What GPRC5D inhibitors are in clinical trials currently?

Introduction to GPRC5D

Definition and Biological Role
GPRC5D is an orphan G protein‐coupled receptor that has captured significant attention in recent years due to its unique expression profile. Unlike many other receptors, GPRC5D exhibits very limited expression in normal tissues—primarily being restricted to hair follicles and a few other tissues—while it is highly expressed in malignant plasma cells in multiple myeloma. This unusual distribution profile makes it an attractive target for therapeutic intervention because drugs that target GPRC5D are expected to spare most healthy tissues, thus reducing the off‐target adverse effects typically associated with many anticancer agents. At a molecular level, GPRC5D belongs to the class C group 5 family of GPCRs. Its function, although still under active investigation, is thought to be connected—at least indirectly—to cellular differentiation and proliferation processes. This role becomes even more significant in the context of multiple myeloma, where aberrant clonal plasma cell proliferation is the hallmark of the disease.

Importance in Disease Context
Multiple myeloma remains one of the more challenging hematologic malignancies to treat, with a high degree of relapse and drug-resistance over time. As traditional treatments such as proteasome inhibitors, immunomodulatory drugs, and CD38-targeted therapies have significantly improved patient outcomes, the unmet need for more effective and durable treatments persists. GPRC5D’s advantageous expression pattern, with high density on malignant plasma cells and limited expression in normal tissues, positions it as a compelling target for immunotherapeutic strategies. Its inhibition may result in effective tumor cell clearance while avoiding toxicity, thus paving the way for the development of innovative therapy candidates such as CAR T cells and bispecific antibodies that precisely target this receptor.

GPRC5D Inhibitors

Overview of GPRC5D Inhibitors
Therapeutic strategies broadly referred to as “GPRC5D inhibitors” encompass a range of modalities designed to block or eliminate the receptor’s function on myeloma cells. Despite the term “inhibitor” conventionally relating to small-molecule agents, in the context of GPRC5D, it generally covers immunotherapy agents that result in the effective inactivation, neutralization, or cellular clearance of receptor-expressing cells. These agents include:

• Chimeric Antigen Receptor (CAR) T-cell therapies that are genetically engineered to recognize and target cells expressing GPRC5D. For instance, RD140 injection is an exploratory therapy that employs fully human anti-BCMA/GPRC5D CAR T-cells to induce tumor cell killing in relapsed/refractory multiple myeloma and plasma cell leukemia.

• Bispecific T-cell redirectors that simultaneously bind to GPRC5D on myeloma cells and CD3 on T cells to facilitate targeted cell-mediated cytotoxicity. Talquetamab is a prominent example of such an agent. Its structure enables it to recruit patient T cells to attack GPRC5D-positive plasma cells, and it has been evaluated in multiple clinical trials across different patient populations.

• Monoclonal antibodies and antibody derivatives that exploit the mechanism of antibody-dependent cellular cytotoxicity (ADCC). SAR446523 is an example of an anti-GPRC5D ADCC-enhanced monoclonal antibody currently in clinical development for relapsed or refractory myeloma patients.

• Trispecific antibodies, such as JNJ-79635322, which add an extra layer of complexity by targeting not only GPRC5D but also additional antigens or immune checkpoints when combined with other therapeutic agents like daratumumab or pomalidomide. This strategy is intended to increase both the specificity and the cytotoxic potential against malignant cells.

These modalities are selected based on their ability to bypass conventional limitations—such as antigen loss or resistance to standard chemotherapies—by directly recruiting the immune system or by precisely blocking pathways crucial for myeloma cell survival.

Mechanism of Action
The diverse range of GPRC5D-targeted therapies each employs its own method of disrupting the pathogenic role of GPRC5D in multiple myeloma, yet they share a common goal: the selective elimination of malignant plasma cells. The mechanisms include:

• For CAR T-cell therapies, the process involves isolating patient T cells, genetically modifying them ex vivo to express a receptor that specifically recognizes GPRC5D (often combined with recognition of other myeloma-associated antigens such as BCMA), expanding these cells, and finally reinfusing them to seek out and destroy GPRC5D-positive cells. This approach leverages the patient’s own immune system, resulting in potent and durable antitumor responses that have shown promise in early and late-phase clinical studies.

