Early Trials of PRMT5 Inhibitors Leave Much to Be Desired, But Optimism Remains

Despite the discovery of protein arginine methyltransferase 5 (PRMT5) more than 20 years ago, interest in the potential oncogene as a treatment target for patients with hematologic and solid malignancies has increased in recent years with the advancement of multiple novel agents through preclinical and early-phase studies.¹

PRMT5 is the major type II arginine methyltransferase and has a hand in several key biological processes, including the regulation of cell growth and migration. It is capable of methylating histone and non-histone substrates and can also undergo methylation. The gene is also involved in the cell cycle and embryonic development.²

Direct arginine methylation by PRMT5 has been shown to affect the activity of multiple proteins that are essential to the growth factor signaling pathway that plays a role in the proliferation, differentiation, and survival of cancer cells. Studies have demonstrated that PRMT5 is upregulated in lymphomas, breast cancer, lung cancer, colorectal cancer, and glioblastoma, leading investigators to believe that it has the potential to be a promising treatment target.^2,3

Investigators have hypothesized that PRMT5 inhibition could represent a novel therapeutic strategy to address cancer-initiating cells. Inhibition of PRMT5 could disable mechanisms protecting tumor cells from DNA damage caused by radiotherapy and chemotherapy. Preclinical study has shown that PRMT5 depletion or inhibition sensitizes tumor cells to agents that induce the DNA damage response, such as PARP and topoisomerase inhibitors.³

Early-Phase Studies of PRMT5 Inhibitors Display Mixed Results

To date, no PRMT5 inhibitors have gained FDA approval for the treatment of patients with cancer.⁴ However, several novel agents are currently being developed for patients with hematologic malignancies, solid tumors, and historically hard-to-treat malignancies (Table).⁵

During the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Ahnert et al presented findings from a phase 1 dose-escalation study (NCT03854227) examining the PRMT5 inhibitor PF-06939999. The study enrolled patients with solid tumors, including endometrial cancer, head and neck squamous cell carcinoma (HNSCC), non–small cell lung cancer (NSCLC), urothelial cancer, cervical cancer, and esophageal cancer.⁶

PF-06939999 was administered at a dose of 0.5 mg to 12 mg daily. Two of 28 efficacy-evaluable patients who were treated with the agent achieved a partial response (PR), 1 with HNSCC and 1 with NSCLC. Safety findings showed that there were no treatment-related deaths or discontinuations due to treatment-related toxicities in the safety population. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia (n = 2), anemia (n = 1), and neutropenia (n = 1). Any-grade treatment-related adverse effects (TRAEs) occurred in 86% of patients and included anemia (43%), thrombocytopenia (32%), dysgeusia (29%), and nausea (29%).⁶

Investigators concluded that PF-06939999 displayed dose-dependent and manageable toxicities and selected 6 mg daily as the recommended dose for the dose-expansion portion of the study. However, in April 2022, Pfizer, the manufacturer of PF-06939999, announced that the phase 1 trial would be terminated based on a strategic evaluation within its current oncology portfolio. Pfizer noted that the decision was not due to safety concerns or requests from regulators.⁷

Another PRMT5 inhibitor, the selective and reversible agent GSK3326595, was first evaluated for the treatment of patients with myeloid malignancies in the phase 1/2 trial Study 208809 (NCT03614728). Part of the mechanism of action of GSK3326595 involves inhibiting cellular mRNA splicing and upregulation of tumor suppressor function. Mutations in splicing factors are present in approximately 40% of patients with myelodysplastic syndrome (MDS) and more than 60% of patients with chronic myelomonocytic leukemia (CMML). Therefore investigators hypothesized that treatment with GSK3326595 could lead to a synthetic lethal phenotype in splicing mutant disease.⁸

Investigators presented the trial design of Study 208809 at the 2019 American Society of Hematology Annual Meeting & Exposition. The trial aimed to enroll approximately 302 patients with relapsed/refractory MDS, CMML, or hypoproliferative acute myeloid leukemia (AML) that had evolved from an antecedent MDS. The study entailed a dose-finding phase, that could be expanded into 3 additional parts if prespecified criteria were met: a randomized comparison of GSK3326595 monotherapy with investigator’s choice of best available therapy in all patients, a single-arm investigation of safety and efficacy of GSK3326595 plus 5-azacitidine in participants with newly diagnosed high-risk MDS, and a single-arm evaluation of the safety and efficacy of GSK3326595 monotherapy in patients with relapsed/refractory AML with mutations in pre-RNA splicing machinery.⁸

But, in February 2022, it was announced by the manufacturer, GSK, that Study 208809 would be terminated after the trial enrolled approximately 10% of its target enrollment. According to GSK, the removal of the program was due to, “prioritization within the synthetic lethal portfolio,” following its fourth-quarter results earning release.⁹

Although the phase 1/2 trial of GSK3326595 in patients with hematologic malignancies was terminated, findings from the phase 1 METEOR-1 trial (NCT02783300) revealed that the agent displayed modest efficacy and safety signals in patients with advanced solid tumors. METEOR-1 was the first-in-human study of GSK3326595 in adult patients with advanced metastatic solid tumors or non-Hodgkin lymphoma (NHL). It enrolled patients with relapsed/refractory disease or disease with no standard of care, adequate organ function, and an ECOG performance status of 1 or 0.¹⁰

