Orphan Drug Designation Sought for Crofelemer to Manage Treatment-Related Diarrhea in Breast Cancer With Brain Metastases

An orphan drug designation (ODD) application for the use of crofelemer to manage diarrhea in adult patients with breast cancer brain metastases who are receiving targeted therapy with or without standard chemotherapy has been submitted to the FDA.1

The submission is supported by results with crofelemer observed in a prespecified subgroup of patients with breast cancer from the phase 3 OnTARGET study (NCT04538625), which were previously shared at the Multinational Association of Supportive Care in Cancer 2025 Annual Meeting and the 2024 San Antonio Breast Cancer Symposium.

"The FDA has identified the condition of breast cancer that has metastasized to the brain as an orphan indication. We have submitted this ODD application for crofelemer to treat diarrhea in these patients," Lisa Conte, founder, president, and chief executive officer of Jaguar Health, the drug’s developer, stated in a news release."Diarrhea is a common side effect of numerous targeted cancer therapies that can lead to dose changes, treatment delays, or cessation of treatment altogether, all of which impact patient outcomes. Given crofelemer's novel and physiological mechanism of action, we would plan to seek breakthrough therapy designation and/or fast track designation from the FDA to support potentially expedited regulatory pathways in the United States [US] for crofelemer for this indication."

What Are the Current Indications for Crofelemer?

Crofelemer is categorized as a botanical (plant-based) drug. It is derived from the red bark sap, commonly known as "dragon’s blood," of the Croton lechleri tree found in the Amazon Rainforest.

Notably, crofelemer previously received ODD for short bowel syndrome with intestinal failure and microvillus inclusion disease for a liquid formulation of crofelemer in both the US and the European Union, as well as for the treatment of diarrhea in cholera in the US. The agent is also approved by the FDA for the symptomatic relief of diarrhea in adult patients with HIV/AIDS who are undergoing antiretroviral therapy.

What Was the Design of the OnTarget Study?

The OnTARGET trial was a multicenter, double-blind, placebo-controlled Phase 3 trial designed to evaluate crofelemer as prophylaxis for diarrhea in adult cancer patients.2 The study enrolled 287 patients across 10 solid tumor types who were treated with 24 different targeted therapies, either alone or in combination with chemotherapy.3

To enroll in OnTARGET, patients were required to be at least 18 years of age, have pathologically and/or radiologically confirmed solid tumors, and be scheduled to receive targeted cancer therapy for which the reported all-grade diarrhea rate was at least 50%. Further inclusion criteria mandated an ECOG performance status of 0 to 2 and a life expectancy of at least 12 weeks. Patients were excluded from the study if they had received any type of immunotherapy; required antidiarrheal prophylaxis for their cancer therapy; had ongoing irritable bowel syndrome or colitis; and had ongoing diarrhea, diarrheal episodes within seven days of randomization, or those had used laxatives within 7 days of enrollment.

Upon enrollment, patients were randomly assigned 1:1 to receive delayed-release crofelemer at 125 mg twice per day with or without food or matching placebo over a 12-week double-blind treatment phase. Stratification factors included type of targeted therapy and tumor type.

The primary end point of the trial was the frequency of loose or watery stools. Secondary end points included the maximum number of loose or watery stools per week, the proportion of durable, clinical responders, and fecal incontinence.

What Results From OnTarget Supported The ODD Application?

Although the trial failed to meet its primary end point of a statistically significant improvement in the incidence of diarrhea compared with placebo across the entire patient population, preliminary analysis revealed clinically meaningful benefit and clinically relevant signals in patients with breast and respiratory cancers, including lung cancer.3 These groups accounted for more than 75% of patients on the trial.

Overall, responders, defined as patients who reported fewer than 9 loose stools per week, experienced significantly better control of diarrhea with crofelemer vs placebo.4 Nearly half (47.1%) of patients receiving crofelemer were considered responders through 12 weeks vs 33.7% of those with placebo. Data from the 12-week double-blind extension phase of the study have not yet been analyzed.

Per additional data evaluating the frequency and severity of diarrhea in patients with breast cancer from the placebo group of OnTarget (n = 77) who received abemaciclib (Bavencio) and pertuzumab (Perjeta)–based therapies, 43% of patients treated with abemaciclib had to reduce or discontinue treatment due to diarrhea; all patients treated with pertuzumab-based regimens required dose reduction or discontinuation. Of note, most of the 183 patients with breast cancer on OnTarget received abemaciclib or pertuzumab.

Regarding safety, crofelemer was reported to be well tolerated. Its adverse event (AE) profile was similar to that of the matching placebo, and AEs were primarily linked to either the underlying disease or the patient's existing anticancer therapy.3

References

1. Jaguar Health Submits Orphan Drug Designation Application to FDA for Crofelemer for Cancer Therapy-Related Diarrhea (CTD) in Patients with Breast Cancer with Metastasis Identified by FDA as a Distinct Condition. News Release. Jaguar Health. September 24, 2025. Accessed September 26, 2025. https://jaguarhealth.gcs-web.com/news-releases/news-release-details/jaguar-health-submits-orphan-drug-designation-application-fda
2. Prophylaxis of diarrhea in adult cancer patients receiving targeted cancer therapy (OnTARGET). ClinicalTrials.gov. Updated April 15, 2024. Accessed July 23, 2024. https://clinicaltrials.gov/study/NCT04538625
3. Jaguar Health reports phase 3 OnTarget trial results for its cancer supportive care drug crofelemer. News release. Jaguar Health. July 23, 2024. Accessed September 26, 2025. https://jaguarhealth.gcs-web.com/news-releases/news-release-details/jaguar-health-reports-phase-3-ontarget-trial-results-its-0
4. Significant Positive Results with Jaguar Health's Crofelemer for Cancer Therapy-Related Diarrhea (CTD) in Breast Cancer Patients Presented at San Antonio Breast Cancer Symposium (SABCS). News Release. Jaguar Health. December 12, 2024. Accessed September 26, 2025. https://jaguarhealth.gcs-web.com/news-releases/news-release-details/significant-positive-results-jaguar-healths-crofelemer-cancer#:~:text=Significant%20Positive%20Results%20with%20Jaguar,2024%20/%20Jaguar%20Health%2C%20Inc.

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