Next Generation Imbruvica Performs Well For Acerta In Early Studies
This article was originally published in Scrip
Acerta Pharma's second generation Bruton's tyrosine kinase (BTK) inhibitor, acalabrutinib (ACP-196), has proved itself to be a more selective, irreversible and improved version in early trials.
The drug, which is partnered with Merck & Co., is being developed by Acerta Pharma, the University of California, Irvine and Cornell Medical Center for the treatment of chronic lymphocytic leukemia (CLL).
Principle investigator for the Phase I/II study of acalabrutinib, John Byrd of the Ohio State University Comprehensive Cancer Center, said, "This data is very exciting because it illustrates that acalabrutinib is a highly potent and selective oral BTK inhibitor that can be given safely in patients with relapsed CLL. What is particularly remarkable is how well patients are tolerating this therapy."
Acalabrutinib works by blocking BTK and halting the flow of these growth signals, causing CLL cells to die. Unlike the first generation BTK inhibitor, AbbVie Inc.'s Imbruvica (ibrutinib), Phase I/II data have shown that Acerta's version selectively blocks the BTK pathway without disrupting other key molecular pathways, better persevering platelet and immune function and decreasing side effects associated with its predecessor product.
The data from 61 relapsed or refractory CLL patients in the drug's first-in-human trial showed that acalabrutinib induced an overall response rate of 95% at a median follow-up of 14.3 months, including 85% with partial response and 10% with partial response with lymphocytosis. The remaining 5% had stable disease. Of the 61 patients, 87% completed treatment in the trial and no patients experienced Richter's transformation, a rare condition where CLL morphs into an aggressive form of lymphoma. One patient treated saw their cancer progress.
Those treated had received a median of three previous therapies for their disease.
Patients enrolled in the Phase I arm of the study received escalating doses of acalabrutinib, with a maximum dose of 400mg once daily. Patients in the Phase II portion were treated with 100mg dose twice daily.
"It is nice to see such selectivity of a drug, which we demonstrated in our pre-clinical models, translate to the clinic for the benefit of patients and predicted improved tolerability," Dr. Bonnie Harrington, an Ohio State University postdoctoral student and co-first author of the study, said in a statement.
Byrd added that BTK inhibitors are "transforming CLL from an incurable to a chronic disease, especially considering that standard CLL therapies typically produce a 35% to 40% response rate in this disease setting."
Data from acalabrutinib's Phase I/II trial were published in The New England Journal of Medicine on Dec. 7. Authors noted that the second generation BTK inhibitor had a promising safety and efficacy profile, including in CLL patients with a 17p deletion. This particular subgroup of patients (31% of those treated) saw a 100% response rate in the trial.
However, Jan Burger, principle investigator for AbbVie's RESONATE-2 study of Imbruvica in first-line use, told Scrip that second generation BTK products have a lot to live up to. "Some second generation BTK inhibitors are in clinical development already, but some are still in preclinical research. In general it is fair to say the bar is high for newer versions."
He added, "It is not going to be easy for competing products to show added benefit because the response rates for Imbruvica are high and it is very durable. The side effect rates are already not very high, but maybe second generation products can improve on complete remission rates or on some side effects. If the second or third generation products can have no bleeding events or no occurrences of atrial fibrillation, then that could potentially be a benefit."
"We will have to wait and see if they are really going to be better products," he said.
Acerta's BTK inhibitor also is being tested in combination with other therapies to improve response and survival rates, including a combination study in B-cell malignancies with Merck's programmed cell death-1 (PD-1) immune checkpoint inhibitor Keytruda (pembrolizumab).