Crofelemer Reduces Diarrhea in Humans and Dogs Being Treated for Cancer, Recent Studies Show

Currently in the United States, there are approximately 18 million cancer survivors,[1] and more than 2 million people are expected to be diagnosed with cancer this year.[2]

Diarrhea is an often-overlooked side effect of cancer therapy that can significantly impact patient outcomes and quality of life. In a study of patient-reported chemotherapy side effects, diarrhea was the second most common side effect reported after fatigue.[3] In response to a patient’s diarrhea, a treating physician may reduce a therapeutic dose or discontinue the cancer therapy altogether, potentially worsening patient outcomes. Specifically, patients with cancer and diarrhea are 40% more likely to discontinue their cancer therapy.[4] Furthermore, the cost of care for patients with cancer and diarrhea is estimated to be nearly 2.9 times higher than for patients with cancer without diarrhea.[5]

In patients with cancer, diarrhea can have many causes, including the cancer itself, infections, various medications, radiation therapy, and surgery of the gastrointestinal tract or other organs. However, the most frequent causes are cancer treatments, especially cytotoxic chemotherapies, immunotherapies, and targeted therapies.

For a number of cancers, targeted therapies (e.g., tyrosine kinase inhibitors [TKIs]) have demonstrated greater treatment success than traditional chemotherapy.[6] However, targeted therapies are often more likely to induce diarrhea or increase diarrhea frequency and/or severity than traditional chemotherapy. In fact, up to 95% (30%-95%) of patients on TKIs suffer from diarrhea that can become chronic, depending on the TKI used.[7]

Interestingly, the field of Comparative Oncology – the study of spontaneous, naturally developing cancers in dogs and other animals as models for human disease – has shown that cancer therapies may cause side effects in dogs that resemble those seen in humans. For example, in a survey of veterinarians, more than half reported that chemotherapy-induced diarrhea (CID) interferes with their canine patient’s chemotherapy treatment plan.[8] This is significant, as approximately 1 in 4 dogs will develop neoplasia at some stage in their life.[9] And, among the estimated 86 million dogs in the United States,[10] roughly 6 million new cancer diagnoses are made each year,[11] and almost half of dogs over 10 years of age will develop cancer.⁹ Depending on the cancer type, dogs with cancer are treated similarly to humans, often through traditional chemotherapy or TKIs.[12]

Reduced Efficacy and Quality of Life
Besides dehydration and electrolyte imbalances that, in some cases, can be life-threatening, cancer therapy–related diarrhea (CTD) – a broader, more inclusive term used when talking about humans versus CID with dogs – can reduce quality of life, interfere with activities of daily living,[13] and negatively affect nutritional status. Persistent and/or uncontrollable CTD has been linked with anxiety, depression, social isolation, and low self-esteem.[14]

Moreover, CTD can result in alterations of cancer management.[15] Studies have shown that CTD can result in delayed or reduced therapeutic dosing, or even complete treatment termination in some patients.[16][17] These alterations can potentially result in less effective cancer treatment, treatment resistance, or failures. Therefore, optimal management of CTD is critical for patients with cancer in the age of targeted cancer therapies.

Unfortunately, for decades there have been no significant advances for managing diarrhea in patients with cancer. Currently available antidiarrheal agents are suboptimal in managing CTD in humans. Many are opioid-based and can cause severe constipation, abdominal distension, central nervous system toxicity, and are only acute therapies. As a result, CTD is commonly viewed as a “necessary evil.”

For dogs, however, there is one treatment option specifically indicated for CID – crofelemer.

Crofelemer: Rainforest Roots
For centuries, Indigenous peoples in South America have used the thick red sap (sangre de drago, “blood of the dragon”) from Croton lechleri trees – found in the Amazon Rainforest – to treat a wide range of ailments, from diarrhea to wound healing.[18][19]

Purified from sap of Croton lechleri trees, crofelemer (brand name Canalevia^®-CA1) is conditionally approved by the FDA for the treatment of CID in dogs. It is the first and only treatment for CID in dogs to receive any approval from the FDA.[20] Under the brand name Mytesi^® (Napo Pharmaceuticals), crofelemer is also FDA-approved for the symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS on antiretroviral therapy.[21] Clinical research is underway for the potential use of crofelemer to prevent and/or treat CTD and other types of diarrhea in humans, and results will be available soon for a Phase 3 randomized, placebo-controlled, double-blind study (NCT04538625; OnTarget) to evaluate the safety and efficacy of crofelemer in providing prophylaxis of diarrhea in adult patients with solid tumors treated with targeted cancer therapy-containing treatment regimens.[22]

Crofelemer works by reducing chloride ion secretion into the gut lumen and normalizing the electrolyte and fluid balance there to produce formed stools. It is a natural, non-opioid, anti-secretory product with minimal systemic absorption, no antimotility activity with central nervous system effects, and no significant drug-drug interactions.[23] Crofelemer is currently the only FDA-approved oral botanical drug in the US.

