FDA Approves First Reversible BTK Inhibitor

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The FDA granted Eli Lilly’s Jaypirca (pirtobrutinib) accelerated approval for the treatment of adults with relapsed or refractory mantle cell lymphoma (MCL), the company announced Friday.

The approval makes Jaypirca the first and only FDA-approved reversible Bruton's tyrosine kinase (BTK) inhibitor. The drug is indicated for patients who have received at least two previous lines of systemic therapy, including a BTK inhibitor.

Jaypirca’s label carries warnings for infections, hemorrhage, cytopenia, embryo-fetal toxicities, second primary malignancies, atrial fibrillation and flutter.

Data from the Phase I/II BRUIN trial supported Jaypirca’s regulatory win. A total of 120 patients were enrolled in the study, 60 of whom responded to Jaypirca treatment, yielding an overall response rate of 50%. Of the responders, 15 showed a complete response to the drug, while 45 demonstrated a partial response answer.

At the 6-month follow-up, more than 65% of participants still showed signs of response to the drug. Jaypirca’s median duration of response was 8.3 months.

BRUIN is a first-in-human global trial assessing Jaypirca in patients with relapsed/refractory MCL, all of whom had previously been treated with a covalent BTK inhibitor.

Aside from efficacy, the study also looked at the drug’s safety and found that 38% of treated patients developed adverse reactions, the most common of which were pneumonia, COVID-19 and musculoskeletal pain.

Drug toxicities led to dose reductions in 4.7% of patients, treatment interruption in 32% and permanent discontinuation in 9%.

To maintain Jaypirca’s approval, Lilly is running the Phase III confirmatory trial BRUIN MCL-321, which is currently enrolling patients.  

Reversible Inhibition

BTK inhibitors work by disabling the enzyme BTK, a cytoplasmic tyrosine kinase central to the development, signaling and proliferation of B lymphocytes. BTK is a well-validated target for several B-cell leukemias and lymphomas.

Typically, BTK inhibitors deactivate the enzyme by creating covalent, or irreversible, bonds with the active site of the BTK protein, thereby shutting down its activity. As a result, these drugs disrupt the B-cell receptor signaling pathway, which otherwise supports cells' hyperactive growth and proliferation in some hematologic malignancies, including MCL.

However, many patients eventually develop point mutations at the active site of BTK, which can leave these inhibitors unable to establish their covalent bonds, leading to drug resistance.

Non-covalent BTK inhibitors like Jaypirca avoid drug resistance by doing away with the need to form irreversible chemical bonds with the enzyme’s active site. Because their mode of action does not rely on the specific amino acid residues at the active site, non-covalent inhibitors can exert their effects on both wild-type and mutant BTK enzymes.

This approach to BTK inhibition is promising for blood cancers dependent on the B-cell receptor pathway.

Jaypirca is in Phase III as a monotherapy or combination therapy for chronic lymphocytic leukemia. Lilly is also running a Phase II trial of the molecule in various B-cell malignancies.

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