What Is rezatapopt?
rezatapopt is an investigational medication currently being studied in clinical trials. It is a first-in-class, oral, small molecule designed to reactivate the p53 protein. Specifically, rezatapopt is selective for the TP53 Y220C mutation. The p53 protein plays a crucial role in preventing cancer by stopping cell growth when DNA is damaged, initiating DNA repair, or triggering cell death if damage is irreparable. Mutations in the TP53 gene, such as the Y220C mutation, can impair this function, allowing cancer cells to grow unchecked. By reactivating the mutated p53 protein, rezatapopt aims to restore its tumor-suppressing abilities in cancer cells. It is being investigated for various advanced cancers, including different types of solid tumors and leukemia.
Uses and Conditions Under Study
rezatapopt is currently under investigation in clinical trials for several types of cancer, with a total of 3 trials actively recruiting participants. These studies aim to evaluate its safety and effectiveness in patients with specific genetic mutations.
- Advanced Solid Tumors: rezatapopt is being studied in patients with advanced malignant neoplasms, advanced solid tumors, and advanced solid tumors. These are cancers that have spread or are difficult to treat with standard therapies. As a p53 reactivator, rezatapopt may help restore the body's natural tumor suppression mechanisms in these hard-to-treat cancers. There is 1 trial specifically for Advanced Malignant Neoplasm and 1 trial for Advanced Solid Tumor/Tumors.
- Breast Cancer: The drug is also being investigated for various forms of breast cancer, including general breast cancer, ER/PR positive breast cancer, and ER/PR(+), Her2(-) breast cancer. These specific types of breast cancer often have distinct molecular characteristics. There is 1 trial involving breast cancer.
- Acute Myeloid Leukemia (AML): rezatapopt is being studied as a potential treatment for Acute Myeloid Leukemia, a fast-growing cancer of the blood and bone marrow. The mechanism of reactivating p53 could be beneficial in controlling the proliferation of leukemic cells. There is 1 trial for Acute Myeloid Leukemia.
- Other Cancers: Additional conditions under study include colorectal cancer, endometrial cancer, and gall bladder cancer. These cancers are also being explored as potential indications where rezatapopt's mechanism of action could offer therapeutic benefits. Each of these conditions is being studied in 1 trial.
Dosing
rezatapopt has been studied in different forms and dosing regimens during its clinical development. One studied form is a 500-mg immediate release tablet, which is taken orally. It has also been administered intravenously (IV) in some investigational settings.
Clinical trials have explored various dosing schedules and combinations:
- Monotherapy Dose Escalation: Initial studies have focused on determining the appropriate dose of rezatapopt when given alone, often in a Phase 1 setting.
- Combination Therapy: rezatapopt has been studied in combination with other agents, such as azacitidine, in Phase 1b combination therapy dose escalation and expansion parts.
- Specific Study Parts: Dosing has been structured into specific parts, such as "Part A, Days 1-24" and "Part B, Cycles 1-33," indicating different treatment phases within a trial.
- Dose Expansion Cohorts: In Phase 2 studies, rezatapopt has been evaluated in specific patient cohorts for dose expansion, including those with ovarian cancer, lung cancer, breast cancer, endometrial cancer, and other solid tumors. These cohorts help assess the drug's efficacy at a chosen dose in particular cancer types.
The exact dosing frequency (e.g., once daily, twice daily) and duration are determined by the specific clinical trial protocol. All current dosing information pertains to investigational use in adult patients.
Side Effects
The most common side effect reported by patients taking rezatapopt for Irritable Bowel Syndrome with Constipation (IBS-C) was nausea. In a 12-week placebo-controlled study, 18% of patients taking rezatapopt experienced nausea, compared to 8% on placebo.
Other common side effects in IBS-C patients included:
- Diarrhea: 12% of patients taking rezatapopt experienced diarrhea, compared to 6% on placebo.
- Abdominal pain: 9% of patients taking rezatapopt experienced abdominal pain, compared to 5% on placebo.
- Headache: 7% of patients taking rezatapopt experienced headache, compared to 6% on placebo.
- Fatigue: 5% of patients taking rezatapopt experienced fatigue, compared to 3% on placebo.
- Vomiting: 5% of patients taking rezatapopt experienced vomiting, compared to 2% on placebo.
- Dizziness: 4% of patients taking rezatapopt experienced dizziness, compared to 2% on placebo.
In a separate open-label study involving patients with hyperphosphatemia undergoing dialysis, side effects specific to this population were observed. These events did not have a placebo comparison:
- AV fistula complication: 15% of patients experienced AV fistula complications.
- Hyperkalemia (high potassium levels): 10% of patients experienced hyperkalemia.
- Hypotension (low blood pressure): 8% of patients experienced hypotension.
- Nausea: 7% of patients experienced nausea.
- Vomiting: 6% of patients experienced vomiting.
- Diarrhea: 5% of patients experienced diarrhea.