• Bispecific antibodies like talquetamab are designed to bind simultaneously to GPRC5D on the tumor and CD3 on T cells. This dual binding forms an immunological synapse that activates the T cell to release cytotoxic granules and cytokines, ultimately leading to tumor cell apoptosis. The technology behind bispecific antibodies thus capitalizes on targeted cellular immunity without the need for genetic modification of immune cells.

• Monoclonal antibodies such as SAR446523 utilize mechanisms like ADCC and complement-dependent cytotoxicity (CDC) to directly induce lysis of GPRC5D-expressing cancer cells. They are engineered to have enhanced Fc-mediated effector functions so that once bound to the target, they recruit natural killer (NK) cells and macrophages to mediate cell death.

• Trispecific antibodies, exemplified by JNJ-79635322, extend this paradigm further by incorporating a third specificity, which can enhance T-cell activation, promote immune synapse formation, or simultaneously inhibit another critical signaling pathway essential for myeloma cell survival. These agents are designed to work hand-in-hand with established monoclonal antibodies such as daratumumab to yield synergistic anti-tumor activity.

Each modality has been designed to leverage the strong expression of GPRC5D on myeloma cells while minimizing systemic toxicity through the selective targeting of this receptor in malignant tissues.

Clinical Trials of GPRC5D Inhibitors

Current Clinical Trials
Several clinical trials are actively evaluating GPRC5D-targeting agents, taking advantage of the promising preclinical rationale behind GPRC5D-directed therapies. The key candidates in current clinical development are:

• RD140 Injection: An exploratory study is underway evaluating the safety, pharmacokinetics, and antitumor activity of RD140, which comprises fully human anti-BCMA/GPRC5D CAR T cells in patients with relapsed/refractory multiple myeloma or plasma cell leukemia. This trial, registered under NCT06655519, represents one of the pioneering efforts to merge dual antigen targeting (BCMA and GPRC5D) in a single CAR T therapy construct. The aim is to overcome resistance that may develop from targeting BCMA alone, especially in the relapse setting.

• BMS-986393: This is a Phase 3, randomized, open-label, multicenter study that compares the efficacy and safety of BMS-986393—a GPRC5D-directed CAR T cell therapy—with standard regimens in adult patients who are relapsed or refractory and lenalidomide-refractory. Registered as NCT06615479, this study provides a head-to-head evaluation of a novel cellular therapy candidate in a patient population that is difficult to treat with existing chemotherapeutic or targeted approaches.

• SAR446523: In this first-in-human Phase 1 study, SAR446523 is delivered via subcutaneous injection. It is an ADCC-enhanced monoclonal antibody targeting GPRC5D that is being tested in adult participants with relapsed or refractory multiple myeloma. The trial seeks not only to understand the safety and tolerability profile of the agent but also to gather preliminary evidence regarding its clinical efficacy and pharmacokinetics/pharmacodynamics (PK/PD) characteristics. This study is registered under NCT06630806.

• Talquetamab-Based Trials: Talquetamab is one of the most prominent bispecific antibodies targeting GPRC5D along with CD3. There are multiple clinical studies evaluating talquetamab across different patient subsets:
  – One study focuses on talquetamab-related oral toxicity by evaluating preventive treatments to mitigate one of its common adverse events, providing critical insight into its safety profile.
  – Another study, "Subcutaneous Talquetamab in Elderly Patients With Multiple Myeloma in Early Relapse" (registered under NCT06827860), assesses the efficacy and safety profile in a more vulnerable patient population, which is crucial given the typical age range of myeloma patients.
  – Additionally, talquetamab is being tested in combination therapy protocols. For instance, a Phase 2 open-label study evaluates different sequences of combination therapies involving Cilta-cel, talquetamab combined with daratumumab, and teclistamab combined with daratumumab in newly diagnosed standard-risk multiple myeloma. This study (NCT06577025) examines not only single-agent activity but also how best to integrate GPRC5D-targeted therapy with other treatment modalities.
  – Another study extends the evaluation of combination approaches by studying a regimen designed for high-risk multiple myeloma patients using a combination of Cilta-cel and talquetamab (NCT06550895). Furthermore, a Phase II study is evaluating bispecific T-cell redirectors—including talquetamab—as part of first-line treatment in transplant-eligible multiple myeloma patients (NCT06505369).

