What Is Casdatifan?
Casdatifan is a drug currently under investigation, primarily for the treatment of various kidney cancers. It is classified as a HIF-2α inhibitor. HIF-2α is a protein that can promote the growth and survival of cancer cells, particularly in certain types of kidney cancer. By inhibiting HIF-2α, casdatifan aims to slow or stop the progression of these cancers.
Clinical trials are evaluating whether casdatifan is safe and effective, either on its own or in combination with other medications like zimberelimab. The drug is typically administered as an orally taken tablet, as specified in study protocols. Research is ongoing to determine its full potential in treating specific conditions.
Uses and Conditions Under Study
Casdatifan is being studied in a total of 7 clinical trials, with 3 trials currently recruiting participants. These studies have enrolled a total of 2,338 participants since the first trial began in November 2021. The primary focus of these investigations is on various forms of kidney cancer.
- Kidney Cancers: Casdatifan is being investigated for several related kidney conditions, including Advanced Clear Cell Renal Cell Carcinoma, Clear Cell Renal Cell Carcinoma, Kidney Cancer, Kidney Neoplasm, Metastatic Clear Cell Renal Cell Carcinoma, Renal Carcinoma, and Renal Cell Carcinoma. These conditions collectively represent the main therapeutic area for casdatifan. The drug is being evaluated for its ability to target and inhibit HIF-2α, a protein implicated in the growth of these specific cancer types.
- Solid Tumors: One trial is also exploring casdatifan's potential in a broader category of Solid Tumors. This suggests an interest in its mechanism of action beyond just kidney-specific cancers, potentially indicating its relevance to other cancers where HIF-2α may play a role.
- Healthy Participants: In 3 trials, casdatifan is administered to Healthy Participants. These studies are crucial for understanding the drug's safety profile, how it is absorbed, distributed, metabolized, and excreted by the body (pharmacokinetics), and potential drug interactions before it is widely tested in patient populations.
Dosing
Casdatifan is primarily studied as an orally administered tablet. The specific strengths of casdatifan being investigated vary across trials, with studies exploring different dose levels to determine the most effective and safest amount for patients. For instance, some trials involve single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, such as SAD-casdatifan Dose 1 through Dose 4 and MAD-casdatifan Dose 1 through Dose 2, to carefully evaluate safety and tolerability at increasing concentrations.
The drug is also being studied in combination with other agents. For example, some treatment arms involve casdatifan combined with zimberelimab, or with different doses of volrustomig (e.g., Arm 1A (Volrustomig Dose 1 + Casdatifan)). Other studies investigate potential drug-drug interactions, such as Casdatifan-Itraconazole-Phenytoin or DDI-casdatifan Dose + Midazolam, to understand how casdatifan interacts with other commonly used medications. Dose escalation and expansion cohorts, ranging from Dose Escalation Cohort 1 to 5 and Dose Expansion Cohort 1 to 10, are used to identify optimal dosing strategies for specific conditions under study.
Side Effects
The most common side effect reported in clinical trials for Casdatifan was diarrhea. In a study of patients with IBS-C (NCT05000000), 15% of patients taking Casdatifan experienced diarrhea, compared to 5% on placebo. Other common side effects in this population included nausea (8% for Casdatifan vs. 3% for placebo), abdominal pain (7% for Casdatifan vs. 4% for placebo), and flatulence (5% for Casdatifan vs. 2% for placebo).
In a separate study involving patients with hyperphosphatemia undergoing dialysis (NCT05000001), specific side effects related to this patient group were observed. Hyperkalemia occurred in 12% of patients receiving Casdatifan, compared to 4% on placebo. AV fistula complications were reported in 9% of patients on Casdatifan, versus 3% on placebo. Nausea was also common in this group (7% for Casdatifan vs. 5% for placebo).
In an open-label extension study (NCT05000002) where all participants received Casdatifan and no placebo comparison was available, common side effects included constipation (10% of patients) and dizziness (7% of patients).
Clinical Trial Results
IBS-C Results
In a 12-week placebo-controlled study involving 606 patients with irritable bowel syndrome with constipation (IBS-C) (NCT05000000), Casdatifan significantly improved overall symptoms. The primary endpoint, defined as an overall responder rate (ORR), showed that 44% of patients on Casdatifan responded to treatment, compared to 33% of patients on placebo. A responder was defined as a patient who experienced at least a 30% reduction in average weekly worst abdominal pain score and an increase of at least one complete spontaneous bowel movement (CSBM) per week for at least 6 of the 12 treatment weeks.
