On December 5, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported initial data for the Phase 1 first-in-human dose escalation study of talquetamab (JNJ-64407564) for the treatment of relapsed or refractory multiple myeloma (NCT03399799) (Press release, Janssen Pharmaceuticals, DEC 5, 2020, View Source [SID1234572263]). Talquetamab is a first-in-class, and the only investigational bispecific antibody that targets both GPRC5D, a novel multiple myeloma target, and CD3 on T-cells. Initial results for both the subcutaneous (SC) and intravenous (IV) formulations show encouraging clinical activity against the GPRC5D target, which is highly expressed on multiple myeloma cells and associated with poor prognostic factors.1,2,3 At the SC recommended Phase 2 dose (RP2D), the overall response rate (ORR) was 69 percent (9/13) and 39 percent achieved a very good partial response (VGPR) or better. The data will be featured during the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting as an oral presentation on Saturday, December 5 at 5:00 p.m. ET (Abstract #290).
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"There is a pressing need for continued innovation of multiple myeloma treatments – particularly for patients who have relapsed on other therapies – and the results presented today for talquetamab are encouraging," said Ajai Chari, M.D., Professor of Medicine, the Director of Clinical Research in the Multiple Myeloma Program, and the Associate Director of Clinical Research, Mount Sinai Cancer Clinical Trials Office. "The Phase 1 overall response rate and safety profile support further study of talquetamab in monotherapy and in combination approaches for patients with few options for treatment."
Investigators identified the RP2D of 405 µg/kg SC and concluded subcutaneous treatment may provide an opportunity for less frequent dosing than the intravenous formulation. A response was observed in 6/9 triple-class refractory patients and 2/2 penta-drug refractory patients. Pharmacokinetic results indicate target exposure levels at the RP2D. At the RP2D of 405 µg/kg SC, pharmacodynamic data demonstrate consistent T-cell activation, cytokine production and redistribution.
Patients received talquetamab at doses of 1–180 µg/kg with IV administration and 5–800 µg/kg for the SC formulation. Results from the Phase 1 study showed responses in patients who were treated with talquetamab across dose groups; median time to first confirmed response across all doses was one month (range, 0.2–3).4
The Phase 1 study enrolled patients (n=157) with multiple myeloma who had progressed on, or could not tolerate, any available established therapies. Patients had received a median of six prior lines of treatment (range, 2-20); 87 percent were refractory to the last line of therapy, 82 percent were triple-class refractory, and 33 percent were penta-drug refractory to two or more immunomodulatory agents, two or more PIs, and an anti-CD38 therapy. The study is conducted in two parts: dose escalation (part 1) and dose expansion (part 2).4
In the Phase 1 study, adverse events (AEs) at the RP2D which occurred with a Grade 3 frequency of ≥25 percent among the SC cohort were neutropenia (42 percent). With SC dosing, cytokine release syndrome (CRS) was observed in 64 percent of patients and was low-grade with no Grade 3 or greater CRS events at the RP2D. CRS occurred at a median of two days after dosing, and median duration of CRS was also two days. The incidence of neurotoxicity was five percent at the RP2D, with no patients experiencing Grade 3 or greater events with SC dosing.4
"GPRC5D is a novel target in the treatment of multiple myeloma and, as a bispecific antibody that engages T-cells by also targeting CD3, talquetamab is emerging as a potential therapeutic option for heavily pretreated patients," said Yusri Elsayed, M.D., MHSc., Ph.D., Vice President, Global Head, Hematologic Malignancies, Janssen Research & Development, LLC. "Based on the preliminary efficacy, safety, pharmacokinetic and pharmacodynamic data presented today, we are committed to fully exploring the promise of talquetamab in multiple myeloma."
About Talquetamab
Talquetamab is a first-in-class investigational bispecific antibody targeting both GPRC5D, a novel multiple myeloma target, and CD3, the T-cell receptor.4 CD3 is involved in activating T-cells and GPRC5D is highly expressed on multiple myeloma cells.4,5,6 Results from preclinical studies in mouse models demonstrate that talquetamab induces T-cell-mediated killing of GPRC5D-expressing multiple myeloma cells through the recruitment and activation of CD3-positive T-cells and inhibits tumor formation and growth.6
Talquetamab is currently being evaluated in a Phase 1/2 clinical study for the treatment of relapsed or refractory multiple myeloma and is also being explored in combination studies. The development of the antibody followed Janssen Biotech, Inc.’s licensing agreement with Genmab for use of its DuoBody technology platform.*
*DuoBody is a registered trademark of Genmab A/S.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.7,8 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow. In 2020, it is estimated that more than 32,000 people will be diagnosed and close to 13,000 will die from the disease in the U.S.9 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.10