• JNJ-79635322: This agent is a novel antibody-based therapeutic candidate that is being evaluated in several clinical studies. In a Phase 1b study (NCT06768489), JNJ-79635322 is being tested in combination with daratumumab or pomalidomide in patients with multiple myeloma. Its mechanism involves multiple antigen targeting, potentially including GPRC5D, as part of a multispecific approach to enhance clinical efficacy in a relapsed/refractory context. Further studies (including a Phase 1, first-in-human dose escalation study registered under JPRN-jRCT2051240071 and another Phase 1b study registered by CTIS2024-515316-44-00) are also assessing the safety, pharmacokinetics, and overall treatment benefits of this agent in similar patient populations.

Phase and Status of Trials
The current clinical evaluation of GPRC5D inhibitors spans a wide range of trial phases, reflecting both early-stage exploratory studies and more advanced Phase 3 trials. For example:

• Early Phase Studies:
  – SAR446523 is in a Phase 1 study that focuses on dose-escalation and safety in a first-in-human setup. This early-phase study is critical for establishing a safe profile and dosing parameters for subsequent trials.
  – Talquetamab-related studies in elderly or early relapse patients (such as the trial registered under NCT06827860) are in Phase 2, designed to generate further evidence on efficacy and safety after promising results in initial dose-finding studies.
  – JNJ-79635322 is under investigation in several Phase 1b studies, highlighting its early-stage evaluation in combination regimens to fine-tune its safety and tolerability profiles.

• Advanced Phase Studies:
  – BMS-986393 is being evaluated in a Phase 3 study, which indicates that it has already met previous safety benchmarks and has shown enough preliminary efficacy to justify a large-scale comparison against standard-of-care therapies.
  – Combination approaches that involve talquetamab and cellular therapies such as Cilta-cel in newly diagnosed or high-risk multiple myeloma have reached Phase 2, with the aim of establishing improved outcomes over existing first-line treatments.

These trials, spread across different phases, are designed to address key therapeutic endpoints such as overall response rate, progression-free survival, durable remission, and the management of associated adverse events (e.g., cytokine release syndrome, oral toxicities). The designs reflect a deliberate time-sequenced approach to build evidence from safety in early-dose studies toward broader efficacy evaluations in later-phase, randomized controlled trials.

Challenges and Future Directions

Challenges in Development
Even though GPRC5D-targeted therapies show immense promise, several challenges emerge during development and clinical translation:

• Safety Concerns and Off-Target Effects: While the restricted normal tissue expression of GPRC5D is beneficial, adverse effects such as talquetamab-related oral toxicities have been observed, prompting the initiation of dedicated trials to evaluate preventive interventions. Adverse events associated with CAR T-cell therapies, such as cytokine release syndrome (CRS) and neurotoxicity, remain a concern despite progress in management protocols.

• Manufacturing and Logistical Complexities: Cellular therapies, including CAR T-cell products like RD140, involve complex manufacturing processes. These complexities can limit scalability and add delays to patient treatment schedules. Consistency in product yield and potency over multiple manufacturing batches further compound these challenges.

• Treatment Resistance and Antigen Escape: A significant hurdle in targeted immunotherapy is the evolutionary pressure that may lead to loss or reduced expression of the targeted antigen (GPRC5D in this case). Such resistance mechanisms highlight the need for combination strategies that address potential antigen escape and improve long-term clinical outcomes.

• Patient Selection and Biomarker Development: Determining which patient subgroups are most likely to benefit from GPRC5D inhibition remains an ongoing challenge. Robust biomarkers are needed for patient stratification, and better understanding the receptor’s expression dynamics through different disease stages or in response to therapy will be critical for optimizing patient outcomes.

Future Prospects and Research Directions
Looking forward, several directions are under active exploration to enhance the therapeutic potential of GPRC5D inhibitors:

• Combination Therapy Strategies: Early studies indicate that combining GPRC5D-targeted agents with other treatments—such as daratumumab (a CD38-targeted monoclonal antibody), pomalidomide, or even other CAR-T therapies that target different antigens—might enhance antitumor efficacy through synergistic mechanisms. Such approaches are being tested in combination trials and hold promise in overcoming treatment resistance observed with single-agent therapy.