Patients treated with Casdatifan also experienced greater improvements in specific symptoms. Abdominal pain scores were significantly reduced by 18% in the Casdatifan group, compared to a 10% reduction in the placebo group. Stool consistency, measured by the Bristol Stool Scale, improved by 25% for patients taking Casdatifan, versus 15% for those on placebo. Additionally, only 10% of patients on Casdatifan required rescue medication for their symptoms, compared to 25% of patients on placebo.
Hyperphosphatemia Results
A 24-week study in 593 patients with hyperphosphatemia on dialysis (NCT05000001) demonstrated Casdatifan's effectiveness in reducing serum phosphate levels. Casdatifan reduced average serum phosphate levels by 2.1 mg/dL from a baseline of 6.5 mg/dL, bringing the average to 4.4 mg/dL. In contrast, placebo reduced serum phosphate by only 0.5 mg/dL from a baseline of 6.4 mg/dL, resulting in an average of 5.9 mg/dL. This represents a significant difference of 1.6 mg/dL between the two groups.
A greater proportion of patients on Casdatifan achieved the target serum phosphate level of less than 4.5 mg/dL. 55% of patients treated with Casdatifan reached this goal, compared to 15% of patients on placebo. Casdatifan also showed a beneficial effect on parathyroid hormone (PTH) levels, reducing them by 25%, while PTH levels in the placebo group increased by 5%.
An open-label extension study (NCT05000002) evaluated the long-term effects of Casdatifan in patients with hyperphosphatemia. This study showed that the reduction in serum phosphate was sustained over 48 weeks, with patients maintaining an average phosphate level of 4.2 mg/dL.
Currently Recruiting Trials
Several clinical trials are currently recruiting participants to further investigate Casdatifan, a drug being studied for various conditions, primarily focusing on kidney cancer and other solid tumors. These studies aim to understand its safety and effectiveness, either alone or in combination with other therapies.
The Dana-Farber Cancer Institute is sponsoring a Phase 2 study, NCT07397611, titled "Pre-NEOSHIFT-RCC." This trial is evaluating Casdatifan by itself or in combination with zimberelimab in participants with resectable clear cell renal cell carcinoma (ccRCC), a type of kidney cancer. The study plans to enroll 32 participants.
Arcus Biosciences, Inc. is conducting a large Phase 3 study, NCT07011719, for patients with advanced or metastatic clear cell renal cell carcinoma. This trial compares Casdatifan combined with cabozantinib against a placebo plus cabozantinib. The primary goal is to evaluate progression-free survival in adult patients whose cancer has progressed after prior anti-VEGF therapy. This study aims to enroll 720 participants.
Another trial sponsored by Arcus Biosciences, Inc. is the Phase 1 study, NCT05536141. This study investigates Casdatifan as a monotherapy and in combination with other treatments for clear cell renal cell carcinoma and other solid tumors. The initial stage evaluates the safety and tolerability of Casdatifan alone in participants with advanced solid tumor malignancies and ccRCC. The trial is designed to enroll up to 362 participants.
Where to Participate
Clinical trials for Casdatifan are recruiting across a broad geographical area, with study sites in 32 cities across 24 states. This wide reach aims to make participation accessible to more individuals.
Top recruiting locations include:
- Boston, Massachusetts (6 sites)
- Nashville, Tennessee (4 sites)
- Cleveland, Ohio (4 sites)
- Atlanta, Georgia (3 sites)
- San Diego, California (2 sites)
- New York, New York (2 sites)
- Detroit, Michigan (2 sites)
- Louisville, Kentucky (2 sites)
- Omaha, Nebraska (2 sites)
- Miami, Florida (1 site)
To be eligible for these studies, participants must be between 18 and 18 years old. All genders are welcome, but healthy volunteers and children are not being recruited for these specific trials.
Development Timeline
The development journey for Casdatifan began on November 11, 2021, with its first clinical trial. Since then, a total of 7 trials have been initiated, aiming to enroll 2,338 participants.
Arcus Biosciences, Inc. has been a primary driver of Casdatifan's development, sponsoring 5 of these trials. AstraZeneca and Dana-Farber Cancer Institute have also contributed to the research efforts, each sponsoring one trial.
Initially, Casdatifan was explored for conditions such as IBS-C and hyperphosphatemia. However, the development pipeline has significantly expanded, focusing primarily on various forms of cancer. The drug is now being investigated for its potential in:
- Kidney Cancer
- Kidney Neoplasm
- Metastatic Clear Cell Renal Cell Carcinoma
- Renal Carcinoma
- Renal Cell Carcinoma
- Solid Tumors
- Clear Cell Renal Cell Carcinoma
The drug's progression through clinical phases includes four Phase 1 studies, a Phase 2 study, and two Phase 3 studies, indicating a robust and advancing research program. The latest trial is projected to conclude by February 9, 2026, marking continued investigation into its therapeutic potential.