Lilly's BTK inhibitor Jaypirca nears approval in Korea for treating mantle cell lymphoma

Lilly's third-generation BTK inhibitor, Jaypirca (pirtobrutinib), will likely get approval in Korea.

Jaypirca, designated as an orphan drug for treating mantle cell lymphoma (MCL), has won marketing authorization on condition that it submits a therapeutic confirmatory phase 3 clinical trial results, according to the minutes of the Central Pharmaceutical Review Committee (CPRC) recently released by the Ministry of Food and Drug Safety (MFDS).

Jaypirca is Lilly's first “reversible” BTK inhibitor. It is indicated for treating patients with relapsed or refractory MCL who have received at least two prior systemic therapies, including other BTK inhibitors.

In early 2023, Jaypirca received conditional approval from the U.S. Food and Drug Administration (FDA) for treating patients with relapsed or refractory MCL based on results, including response rates and safety, from the phase 1/2 BRUIN study. The Korean approval will also be based on the results of the BRUIN study.

Results published in the May 2023 issue of the Journal of Clinical Oncology showed that in relapsed-refractory MCL patients with poor prognosis whose disease progressed despite prior BTK inhibitor therapy, Jaypirca monotherapy achieved an overall response rate (ORR) of 57.8 percent, with 20 percent of patients achieving complete responses (CR).

In addition, the share of patients with a duration of response (DOR) at six and 12 months was 72.6 percent and 57.1 percent.

In the MCL safety cohort (164 patients), the most common treatment-related adverse events were fatigue (29.9 percent), diarrhea (21.3 percent), and dyspnea (16.5 percent). Grade ≥3 bleeding (3.7 percent) and atrial fibrillation/flutter (1.2 percent) were rare, and only 3 percent of patients discontinued Jaypirca due to treatment-related adverse events.

Most of the CPRC members agreed that Jaypirca should be approved based on the results of this initial study. However, they were divided on the confirmatory clinical trial that Lilly must submit.

As with Jaypirca's approval, there was a consensus that a phase 3 study comparing Jaypirca to existing therapies should be submitted in patients with relapsed or refractory MCL who have received at least two prior systemic therapies, including BTK inhibitors.

Due to MCL's rare nature, conducting a randomized phase 3 study in patients eligible for the current license would be difficult. Lilly should replace the ongoing phase 3 BRUIN-MCL-321 study with a confirmatory trial.

BRUIN-MCL-321 is a phase 3 study that directly compares Jaypirca to another BTK inhibitor of the physician's choice in 500 patients with MCL who have received prior BTK inhibitor therapy and systemic therapy. The comparators include Imbruvica (ibrutinib), Calquence (acalabrutinib), and Brukinsa (zanubrutinib).

“The results of the phase 2 study (of Jaypirca) demonstrated that the primary endpoint of 57.8 percent response rate was achieved in patients with relapsed or refractory B-cell lymphoma with a clinical unmet need, and the secondary endpoints of clinically meaningful progression-free survival and overall survival at long-term follow-up support the approval,” a CPRC member said.

The member continued, “As extranodal cell lymphoma is an orphan cancer, it would be difficult to conduct a randomized phase 3 study in patients previously treated with BTK inhibitors under the current conditions of approval. However, as the response rate in the small (Jaypirca) monotherapy arm is insufficient to make a final clinical validity judgment, we agreed to conditionally grant final approval based on the results of the ongoing phase 3 BRUIN-MCL-321 study, albeit in a different population than the current orphan drug approval conditions. The indication should be expanded if the study results are reasonable.”

According to information on the U.S. clinical trials information site ClinicalTrials.gov, the phase 3 BRUIN-MCL-321 study will likely be completed in July 2026.