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Introduction
Rain Oncology (NASDAQ:RAIN) (formerly Rain Therapeutics) is a late-stage oncology company established in Delaware in 2017, specializing in precision oncology by targeting oncogenic drivers. They use a tumor-agnostic approach to select patients based on their tumor genetics. Their lead product, milademetan, is an oral inhibitor of the MDM2-p53 complex that reactivates p53. The company is also working on a preclinical program focused on inducing synthetic lethality in cancer cells by inhibiting RAD52. Its operations are based in the US with headquarters in Newark, California.
The following article will focus on milademetan’s potential in dedifferentiated liposarcoma.
Financials
Before we begin, let’s take a look at Rain’s financials. Rain recently released its financial report for the past three months. They saw a loss of $18 million, which is a slight increase from the same period last year when they saw a loss of $18.4 million. Their expenses for research and development went down from $15.3 million to $14.5 million this year, mainly due to lower fees and higher payroll costs for R&D employees. On the other hand, general and administrative expenses went up from $3.2 million to $3.9 million, mainly due to increased payroll and outside consulting expenses. Rain had $90.7 million in cash, cash equivalents, and short-term investments as of September 30, 2022, which is less than the previous year’s end-of-year balance of $140.2 million. However, they recently raised $50 million through a stock offering, which will help keep them afloat through 2025. Rain is without significant long-term debt.
As of writing (February 5, 2023), Rain’s market capitalization is $342 million (~$200 million enterprise value).
Liposarcoma pathophysiology/current treatments
Liposarcoma is a type of cancer that originates in the body’s fat cells. Dedifferentiated liposarcomas (DDLPS), nonlipogenic sarcomas characterized by an amplification of MDM2 and CDK4, are challenging to treat with chemotherapy and other systemic treatments. Currently, the FDA-approved second-line treatments for patients with unresectable or metastatic DDLPS are trabectedin and eribulin, however, these treatments have shown limited success with a median progression-free survival, or PFS, of only 2.0-2.2 months. On the other hand, inhibitors of CDK4, a protein that is frequently overexpressed in DDLPS along with MDM2, have shown more promising results with a median PFS of 4.1 months with palbociclib and 7.0 months with abemaciclib, but are not approved in this indication and, thus, utilized off-label.
DDLPS market
Every year, around 1000 new cases of DDLPS are estimated to occur in the US. The interest in finding effective treatments for DDLPS is increasing, despite the uncommonness of the condition. Patients and their families are seeking better results and a better quality of life, but currently available treatments are limited, particularly for those with advanced or metastatic disease. This presents a big chance for Rain to come up with new and imaginative therapies as the demand for DDLPS treatments continues to grow.
If Rain can attain significantly improved results compared to existing treatments, it could price milademetan competitively, potentially generating annual revenue of between $100 million and $200 million for the company, just in this specific indication. It’s worth noting that Rain is also testing milademetan for other indications.
Role of MDM2 inhibition in DDLPS
MDM2 inhibition is a topic of focus for DDLPS treatment. Despite many years of research, no MDM2 inhibitors have made it past the early stages of clinical trials in solid tumors. The main hindrance to the development of MDM2 inhibitors is myelosuppression, a side effect caused by reactivation of p53, leading to apoptosis of megakaryocyte progenitor cells and reduced platelet production. Despite attempts to mitigate myelosuppression through dosage adjustments or informed by pharmacokinetic and pharmacodynamic modeling, no effective solution has been identified yet.
Milademetan – preclinical & first in-human data
Milademetan (RAIN-32) is a selective small-molecule inhibitor that targets the interaction between MDM2 and p53 and activates p53 function at nanomolar concentrations in vitro. In preclinical studies, milademetan induced p53-dependent apoptosis in human cancer cell lines and demonstrated efficacy against tumors with functional, wild-type p53 in xenograft models.
In early human studies, traditional continuous dosing schedules of milademetan led to unfavorable myelosuppression, including thrombocytopenia. To overcome this, alternative intermittent dosing schedules were explored and found to reduce the occurrence and severity of hematologic events and allow for continued therapy with fewer interruptions. The chosen dosing schedule for future clinical development is 260 mg on days 1-3 and 15-17 every 28 days.
The study showed that milademetan had a disease control rate of 46% in the overall population and 59% in the DDLPS subgroup, with two patients experiencing prolonged partial responses and a median progression-free survival of 7.2 months (n=53). The use of an intermittent dosing schedule for milademetan shows promise in overcoming challenges faced by previous MDM2 inhibitors:
Respective rates of all-grade and grade 3/4 drug-related thrombocytopenia were 44.7% and 15.8% with intermittent schedules (n = 38) versus 69.6% and 36.2% with extended/continuous schedules (n = 69); similar trends were observed for other hematologic events (Table 2). Dose reductions and dose interruptions for drug-related thrombocytopenia with intermittent schedules were required in eight (21.1%) and six (15.8%) patients, respectively, and with extended/continuous schedules in 16 (23.2%) and 24 (34.8%), respectively. Drug-related serious adverse events were reported in 0% of patients with intermittent versus eight (11.6%) patients with extended/continuous schedules. There were no reports of severe bleeding with milademetan, or drug-related adverse events associated with a fatal outcome.
Ongoing phase III registration study
The results of a recently initiated phase III randomized registration study (MANTRA; RAIN-3201) will be pivotal in determining the efficacy of milademetan in treating DDLPS. The study compares milademetan with trabectedin in patients with unresectable or metastatic disease who have experienced progression on at least one previous systemic therapy. The results of this study will be crucial in deciding whether milademetan can be a new treatment option for DDLPS patients. Encouraging early-stage data provides hope for this potential new treatment.
Rain anticipates top-line results in Q1 2023.
Conclusion
Milademetan, a selective small-molecule inhibitor of the MDM2-p53 interaction, offers promising potential as a treatment for DDLPS, a type of cancer that originates in fat cells and is resistant to chemotherapy. Results from the first-in-human study showed single-agent efficacy, with a 46% disease control rate and an even higher rate of 59% in the subgroup of DDLPS patients. Intermittent dosing schedules were also evaluated and found to reduce the occurrence and severity of hematologic events and allow for more consistent therapy. The same intermittent dosing schedule will be used in the upcoming pivotal trial. The outcome of the phase III registration study comparing milademetan and trabectedin will be critical in determining the efficacy of milademetan for treating DDLPS.
While the prospects for milademetan are promising, investors should exercise caution and not allocate too much capital in Rain Oncology, due to its speculative nature. Rain Oncology is a speculative buy heading into pivotal, phase III data for DDLPS.
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