Pipeline

Rain has an exciting precision oncology pipeline.

Rain is building a precision oncology pipeline that’s focused on genetically selecting the patients most likely to benefit from treatment.

MILADEMETAN

Rain’s lead product candidate, milademetan, an oral small molecule, inhibitor of mouse double minute 2 (MDM2) is being developed in patients with wildtype tumor protein 53 (p53) cancers that are also exhibiting MDM2 dependence.  MDM2 dependence may be occurring either through MDM2 gene amplification, protein overexpression, loss of an MDM2 regulator or other mechanism.  

The tumor suppressor p53, commonly known as the "guardian of the genome", plays a central role in the arrest of the cell cycle and apoptosis to prevent malignant transformation and cancer progression. MDM2, a critical regulator of p53 activity and its tumor suppressor function, is often overexpressed in various cancers. By inhibiting MDM2, milademetan may restore wild-type p53 activity to resume its role in controlling growth of tumors with MDM2 amplification.  

In contrast to previous attempts at targeting MDM2, the properties of milademetan have enabled a differentiated dosing schedule. As hematopoietic cells also possess substantial levels of MDM2, on-target toxicities of the MDM2-class of compounds are blood-based toxicities, such as the cytopenias.  Thrombocytopenia, neutropenia and anemia have resulted from MDM2 inhibition and are on-mechanism.  However, the properties of milademetan have enabled a rationally designed dosing schedule in the prior Phase 1 study that has moderated these cytopenias to enhance the therapeutic index.  A more tolerable regimen, we believe, will preserve patient therapy, minimizing dose reductions, interruptions or discontinuations due to toxicity, ultimately enabling continuous treatment of the cancer.

Rain is initially evaluating milademetan for the treatment of well-differentiated (WD)/de-differentiated (DD) liposarcoma. Nearly 100% of WD/DD liposarcoma patients exhibit MDM2 gene amplification. The incidence of WD/DD liposarcoma is estimated at approximately 2,000 patients annually in the U.S. for which there are few effective treatment options. Rain commenced a pivotal Phase 3 trial for milademetan in liposarcoma patients (MANTRA) in July 2021.

Rain also commenced an additional Phase 2 trial in a multicenter, single arm, open-label, basket trial evaluating milademetan for the treatment of MDM2-amplified advanced solid tumors (MANTRA-2) in November 2021. Rain Therapeutics also anticipates commencing a Phase 2 clinical trial of milademetan (MANTRA-3), for the treatment of patients with Merkel cell carcinoma who are polyoma virus-positive and refractory to immune checkpoint inhibition, in mid-2022.


RAD52

RAD52 plays a central role in the DNA Damage Response (DDR) pathway. Targeting RAD52 represents a novel strategy for patients that may exhibit homologous recombination deficiencies (HRD+), or a loss of function, of several pathway constituents including BRCA1/2, PALB2 or several others in tumor types frequently characterized by these deficiencies. These tumors include breast, prostate, pancreatic, ovarian and possibly other cancers. Current approaches to treating these cancers include PARP inhibitors, however, patients often relapse to PARP inhibitors and are left with few options.

In cancer patients with BRCA1/2 deficiencies, or in patients relapsed to PARP inhibitor therapies, RAD52 may provide an alternative strategy. Rain anticipates selecting a lead clinical candidate for its RAD52 program in 2022.

Preclinical

pHASE 1

pHASE 2

pHASE 3

cOMMERCIAL RIghts

milademetan

MDM2 Inhibitor

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milademetan
Milademetan MDM2 Inhibitor
WD/DD Liposarcoma
Phase 3
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling

MANTRA -The MANTRA trial, a randomized, multicenter, open-label, Phase 3 registrational study, is designed to evaluate the safety and efficacy of RAIN-32 compared to trabectedin, a current standard of care, in patients with unresectable or metastatic DD LPS with or without a well-differentiated (WD) LPS component that has progressed on one or more prior systemic therapies, including at least one anthracycline-based therapy. Approximately 160 patients are expected to be randomized in a 1:1 ratio to receive milademetan or trabectedin. The primary objective of the trial is to compare progression-free survival (PFS) by blinded independent review between the milademetan treatment arm and the trabectedin control arm. Secondary endpoints include overall survival, PFS by investigator assessment, objective response rate, duration of response, disease control rate, safety and patient reported outcomes.