Recent studies in patients and dogs undergoing targeted therapy for cancer have reinforced the potential of crofelemer for the treatment of CTD in humans and of CID in dogs.

Independent Pilot Phase 2 Study: Crofelemer for the Management of Neratinib-Associated Diarrhea in Patients With HER2+ Early-Stage Breast Cancer[24]

Purpose
This was the first study to evaluate crofelemer in managing neratinib-induced diarrhea in patients with early-stage breast cancer.

Methods

• Single-center, open-label, Phase 2 trial that enrolled 11 patients with Stage 2 to 3 HER2+ breast cancer and taking adjuvant neratinib.
• One patient cohort took prophylactic crofelemer 125 mg bid and loperamide in the first two 21-day cycles, and as needed in subsequent cycles.
• A second cohort took dose-escalated (DE cohort, n=4) neratinib with loperamide as needed.
• The primary endpoint was incidence of grade ≥3 diarrhea in the first two cycles.

Results

• During the first 2 cycles, two patients (29%) in the crofelemer cohort and two patients (50%) in the DE cohort experienced grade 3 diarrhea lasting 1 day on average.
• During the first 2 cycles, patients in the crofelemer cohort had an average of 1.05 diarrhea episodes/day; those in the DE cohort had an average of 1.27 episodes/day.
• For all cycles, three patients (43%) in the crofelemer cohort and 3 patients (75%) in the DE cohort reported quality-of-life impact for diarrhea.
• Three patients in the crofelemer cohort dose-reduced neratinib due to unreported causes in the first 2 cycles, and two patients dose-reduced due to diarrhea in the DE cohort.
• 82% experienced constipation, all grade 1.

Conclusion

• The study findings add to the current landscape of potential antidiarrheal options for patients with breast cancer.
• The results support the ongoing evaluation of crofelemer as an antidiarrheal option for treating neratinib-induced diarrhea as well as more broadly for diarrhea induced by other TKIs and cancer therapies.

Phase 2 HALT-D Study: Impact of Crofelemer on CTD for Patients with HER2-Positive Breast Cancer Receiving Trastuzumab, Pertuzumab, and a Taxane[25]

Purpose
This study assessed whether crofelemer can prevent CTD in patients with HER2+, any-stage breast cancer and are receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with or without carboplatin (C; always combined with docetaxel but not with paclitaxel).

Methods

• This was a randomized open-label Phase 2 study.
• Fifty-one patients scheduled to receive ≥3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally bid (n=26) during chemotherapy cycles 1 and 2 or no scheduled antidiarrheal prophylaxis (control) (n=25).
  • All received standard breakthrough antidiarrheal medication (BTAD) as needed.
• The primary endpoint was the incidence of any-grade CTD for ≥2 consecutive days.
• Secondary endpoints included:
  • Incidence of all-grade and grade 3/4 CTD by cycle/stratum
  • Time to onset and duration of CTD
  • Stool consistency
  • Use of BTAD
  • Quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score).

Results

• There was no statistically significant difference between the arms for the primary endpoint; however, the incidence of grade ≥2 CTD was reduced with crofelemer vs control (8.0% vs 39.1% in cycle 2, p=0.0196), and no patients in the crofelemer arm experienced grade 3/4 diarrhea compared to 17.3% of the patients receiving standard-of-care antidiarrheal medications.
• Watery diarrhea occurred less frequently in the crofelemer arm than in the control arm in cycle 1 by 23% (patient diary data).
• Patients receiving crofelemer were 1.8 times more likely to have their diarrhea resolve.

Conclusion

• Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CTD in patients with HER2+ breast cancer receiving paclitaxel-based therapy.
• These data support further testing of crofelemer in CTD.

Crofelemer Reduces CID in Dogs[26]

Purpose

This study evaluated the prophylactic effects of crofelemer in 24 healthy female beagle dogs with neratinib-induced diarrhea without concomitant loperamide administration.