Findings from METEOR-1 presented during the 2022 European Society for Medical Oncology Congress showed that the agent induced 3 confirmed PRs in patients with solid tumors: 2 in the cohort of patients with adenoid cystic carcinoma (ACC; n = 50) and 1 PR in a patient with estrogen receptor–positive breast cancer (n = 37). Additionally, patients with NHL (n = 29) experienced an overall response rate (ORR) of 10%; 1 patient with follicular lymphoma and 1 with diffuse large B-cell lymphoma experienced a complete response (CR). The duration of response (DOR) was 32.4 months and 3.4 months, respectively, in the 2 patients with a CR.¹⁰

“The waterfall plot shows some regression among different tumor types,” Ulrik N. Lassen, MD, a clinical professor in the Department of Clinical Medicine at the University of Copenhagen in Denmark, said in an invited discussion of the findings after the presentation. “That was especially [true] in cystic carcinomas and NHL. The study drug was well tolerated, and the actual data corresponds to what was seen in the dose-escalation part [of the study].”

Regarding safety, TRAEs of any grade were reported in 95% of the 218-patient safety population. Grade 3 TRAEs occurred at a rate of 46%, grade 4 treatment-emergent adverse effects (TEAEs) were present in 7% of patients, and no grade 5 events related to study treatment were observed.¹⁰

Any-grade serious TRAEs were seen in 19% of patients. Dose reduction due to any AE, treatment interruption or delay due to any AE, and treatment discontinuation due to any AE occurred at a rate of 56%, 70%, and 12%, respectively.¹⁰

Investigators concluded that the observed tolerability and single-agent efficacy of GSK3326595 were consistent with those of other PRMT5 inhibitors with published data available. METEOR-1 is still active but is not recruiting additional patients.¹¹

Newer Data Show Promise in Effectively Targeting PRMT5

Despite early phase trials of PF-06939999 and GSK3326595 ending before data were fully mature, recent updates from other clinical trials evaluating PRMT5 inhibitors have displayed more promising results, with the agents examined in these studies poised to advance into later phases of development. During the 2023 ASCO Annual Meeting, findings were presented from a phase 1 clinical trial (NCT04089449) that examined the potent, selective PRMT5 inhibitor PRT811 in patients with advanced solid tumors, central nervous system lymphoma, and/or recurrent high-grade glioma.¹²

“This is a very novel compound targeting PRMT5, which is highly expressed in patients with glioblastoma and high-grade glioma and also is active in patients whose tumors are splicing mutation positive,” Varun Monga, MD, clinical associate professor of internal medicine—hematology, oncology, and blood and marrow transplantation in the Department of Internal Medicine at the University of Iowa Carver College of Medicine in Iowa City, said in an interview with OncologyLive^®. “PRT811 is brain-penetrant. PRMT5 has a functionality of epigenetic regulation, it demethylates the protein substrates, and it controls these key cellular processes via epigenetic mechanism and spliceosome inhibition mechanism.”

The first-in-human, open-label, multicenter study included 86 patients. In the recurrent, high-grade glioma cohort (n = 38), 16 patients had IDH-positive tumors and 22 had IDH-negative tumors. In the advanced/metastatic uveal melanoma cohort (n = 23), 10 patients were splicing mutation (SPLC) positive and 13 were SPLC negative. The primary end point was determining the recommended phase 2 dose (RP2D) of PRT811.¹²

The ORR in the glioma cohort was 5.3%, with the best overall response being a CR. Moreover, 2.6% of patients in the cohort had unconfirmed PRs, 28.9% achieved stable disease (SD), 52.6% had progressive disease (PD), and 22% were not evaluable.

Patients in the uveal melanoma group experienced an ORR of 4.4%. In this cohort, the best response was a PR; however all responses were unconfirmed. SD was seen in 34.8% of the patients with uveal melanoma, 43.5% had PD, and 13% of patients were not evaluable.¹²

Notably, among patients with IDH-positive glioma, 2 durable CRs were observed. One patient had a CR for 31.0 months that was ongoing at data cutoff, and the other who had a CR had a median DOR of 7.5 months followed by PD. In the uveal melanoma group, 1 patient with a PR had a median DOR of 10.0 months followed by PD.¹²

“In [patients with IDH-mutant glioma], there are not many good treatment options for those who have received several lines of treatment before; [this is similar] in uveal melanoma,” Monga noted. “PRT811 certainly offers those patients a treatment option by itself. The ORR was at most modest, but there is potential for studying combination treatments, like with CDK4 inhibitors and IDH1 inhibitors.”

