Pirtobrutinib (Jaypirca) Now FDA Approved for Previously-treated CLL

Pharmaceutical company Eli Lilly announced on Friday, December 1, 2023, that the non-covalent BTK inhibitor pirtobrutinib (Jaypirca) received accelerated FDA approval for the treatment of CLL/SLL patients who have received at least two prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor. 

What is BTK and What is the Difference Between a Covalent BTK Inhibitor and a Non-covalent BTK Inhibitor? 

The BTK (Bruton's tyrosine kinase) enzyme is found in B-cells. This includes CLL cells that are dysfunctional B-cells. When BTK is activated, it starts the process of activating and replicating the B-cell. Stopping the BTK enzyme with medicines called BTK inhibitors helps stop this response. 

Covalent BTK inhibitors (cBTKi) (acalabrutinib [Calquence], zanubrutinib [Brukinsa], and ibrutinib [Imbruvica]) bind to the BTK enzyme permanently to stop the enzyme. Long-term use of cBTKis often causes the BTK enzyme to mutate, and the CLL cells will no longer respond to treatment. 

Non-covalent BTK inhibitors (ncBTKi) (pirtobrutinib [Jaypirca]) bind to the BTK enzyme non-permanently through the use of hydrogen bonds and ionic bonds. This altered way of binding helps stop the activation of BTK despite BTK mutations from prior cBTKi use (see here for more about BTK mutations following BTKi treatment). 

Data from the BRUIN Study 

Data from the BRUIN study showed the following related to how pirtobrutinib worked for CLL patients who had previously taken a cBTKi and BCL-2 inhibitor: 

• 72% of CLL patients had a partial reduction of CLL signs/symptoms while taking pirtobrutinib
• The CLL cells were held off from progressing for an average of 12.2 months before the CLL cells stopped responding to pirtobrutinib (refractory) and the CLL cells progressed again
• The use of pirtobrutinib caused more mutations in CLL cells for 69% of patients both in the BTK enzyme and in other parts of the CLL cells following its use 
• The most common side effects were decreased blood counts (neutrophil, hemoglobin, platelet, and lymphocyte), fatigue, musculoskeletal pain, diarrhea, COVID-19, bruising, and cough (see here for side-effect solutions for CLL medicines) 

"Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients. Jaypirca offers a new treatment option and different approach to targeting BTK, providing clinical benefit for a high proportion of patients with CLL or SLL in the BRUIN Phase 1/2 trial whose disease progressed following treatment with a covalent BTK inhibitor and with a BCL-2 inhibitor." -Dr. William G. Wierda, M.D., Ph.D., CLL section head for the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

In conclusion, the newly FDA-approved non-covalent BTK inhibitor pirtobrutinib (Jaypirca) offers a time extension in holding off disease progression for the majority of CLL patients who have limited treatment options after other covalent BTK inhibitors and BCL-2 inhibitors stopped effectively treating their disease. This time extension is a step in the right direction for this patient group with limited treatment options.