to approve Vanda Pharmaceuticals’ New Drug Application (NDA) for tradipitant for the treatment of symptoms in gastroparesis, providing Vanda with a Complete Response Letter (CRL).¹

According to a September 19, 2024, press release from Vanda, the CRL was conclusory in nature, generally disregarded the evidence provided, and instead suggested that Vanda conduct additional studies with a design and duration inconsistent with the advice of key experts in the field and not appropriate based on the scientific understanding and natural course of gastroparesis.¹

Additionally, Vanda noted the FDA's action was delayed by more than 185 days and fails to satisfy the requirements specified by the Food Drug and Cosmetic Act (FDCA), requiring that the FDA review an NDA and within 180 days of submission provide either an approval or an opportunity for a hearing.¹

According to the release, Vanda has repeatedly requested that the FDA convene an expert advisory committee to review the application and advise the Commissioner on the approval of this application, but the FDA has refused to do so. Additionally, patients currently treated with tradipitant have filed a Citizen Petition urging FDA to approve tradipitant for this indication.¹

Tradipitant is a neurokinin receptor 1 (NK-1R) antagonist licensed by Vanda from Eli Lilly and Company and is currently in clinical development for gastroparesis and motion sickness. The FDA has imposed a partial clinical hold on tradipitant clinical protocols of > 12 weeks duration.¹

The NDA for its use in gastroparesis was based on results from clinical efficacy studies 2301 and 3301, evidence from a large 12-week open-label study, and data from the Expanded Access program.¹

VP-VLY-686-2301

In the 4-week phase 2 VP-VLY-686-2301 study, tradipitant exhibited statistically and clinically meaningful improvements in overall gastroparesis symptoms, particularly a reduction in nausea. The study met its primary endpoint of change in nausea score as measured by patient daily diaries (change of -1.2 for tradipitant vs -0.7 for placebo; P = .0099) and also met the related endpoint of improvement in the number of nausea-free days (an addition of 28.8% of days for tradipitant vs 15.0% for placebo; P = .0160).²

Tradipitant also showed significant improvement in several secondary endpoints, including the key scales reflecting overall gastroparesis symptoms: Gastroparesis Cardinal Symptom Index (GCSI) (P = .0223); Patient Assessment of Gastrointestinal Disorders – Symptoms (PAGI-SYM) (P = .0497); Clinician Global Impression of Severity (CGI-S) (P = .0207); Patient Global Impression of Change (PGI-C) (P = .0429).²

In a subgroup analysis of patients who experienced both nausea and vomiting at baseline, tradipitant showed significant effects on the primary endpoint of change in nausea score (change of -1.4 for tradipitant vs -0.4 for placebo; P = .00002) as well as the number of nausea free days (an addition of 32.3% for tradipitant vs 7.6% for placebo; P = .0003).²

VP-VLY-686-3301

In the 12-week phase 3 VP-VLY-686-3301 study, both tradipitant and placebo showed significant and similar reductions from baseline in change in nausea as measured by a 5-point Gastroparesis Core Symptom Daily Diary (1.55 vs 1.49, respectively) and did not reach statistical significance. However, in the PGI-C scale, more patients treated with tradipitant demonstrated response compared with placebo at weeks 2 (74% vs 58%; P = .019) and 12 (78% vs 66%; P = .065). Similarly, in the Overall Patient Benefit (OPB) scale, more patients treated with tradipitant demonstrated response compared with placebo both at week 2 (81% vs 62%; P = .0003) and week 12 (86% vs 71%; P = .011).³

Initial exploratory analysis revealed potential confounders that could have masked the beneficial effect of the drug previously observed in VP-VLY-686-2301, including a baseline imbalance of rescue medication use between the 2 treatment arms and poor compliance with the study drug for some patients. When restricting the analysis in the group of patients that used no rescue medications at baseline and adjusting for poor compliance, Vanda identified strong evidence of a drug effect across a number of symptoms and across the duration of the study, including a significant and meaningful effect at the prespecified primary endpoint of nausea change at week 12.³

At the time of these results, Vanda indicated they planned to continue the analysis of the data from this study and prepare the results for submission to peer review journals and regulatory authorities.³

Data later published in Clinical Gastroenterology and Hepatology showed that although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. Additional post hoc sensitivity analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation, with results showing tradipitant treatment demonstrated strengthened effects and statistically significant improvements in nausea at week 12.⁴

The Future of Tradipitant

According to the release from Vanda, the company will continue to pursue the marketing authorization for tradipitant and will continue to support the expanded access program that is currently serving patients with gastroparesis. Additionally, Vanda plans to submit a separate NDA for tradipitant for the prevention of vomiting in motion sickness later this year.¹

References

1. ^{Vanda Pharmaceuticals. FDA Declines to Approve Vanda's Marketing Application for Tradipitant in Gastroparesis. September 19, 2024. Accessed September 19, 2024. https://vandapharmaceuticalsinc.gcs-web.com/node/16141/pdf}
2. ^{BioSpace. Vanda Announces Positive Phase II Study Results for Tradipitant in Patients with Gastroparesis. December 3, 2018. Accessed September 13, 2024. https://www.biospace.com/vanda-announces-positive-phase-ii-study-results-for-tradipitant-in-patients-with-gastroparesis}
3. ^{Carlin JL, Polymeropoulos C, Fisher M, et al. Efficacy Analysis of Tradipitant in Idiopathic and Diabetic Gastroparesis in Study VP-VLY-686-3301. The American Journal of Gastroenterology. doi:10.14309/01.ajg.0000863008.71548.4f}
4. ^{Carlin JL, Polymeropoulos C, Camilleri M, et al. The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial. Clinical Gastroenterology and Hepatology. 10.1016/j.cgh.2024.01.005}