Emergence of 3rd-generation BTK inhibitors raises availability question in Korea

The market for Bruton tyrosine kinase (BTK) inhibitors treating B-cell malignancies has been gradually expanding globally, especially with the recent introduction of third-generation drugs.

However, even the second-generation drugs are struggling, faced with the high threshold of insurance coverage in Korea, raising questions about whether the third-generation BTK inhibitors will fulfill their clinical functions, industry watchers said.

Ely Lilly's Jaypirca (pirtobrutinib) is a third-generation BTK inhibitor approved in the U.S. early this year to treat relapsed or refractory mantle cell lymphoma (MCL).

Jaypirca is the first "reversible" BTK inhibitor indicated to treat patients with relapsed or refractory MCL who have received at least two prior systemic therapies, including other BTK inhibitors. On July 6, data from a phase 1/2 clinical trial (BRUIN study) was published in the New England Journal of Medicine (NEJM).

The data demonstrated significant anticancer activity in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who have failed other BTK inhibitors, suggesting an expanded indication.

Ely Lilly Korea, which owns Jaypirca in Korea, also prepares to apply for approval from the Ministry of Food and Drug Safety.

The company recently applied for Jaypirca’s inclusion in drug candidates for the Ministry of Health and Welfare's "Permit-Evaluation-Negotiation Linkage System Pilot Program. It aims to shorten the time to get reimbursement, as MCL is an uncommon blood cancer, and there are currently no treatment options other than salvage chemotherapy for patients who have failed first and second-generation BTK inhibitors.

Unfortunately, it failed to be included in the pilot program, and Jaypirca’s domestic rollout has since stalled.

In the Korean BTK inhibitor market, all second-generation drugs are struggling before the reimbursement threshold, except for Janssen's Imbruvica (ibrutinib), a first-generation BTK drug.

Four BTK inhibitors have been introduced in Korea. They are the first-generation Imbruvica, the second-generation Calquence (acalabrutinib) of AstraZeneca, Velexbru (tirabrutinib) of Ono Pharmaceutical, and the third-generation Brukinsa (zanubrutinib) of BeiGene.

Imbruvica, approved in August 2014 for the first time, has the most indications, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and Waldenstrom macroglobulinemia (WM).

However, Brukinsa, the most recently approved in February 2022, is also aggressively tapping the domestic market, adding an indication for marginal zone lymphoma (MZL), which no other BTK inhibitor has, in addition to MCL, CLL/SLL, and WM.

However, Brukinsa has only one indication of WM that gets coverage. BeiGene Korea, which owns Brukinsa, has tried twice to get insurance coverage for the MCL indication since its approval by the Ministry of Food and Drug Safety. However, the Health Insurance Review and Assessment Service rejected it.

Calquence has only one indication of relapsed and refractory chronic lymphocytic leukemia (CLL) in Korea and has had virtually no sales activity since its approval in February 2021. Velexbru, approved in November 2021 for relapsed or refractory B-cell primary central nervous system lymphoma, is being sold but has not even applied for insurance coverage.

To market Calquence, AstraZeneca must form a hematologic cancer division, but it is not the company’s priority, considering the competition and marketability of other BTK inhibitors in Korea.

Ono Pharmaceutical believes that insurance coverage of Velexbru is not feasible for now. The company said it is difficult to evaluate the economic feasibility of approval based on phase 2 clinical trial without a control group, and there is only one country where Velexbru is covered by insurance, Japan.

For this reason, Ono Pharmaceuticals is preparing to launch an expanded access program (EAP) for patients who need treatment with Velexbru.

All this shows that without insurance coverage, second-generation drugs are virtually unavailable for clinical use in the domestic environment, the market watchers said.

Doubts are growing as to whether Jaypirca, a third-generation drug, will fulfill its function after its introduction in a domestic clinical environment where even second-generation BTK inhibitors, which have been evaluated for their superior anticancer activity compared to first-generation drugs, cannot play an appropriate role, they added.