Methods

• The dogs (8 per group) received daily oral dosing of neratinib and either placebo capsules or crofelemer delayed-release tablets 125 mg bid or qid for 28 consecutive days.
• Neratinib, an irreversible pan-human epidermal growth factor receptor (HER) TKI, was chosen as the targeted therapy for dogs because it causes a high incidence of CTD in humans.[27]

Results

• Over the 4-week study period, dogs in the two crofelemer groups had significantly lower average numbers of weekly loose/watery stools compared to dogs receiving neratinib with placebo:
  • 31% fewer weekly loose/watery stools with crofelemer bid vs. placebo (5.96 vs. 8.70, p=0.028)
  • 34% fewer weekly loose/watery stools with crofelemer qid vs. placebo (5.74 vs. 8.70, p=0.021)
  • No statistically significant difference between the crofelemer bid and qid groups in reducing neratinib-induced diarrhea (p=0.84)
• Crofelemer also demonstrated significant improvement in the proportion of responder dogs – defined as those with an average of one or no loose/watery stools per day or seven or fewer loose/watery stools per week for at least two of the four weeks of the study.
• There was a trend for fewer neratinib dose reductions in both crofelemer treatment groups compared to the control group.

Conclusions

• Crofelemer prophylaxis reduced the incidence/severity of neratinib-associated diarrhea in female beagle dogs without the use of any loperamide treatment.

OnTarget: Phase 3 Pivotal Trial Analysis In Progress[28]

Purpose
Crofelemer is also being investigated for the prophylaxis of diarrhea in a randomized, double-blind, placebo-controlled Phase 3 clinical trial for adult patients with solid tumors receiving targeted cancer therapies with or without standard chemotherapy regimens (NCT04538625; OnTarget study).

Methods

• This study enrolled patients with solid tumors initiating a targeted therapy associated with a high incidence of diarrhea (incidence rate greater than 50% of patients).
• Crofelemer or matching placebo was administered concomitant with targeted therapy and continued for 12 weeks, with an option to continue blinded treatment through 24 weeks. Rescue antidiarrheal medication was permitted.
• Patients assessed the frequency and severity of diarrhea during study participation with PRO diaries using the Bristol Stool Form Scale. The primary endpoint compared the average number of weekly loose/watery stools.
• Secondary endpoints included targeted and chemotherapy dose reduction/ discontinuations, and PRO diaries captured all stool forms, use of antimotility drugs, urgency, and fecal incontinence daily as well as the quality-of-life impacts weekly.
• Randomization was stratified by tumor type and type of targeted therapy, including abemaciclib, pertuzumab, and multiple other kinase inhibitors for EGF receptors, VEGF receptors, and other targets.

Results

• Results are anticipated in the second half of 2024.

Overall Conclusions
The physical and psychological effects of CTD can have a major, negative impact on a patient’s quality of life. Current options for managing CTD are suboptimal, as many are opioid-based and can cause severe constipation, abdominal distension, and CNS toxicity. Collectively, the three completed trials described above provide a scientific rationale for the use of crofelemer to treat CTD in humans and CID in dogs. CTD is not a “necessary evil” – we can do better for our patients.

Disclosures
Pablo Okhuysen, MD, is a professor in the Department of Infectious Diseases, Infection Control and Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. Conflict of interest: faculty grant/research support from Merck Sharp and Dohme Corp, Deinove Pharmaceuticals, Summit Pharmaceuticals, Melinta Pharmaceuticals, and Napo Pharmaceuticals. Consultant to Napo Pharmaceuticals, Ferring Pharmaceutical, Summit Pharmaceutical, and SNIPR Biome Company.