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milademetan

MDM2 Inhibitor

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milademetan
Milademetan MDM2 Inhibitor
MDM2-amplified Solid Tumors
Phase 2
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling
Enrolling

MANTRA-2 -The MANTRA-2 trial is designed to evaluate the safety and efficacy of milademetan in patients with advanced or metastatic solid tumors refractory or intolerant to standard-of-care therapy and that exhibit wild-type p53 and a prespecified minimum MDM2 gene copy number. Approximately 65 patients are anticipated to be enrolled to receive milademetan. The primary endpoint of the trial is objective response rate as measured by RECIST criteria. Secondary endpoints include duration of response, disease control rate progression-free survival by investigator assessment, overall survival and, and growth modulation index.

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milademetan

MDM2 Inhibitor

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milademetan
Milademetan MDM2 Inhibitor
Merkel Cell Carcinoma
Phase 2
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022
Planned 2H 2022

MANTRA-3 -The MANTRA-3 trial is designed to evaluate the efficacy of milademetan as a monotherapy in patients with MCC that have progressed on immune checkpoint inhibitors. Approximately 30 patients are expected to be enrolled to receive milademetan. The primary endpoint of the trial is objective response rate (ORR) as measured by RECIST criteria. Secondary endpoints include duration of response, disease control rate, progression free survival by investigator assessment, growth modulation index, overall survival and safety.

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milademetan

MDM2 Inhibitor

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milademetan
Milademetan MDM2 Inhibitor
CDKN2A Loss, p53 WT Advanced Solid Tumors
Phase 1
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022
Planned 2H-2022

MANTRA-4 - The MANTRA-4 trial is a phase 1 study designed to evaluate the safety and efficacy of milademetan in combination with atezolizumab in patients with advanced solid tumors with CDKN2A functional loss and wild type p53. Approximately thirty patients are anticipated to be enrolled in the study. The primary objective of the trial is to determine a recommended dose and schedule to move into phase 2 trials. Secondary endpoints will include objective response rate (ORR) as measured by RECIST criteria, duration of response, disease control rate, progression free survival and growth modulation index.

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RAD52

Research Program

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RAD52
RAD52 Research Program
HRD+ Tumors
Preclinical
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022
Lead ID in 2022

RAD52 -RAD52 plays a central role in the DNA Damage Response (DDR) pathway. Targeting RAD52 represents a novel strategy for patients that may exhibit homologous recombination deficiencies (HRD+), or a loss of function, of several pathway constituents including BRCA1/2, PALB2 or several others in tumor types frequently characterized by these deficiencies. In cancer patients with BRCA1/2 deficiencies, or in patients relapsed to PARP inhibitor therapies, RAD52 may provide an alternative strategy.

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We are currently developing milademetan and RAD52 programs.

Our Scientific programs

Milademetan
Rad52
Research program

Rain’s biomarker-driven therapeutic pipeline is composed of a  MDM2 inhibitor drug candidate in late-stage clinical trials for various cancer indications, and a first-in-class preclinical program as a novel DNA damage response strategy.  Both programs are being developed in cancers that depend on specific proteins for cancer cell survival, with the aim that inhibition of that target leads to cancer cell death by restoring innate anti-cancer mechanisms or by preventing cancer cells from correcting natural defects in their DNA.  Our RAD52 program strategy may have synthetic lethal avenues available where inhibition of the target is more potent in cancer cells when another, concomitant, aberrant gene signature co-exists, thereby leading to cancer cell killing while not impacting healthy cells.