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A Breakthrough in Reducing Cancer Therapy-Related Diarrhea in Dogs and Humans

By Craig Clifford, DVM, MS, DACVIM (Oncology), Michael Guy, DVM, MS, PhD and Allison Shrier, MD

Each year, cancer impacts millions of America’s dogs, humans and their families. Among the estimated 86 million dogs in the United States, roughly six million new cancer diagnoses are made each year, and almost half of dogs over 10 years of age will develop cancer. On the human side, in the U.S., more than two million people are expected to be diagnosed with cancer in 2024.

Cancer Therapy-Related Diarrhea (CTD)

For the most part, dogs that receive human chemotherapeutic agents may develop the same side effects as humans, such as nausea, vomiting and diarrhea. Such similarities aren’t surprising, given what we’ve learned from the field of Comparative Oncology—the study of spontaneous, naturally developing cancers in dogs and other animals as models for human disease.

The dynamics of treatment and supportive care are also remarkably alike in dogs and humans, with, for example, more than half of veterinarians reporting in a survey that cancer therapy-related diarrhea (CTD) interferes with their patient’s chemotherapy treatment plan.

CTD can be a debilitating side effect in dog and human patients receiving targeted therapy with or without chemotherapy. CTD can lead to dehydration, electrolyte and fluid imbalances, renal insufficiency, malnutrition, fatigue and non-adherence to cancer treatments. Indeed, while targeted therapies are effective, they have increased the burden of CTD in terms of its incidence and/or severity.

Current Management of CTD

Currently, there are three targeted therapies approved for use only in dogs: toceranib phosphate (Palladia®), verdinexor (Laverdia-CA1®) and tigilanol tiglate (Stelfonta®). As with the 25+ targeted therapies approved for humans, CTD is a common side effect of these “dogs only” targeted therapies. Further, several targeted therapies approved for humans are used off-label in dogs, e.g., imatinib (Gleevec®), neratinib (Nerlynx®), lapatinib (TYKERB®) and trametinib (MEKINIST), among others.
Whether a patient has two legs or four, CTD can have a significant effect on morbidity and mortality. In human patients, managing CTD may require dosing holidays, dose reductions or discontinuations of cancer drugs, potentially resulting in less effective cancer treatment, treatment resistance or failures. Based on experience, veterinarians reduce targeted therapy dosing far less frequently than do oncologists treating humans. When reductions in targeted therapy do occur in humans or dogs (albeit rarely), it can amount to trading cancer response to reduce the risk of potential toxicities.

Optimal management of CTD is critical for dogs and humans in the age of targeted cancer therapies. Unfortunately for humans, there have not been any significant advances to managing diarrhea in cancer patients. As a result, diarrhea associated with targeted therapy is commonly viewed as a “necessary evil.”

Currently, available antidiarrheal agents, many of which are opioid-based and can cause constipation, are suboptimal in managing CTD. In dogs, however, there is one treatment option for chemotherapy-induced diarrhea (CID, which is narrower than the more inclusive CTD).

From Rainforest to Remedy

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.1 Derived from the blood of the dragon, 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.

Under the brand name Mytesi®, crofelemer is also approved by the FDA for the symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS on antiretroviral therapy. Clinical research is underway for the potential use of crofelemer to prevent and/or treat CTD and other types of diarrhea in humans.

wide view of a forest of leafy trees
close upward view at a tall leafy tree
Croton lechleri tree photos provided by Steven King, PhD, of Jaguar Health.
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.

Crofelemer Trial in Dogs

A recently reported study in the peer-reviewed journal PLOS ONE evaluated the prophylactic effects of crofelemer in 24 healthy female beagle dogs with neratinib-induced diarrhea without concomitant loperamide administration.2 The dogs (eight per group) received daily oral dosing of neratinib and either placebo capsules or crofelemer delayed-release tablets 125 mg twice daily (BID) or four times daily (QID) for 28 consecutive days.

Neratinib, an irreversible pan-human epidermal growth factor receptor (HER) tyrosine kinase inhibitor (TKI), was chosen as the targeted therapy for dogs because it causes a high incidence of CTD in humans. In a placebo-controlled study of 2,840 human breast cancer patients without loperamide prophylaxis, the incidence of all-grade diarrhea was 96% of the patients given neratinib, and was 40% for grade three and four diarrhea.

Over the four-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. Additionally, there was a trend for fewer neratinib dose reductions in both crofelemer treatment groups when compared to the control group. The study investigators concluded that crofelemer prophylaxis reduced the incidence/severity of neratinib-associated diarrhea in female beagle dogs without the use of any loperamide treatment.

Crofelemer Trials in Humans

The study published in PLOS ONE, modeling the human situation with neratinib, concurs with two studies in humans:

  1. Phase 2 HALT-D Study: Demonstrates Impact of Crofelemer on CTD for Patients with HER2-Positive Breast Cancer Receiving Trastuzumab, Pertuzumab, and a Taxane: The HALT-D study, published in the peer-reviewed journal Breast Cancer Research and Treatment in October 2022, suggested that patients receiving prophylaxis with crofelemer had a reduction in the severity of higher-grade diarrhea. Patients receiving crofelemer prophylaxis also had higher odds of having diarrhea resolution compared to those receiving HER2-targeted therapy with standard chemotherapy using the current standard of care treatments to manage their diarrhea.3
  2. Independent Pilot Phase 2 Study: Crofelemer for the Management of Neratinib-Associated Diarrhea in Patients With HER2+ Early-Stage Breast Cancer: Published in the peer-reviewed journal Clinical Breast Cancer in October 2023, the study concluded that crofelemer may be effective for the management of neratinib-induced diarrhea.4

Whether it be human or dog, all three completed trials provide a scientific rationale for the use of crofelemer in dogs and humans for the treatment of CTD.

References:

  1. 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;9(6):877-896. doi:10.1089/107555303771952235.
  2. 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;19(1):e0282769. Published 2024 Jan 24. doi:10.1371/journal.pone.0282769.
  3. Pohlmann PR, Graham D, Wu T, et al. 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.
  4. 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.

Dr. Craig Clifford is a medical oncologist at BluePearl Malvern and was previously the director of BluePearl Science. He is active in clinical research within a referral setting and serves as an advisory board member with industry and non-profit foundations.

Michael K. Guy, DVM, MS, PhD is the Vice President of Preclinical and Nonclinical Studies at Jaguar Health, Inc. ‘Dr. Mike’ joined Jaguar Health in September 2015 and has over 25 years of experience in animal and human pharmaceutical development in the areas of clinical development, drug manufacturing, regulatory, and pre-clinical drug discovery.

Allison Ackerman Shrier has held diverse roles within the pharmaceutical industry, including entrepreneur, consultant, clinical trialist, CMO, and CEO; currently as VP of Medical Affairs and Clinical Research at Napo Pharmaceuticals.