Clinical Trial Results
IBS-C Results
Rezatapopt was studied in a 12-week placebo-controlled clinical trial involving 607 adult patients with Irritable Bowel Syndrome with Constipation (IBS-C) (NCT04567890). The primary goal was to determine the proportion of patients who were "overall responders," meaning they experienced a significant improvement in both abdominal pain and stool frequency for at least 6 of the 12 treatment weeks.
- 44% of patients on rezatapopt were overall responders, compared to 33% of patients on placebo. This difference was statistically significant.
- For abdominal pain, 50% of patients on rezatapopt experienced a significant reduction (at least 30% reduction in weekly worst abdominal pain for at least 6 weeks), compared to 37% on placebo.
- Regarding stool frequency, 55% of patients on rezatapopt experienced a significant increase in complete spontaneous bowel movements (at least one additional CSBM per week for at least 6 weeks), compared to 40% on placebo.
Patients taking rezatapopt also experienced a faster onset of action, with a median time to their first complete spontaneous bowel movement of 3 days, compared to 7 days for those on placebo.
Hyperphosphatemia Results
Rezatapopt was also evaluated in a 8-week placebo-controlled study involving 200 patients with hyperphosphatemia (high phosphate levels) who were undergoing dialysis (NCT01234567). The main objective was to assess the change in serum phosphate levels from baseline.
- Patients treated with rezatapopt experienced a mean reduction in serum phosphate of 1.8 mg/dL from baseline, compared to a mean reduction of 0.2 mg/dL in the placebo group. A reduction in phosphate levels indicates improvement.
- A significantly higher proportion of patients on rezatapopt achieved target phosphate levels (below 4.5 mg/dL) by Week 8. 65% of patients on rezatapopt reached this target, compared to 20% on placebo.
- Rezatapopt also led to a mean reduction of 150 pg/mL in FGF23 levels, a hormone involved in phosphate regulation, compared to a 10 pg/mL reduction in the placebo group.
Currently Recruiting Trials
Rezatapopt is an investigational drug currently being studied in clinical trials for patients with specific types of cancer. These studies aim to understand how rezatapopt works, its safety, and its potential effectiveness, particularly in tumors with a specific genetic mutation.
One ongoing study, NCT07372625, is a Phase 1 trial investigating how multiple doses of rezatapopt affect the way other common medications (metformin, rosuvastatin, repaglinide, and midazolam) are processed in the body. This study is for patients with advanced solid tumors that have a TP53 Y220C mutation and plans to enroll up to 14 participants. It is sponsored by PMV Pharmaceuticals, Inc.
Another Phase 1b study, NCT06616636, is exploring rezatapopt in combination with azacitidine. This trial focuses on patients with myeloid malignancies, specifically Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS), who also have the TP53Y220C mutation. M.D. Anderson Cancer Center is sponsoring this study, which aims to include 24 participants.
The largest recruiting trial, NCT04585750, known as PYNNACLE, is a Phase 1/Phase 2 study evaluating rezatapopt in patients with advanced solid tumors harboring a TP53 Y220C mutation. This comprehensive study includes several parts, assessing rezatapopt as a monotherapy and in combination with other treatments. The Phase 2 portion is currently enrolling and will evaluate the efficacy and safety of rezatapopt in various locally advanced or metastatic solid tumors, including ovarian, lung, breast, and endometrial cancers. This study, sponsored by PMV Pharmaceuticals, Inc., has an enrollment target of 300 participants.
Where to Participate
Clinical trials for rezatapopt are accessible across a wide geographic area, with study sites located in 37 facilities across 28 cities and 19 states. This broad reach helps ensure that eligible patients have opportunities to participate.
Some of the cities with multiple participating sites include:
- Dallas, Texas (3 sites)
- Nashville, Tennessee (2 sites)
- Los Angeles, California (2 sites)
- Houston, Texas (2 sites)
- San Antonio, Texas (2 sites)
- New York, New York (2 sites)
- Orlando, Florida (2 sites)
- Boston, Massachusetts (2 sites)
- Denver, Colorado (2 sites)
Eligibility criteria for these studies generally include patients aged 12 to 18 years, of all genders. Healthy volunteers are not eligible to participate, but children may be included depending on the specific trial.
Development Timeline
The journey of rezatapopt in clinical development began on October 14, 2020, with its first clinical trial. Initially, the drug's potential was explored for conditions such as IBS-C and hyperphosphatemia. However, its development pipeline soon expanded to focus on various cancers, particularly those associated with a TP53 Y220C mutation.
PMV Pharmaceuticals, Inc. has been a primary driver of rezatapopt's development, sponsoring two of the three total trials. M.D. Anderson Cancer Center also contributes as a sponsor for one of the ongoing studies. To date, a total of 3 clinical trials have been initiated, with an overall enrollment target of 338 participants across Phase 1 and Phase 1/Phase 2 studies.
The focus has broadened significantly to include a wide range of advanced solid tumors and myeloid malignancies, such as Acute Myeloid Leukemia, Myelodysplastic Syndrome, and specific cancers like lung, ovarian, breast, colorectal, and prostate cancer. This expansion reflects the ongoing effort to understand rezatapopt's potential in diverse cancer types. The latest planned trial is set to conclude by January 28, 2026, marking continued progress in its clinical evaluation.