• Improved Safety Profiles and Management of Adverse Events: Future research is likely to focus on optimizing the safety profiles of these novel agents, particularly through dose modifications, better patient monitoring, and prophylactic measures against known adverse events. This includes developing strategies to mitigate talquetamab-related oral toxicity as evidenced by dedicated studies.

• Enhanced Cellular Therapy Constructs: Innovations in CAR T-cell and other cellular therapies, such as improved design modifications to reduce the incidence of CRS and neurotoxicity while increasing specificity for GPRC5D, are an area of intense research. Refining the genetic constructs to include safety switches or self-regulating mechanisms can help enhance both safety and efficacy.

• Next-Generation Bispecifics and Trispecifics: The evolution from monospecific to bispecific and trispecific antibodies is a reflection of the drive toward improved efficacy. Future developments may include agents that integrate multiple immune-modulatory functions into a single molecule, thereby providing a more potent and durable antitumor response. Continued preclinical and clinical evaluation of agents such as JNJ-79635322 will help define their role relative to other mono- or bispecific agents.

• Expansion of Clinical Indications: While the current focus is on multiple myeloma, the unique expression pattern of GPRC5D may have implications for other malignancies where similar expression profiles or related signaling pathways are involved. Research into broadening the therapeutic indications of GPRC5D-targeted drugs beyond multiple myeloma is warranted.

• Integration with Real-World Evidence and Advanced Imaging: In addition to traditional clinical endpoints, future trials may incorporate advanced imaging techniques and next-generation sequencing technologies to better monitor treatment response, trace cellular dynamics, and capture the heterogeneity of tumor responses. This will not only refine patient selection but also allow real-time adjustments based on measurable biomarkers.

• Regulatory and Market Considerations: As clinical trials progress through various phases, it is crucial to maintain close dialogue with regulatory bodies to streamline approval processes. Successful clinical outcomes in Phase 3 studies like those evaluating BMS-986393 and combination therapies can catalyze market approval and facilitate faster patient access to these innovative therapies.

In summary, the continuum from initial target validation and early-phase studies to advanced phase randomized controlled trials reflects both the promise and complexity of GPRC5D-targeted therapeutics in multiple myeloma. Future research efforts are anticipated to drive forward not only the safety and efficacy of these agents but also the potential for broader applications across other malignancies.

Conclusion
To conclude, a thorough review of the latest clinical trial activity indicates that multiple innovative GPRC5D-directed therapies are actively being evaluated in the clinical setting. This constellation of agents—ranging from CAR T-cell therapies such as RD140 and BMS-986393, to bispecific antibodies like talquetamab, and monoclonal antibodies such as SAR446523, along with advanced therapeutic candidates like JNJ-79635322—demonstrates a multifaceted approach to targeting the unique biology of multiple myeloma. Each therapy employs a distinct mechanism, whether by reprogramming a patient’s T cells, mediating antibody-dependent cellular cytotoxicity, or engaging multiple antigens through trispecific formats, but all are unified by their specificity for GPRC5D.

The clinical trials span a range of phases—from early Phase 1 dose-escalation studies critical for establishing safety and pharmacodynamics, to Phase 3 randomized studies aimed at comparing these novel agents with current standard regimens. Challenges such as managing treatment-related toxicities, overcoming complex manufacturing logistics, and addressing resistance mechanisms remain key focal points. However, future research directions, including combination strategies, optimized cellular engineering, and improved patient stratification, offer promising avenues to refine and enhance the overall therapeutic benefit of these agents.

In summary, the current pipeline of GPRC5D inhibitors in clinical trials is robust and diversified, reflecting the broader trend towards precision immunotherapy in multiple myeloma. As these studies mature, they hold the potential to provide transformative treatment options and improve clinical outcomes for patients facing this challenging disease. Continued rigorous evaluation, adaptive clinical trial designs, and innovative combinatorial approaches promise to address current challenges, thereby solidifying the role of GPRC5D-targeted therapies as a cornerstone in the fight against multiple myeloma.