In terms of safety, any-grade TEAEs occurred in 98.4% of the safety population (n = 61), and grade 3 or higher TEAEs were observed in 52.5%. Any-grade TEAEs leading to dose reduction or dose interruption occurred in 78.7% of patients, and grade 3 or higher TEAEs led to dose reduction or interruption in 19.7% of patients. Serious TEAEs were observed in 21.3%, and these serious TEAEs were grade 3 or higher in 16.4%. Grade 5 TEAEs occurred in 3.3% of patients.¹²

The study authors concluded that PRT811 displayed an acceptable safety profile and clinical activity in patients with glioma and metastatic uveal melanoma. The RP2D was determined to be 600 mg administered orally on a once-daily basis.¹²

In April 2023, during the American Association for Cancer Research Annual Meeting, investigators presented findings from a phase 1 trial (NCT03573310) of the novel PRMT5 inhibitor JNJ-64619178 for the treatment of patients with advanced solid tumors, NHL, and lower-risk MDS.¹³ JNJ-64619178 is a highly potent and selective oral PRMT5 inhibitor that has been shown in preclinical study to induce widespread RNA splicing changes, as well as broad antitumor activity in solid and hematologic models.¹⁴

The first-in-human, dose-escalation study of JNJ-64619178 enrolled adult patients with relapsed/refractory B-cell NHL or solid tumors. Data from the study showed that among efficacy-evaluable patients (n = 90), the ORR was 5.6%. Notably, patients with ACC (n = 26) achieved an ORR of 11.5% with a median progression-free survival of 19.1 months. Thrombocytopenia was determined to be the only DLT.¹³

Finally, during the 2022 ASCO Annual Meeting, investigators presented the design of a phase 1/1b/2 trial (NCT05094336) that is evaluating the novel PRMT5 inhibitor AMG 193. AMG 193 belongs to a new class of PRMT5 inhibitors known as methylthioadenosine phosphorylase (MTAP) cooperative.¹⁵

Deletion of the MTAP gene and the neighboring tumor suppressor gene CDKN2 can be found in approximately 10% to 15% of cancers and results in buildup of methylthioadenosine in cells. This buildup leads to partial inhibition of PRMT5; thus it has been hypothesized by investigators that MTAP-null tumors could be vulnerable to additional inhibition of PRMT5.

MTAP cooperative agents such as AMG 193 target and selectively inhibit the MTA-bound state of PRMT5 that is enriched in tumors harboring an MTAP deletion. This approach has demonstrated the ability to preferentially inhibit cell viability as well as inhibit tumor growth in MTAP-null cancer cell lines and tumor xenograft models, respectively.¹⁵

The first-in-human, multicenter trial of AMG 193 is enrolling approximately 30 adult patients with MTAP-null advanced/metastatic solid tumors not amenable to curative surgery and/or radiation. The dose exploration phase 1a/b portion will examine the agent at 5 dose levels until PD or withdrawal.¹⁵

The coprimary end points in phase 1a/b are DLTs, TEAEs, serious adverse effects, as well as changes in vital signs and clinical laboratory tests.¹⁵

References

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7. A dose escalation study of PF-06939999 In participants with advanced or metastatic solid tumors. ClinicalTrials.gov. Updated November 22, 2022. Accessed September 21, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03854227
8. Watts JM, Bradley TJ, Thomassen A, et al. A phase I/II study to investigate the safety and clinical activity of the protein arginine methyltransferase 5 inhibitor GSK3326595 in subjects with myelodysplastic syndrome and acute myeloid leukemia. Blood. 2019;134(suppl 1):2656. doi:10.1182/blood-2019-130337
9. Taylor NP. GSK kills one of Barron’s early darlings, axing 2 synthetic lethal programs and Epizyme pact. Fierce Biotech. February 9, 2022. Accessed September 22, 2023. https://www.fiercebiotech.com/biotech/gsk-kills-one-barron-s-early-darlings-axing-two-synthetic-lethal-programs-and-epizyme-pact#:~:text=Shortly%20after%20becoming%20GlaxoSmithKline’s%20chief,molecule%20GSK3368715%20from%20its%20pipeline
10. Postel-Vinay S, Italiano A, Romano PM, et al. METEOR-1: a phase I study of the safety and efficacy of the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 in advanced solid tumors. Ann Oncol. 2022;33(suppl 7):S746-S747. doi:10.1016/j.annonc.2022.07.585
11. An open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in participants with solid tumors and non-Hodgkin’s lymphoma (Meteor 1). ClinicalTrials.gov. Updated June 28, 2022. Accessed September 22, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02783300
12. Monga V, Johanns TM, Stupp R, et al. A phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients (pts) with recurrent high-grade glioma or uveal melanoma (UM). J Clin Oncol. 2023;41(suppl 16):3008. doi:10.1200/JCO.2023.41.16_suppl.3008
13. Vieito M, Moreno V, Spreafico A, et al. Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in advanced solid tumors. Clin Cancer Res. 2023;29(18):3592-3602. doi:10.1158/1078-0432.CCR-23-0092
14. Villar MV, Spreafico A, Moreno V, et al. First-in-human study of JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced cancers. Ann Oncol. 2020;31(suppl 4):S470. doi:10.1016/j.annonc.2020.08.651
15. Villalona-Calero MA, Patnaik A, Maki RG, et al. Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors. J Clin Oncol. 2022;40(suppl 16):TPS3167. doi:10.1200/JCO.2022.40.16_suppl.TPS3167