References
[1] American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2022-2024. Atlanta: American Cancer Society; 2022. Online. Last accessed on July 10, 2024
[2] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024 [published correction appears in CA Cancer J Clin. 2024 Mar-Apr;74(2):203]. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
[3] Pearce A, Haas M, Viney R, Pearson SA, Haywood P, Brown C, Ward R. Incidence and severity of self-reported chemotherapy side effects in routine care: A prospective cohort study. PLoS One. 2017 Oct 10;12(10):e0184360. doi: 10.1371/journal.pone.0184360. PMID: 29016607; PMCID: PMC5634543.
[4] Okhuysen PC, Schwartzberg LS, Roeland E, et al. The impact of cancer-related diarrhea on changes in cancer therapy patterns. J Clin Oncol. 2021; 39:15_suppl, 12111-12111. [Article]
[5] Roeland E, Schwartzberg LS, Okhuysen PC, et al. Healthcare utilization and costs associated with cancer-related diarrhea. J Clin Oncol. 2021; 39:15_suppl, e18623-e18623. [Article]
[6] Targeted Therapy: Stopping cancer in its tracks. March 5, 2018. Online. Last accessed on July 10, 2024
[7] Moschen AR, Sammy Y, Marjenberg Z, Heptinstall AB, Pooley N, Marczewska AM. The Underestimated and Overlooked Burden of Diarrhea and Constipation in Cancer Patients. Curr Oncol Rep. 2022 Jul;24(7):861-874. doi: 10.1007/s11912-022-01267-3. Epub 2022 Mar 24. PMID: 35325401.
[8] Survey of US veterinarians, sponsored by Jaguar Health.[On file]
[9] American Veterinary Medical Association (AVMA). Online  Last accessed on February 10, 2024
[10] American Veterinary Medical Association (AVMA). Online  Last accessed on February 10, 2024
[11] National Cancer Institute, Center for Cancer Research. What is comparative oncology? Online. Last accessed on February 10, 2024
[12] Coelho YNB, Soldi LR, da Silva PHR, Mesquita CM, Paranhos LR, Dos Santos TR, Silva MJB. Tyrosine kinase inhibitors as an alternative treatment in canine mast cell tumor. Front Vet Sci. 2023 Jun 8;10:1188795. doi: 10.3389/fvets.2023.1188795. PMID: 37360406; PMCID: PMC10285312.
[13] Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol. 2010 Jan;2(1):51-63. doi: 10.1177/1758834009355164. PMID: 21789126; PMCID: PMC3126005.
[14] Viele CS. Overview of chemotherapy-induced diarrhea. Semin Oncol Nurs. 2003 Nov;19(4 Suppl 3):2-5. doi: 10.1053/j.soncn.2003.09.007. PMID: 14702926.
[15] Verstappen CC, Heimans JJ, Hoekman K, Postma TJ. Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs. 2003;63(15):1549-63. doi: 10.2165/00003495-200363150-00003. PMID: 12887262.
[16] Arbuckle RB, Huber SL, Zacker C. The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist. 2000;5(3):250-9. doi: 10.1634/theoncologist.5-3-250. PMID: 10884503.
[17] Dranitsaris G, Maroun J, Shah A. Estimating the cost of illness in colorectal cancer patients who were hospitalized for severe chemotherapy-induced diarrhea. Can J Gastroenterol. 2005 Feb;19(2):83-7. doi: 10.1155/2005/618504. PMID: 15729427.
[18] Jones K. Review of sangre de drago (Croton lechleri)–a South American tree sap in the treatment of diarrhea, inflammation, insect bites, viral infections, and wounds: traditional uses to clinical research. J Altern Complement Med. 2003 Dec;9(6):877-96. doi: 10.1089/107555303771952235. PMID: 14736360.
[19] Bennett H. From folklore to pharmacy. Chemistry World. August 13, 2018:1-11.
[20] Canalevia®-CA1 (Crofelemer) [Freedom of Information Summary]. San Francisco, CA: Jaguar Health; 2021. Online. Last accesses on July 10, 2024
[21] Mytesi® (Crofelemer) [package insert]. San Francisco, CA: Jaguar Health; 2020. Online. Last accessed on July 10, 2024
[22] U.S. National Library of Medicine. 12 studies found for: Crofelemer. Online. Last accessed on July 6, 2022.
[23] Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010 Jan;77(1):69-78. doi: 10.1124/mol.109.061051. Epub 2009 Oct 6. PMID: 19808995; PMCID: PMC2802429.
[24] Jacob S, Johnson M, Roque B, Quintal L, Rugo HS, Melisko M, Chien AJ. Crofelemer for the Management of Neratinib-Associated Diarrhea in Patients With HER2+ Early-Stage Breast Cancer. Clin Breast Cancer. 2023 Oct;23(7):721-728. doi: 10.1016/j.clbc.2023.06.014. Epub 2023 Jul 4. PMID: 37474374.
[25] Pohlmann PR, Graham D, Wu T, Ottaviano Y, Mohebtash M, Kurian S, McNamara D, Lynce F, Warren R, Dilawari A, Rao S, Mainor C, Swanson N, Tan M, Isaacs C, Swain SM. HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane. Breast Cancer Res Treat. 2022 Dec;196(3):571-581. doi: 10.1007/s10549-022-06743-9. Epub 2022 Oct 25. PMID: 36280642; PMCID: PMC9633499.
[26] Guy M, Teixeira A, Shrier A, Meschter C, Bolognese J, Chaturvedi P. Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs. PLoS One. 2024 Jan 24;19(1):e0282769. doi: 10.1371/journal.pone.0282769. PMID: 38265977; PMCID: PMC10807780.
[27] Nerlynx® (neratinib) Package Insert. Revised 07/2017. Online. Last accessed on July 10, 2024
[28] National Library of Medicine (U.S.). (2020, October). Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy (OnTARGET) Identifier. NCT04538625.

Featured image: A patient having consultation with doctor. Photo Courtesy: © 2019 – 2024 Fotolia/Adobe. Used with permission.

DOI:10.14229/onco.2024.07.12.001