ORLANDO — The launch of AbbVie and Johnson & Johnson's Imbruvica transformed treatment of the blood cancer chronic lymphocytic leukemia, helping patients stay disease free for years with a pill rather than chemotherapy combinations.
But with several years of real-world experience, physicians now know that low-frequency side effects like irregular heartbeat and high blood pressure detected in clinical trials are bigger problems for patients on years-long courses of Imbruvica, the first of a class of drugs called Bruton's tyrosine kinase, or BTK, inhibitors.
"Some of the toxicities last for the whole time a patient is on therapy, so maybe it won't bother you at the beginning," said Jacqueline C Barrientos, associate professor at the Feinstein Institutes for Medical Research and Northwell Health in New York, in a session at the American Society of Hematology's annual meeting.
"But what will you do when you develop atrial fibrillation? Do you continue on the drug?"
This has emboldened competitors like AstraZeneca with its drug Calquence and BeiGene with its newly approved Brukinsa, both of which are attempting to steal Imbruvica's crown with a better-tolerated BTK inhibitor. Signs of this promise were on display at ASH.
In addition, results released at the conference for Eli Lilly's LOXO-305 and ArQule's ARQ 531 — the subject of Monday's $2.7 billion buyout bid by Merck & Co. — suggest those drugs can treat patients whose cancers become resistant to Imbruvica.
Calquence recently got on even footing with Imbruvica by winning approval for CLL patients who have never been treated before thanks to the ELEVATE-TN trial. Data from that study showed Calquence monotherapy reduces the risk of disease progression by 80% when compared to chlorambucil, a number that rose to 90% when Calquence was combined with a second drug called Gazyva.
While Calquence hasn't amassed the treatment history that Imbruvica has, the initial signs look positive on the safety side, Kanti Rai, a professor at the Feinstein Institutes, said in an interview with BioPharma Dive. "It seems that cardiac irregularity, atrial fibrillation or bleeding disorders are somewhat less than ibrutinib," he said, using the non-branded name for Imbruvica.
This is also the hope of BeiGene. Cleared by the Food and Drug Administration last month, Brukinsa followed in the footsteps of Imbruvica and Calquence by first winning approval in the rarer mantle cell lymphoma.
However, the Chinese drugmaker has thrown down a gauntlet by challenging Imbruvica in a head-to-head trial in relapsed disease, in addition to testing Brukinsa against bendamustine and Rituxan in first-line treatment.
"Physicians who hear of better-tolerated drugs will often try them," said Jane Huang, BeiGene's chief medical officer for hematology. "Where there's decreased side effects, the patients tell you right away that they feel better."
AbbVie, for one, appears to be aware of this threat to its blockbuster, which had combined sales of $4.7 billion for it and partner J&J in the first nine months of 2019. It is testing a fixed duration combination of Imbruvica with Venclexta, which it hopes will limit those side effects.
The Phase 2 Captivate trial found the combination eliminated diseased cells in 75% of patients' peripheral blood and 72% of patients' bone marrow after 12 cycles.
"We're working with the field's leaders to make it a more manageable therapy and know more about the side effects so that patients and their physicians will be comfortable," Danelle James, Imbruvica clinical development lead, said in an interview. "There'll still be some patients and some physicians that will continue on that continuous regimen because it's so well established."
The data for the experimental drugs LOXO-305 and ARQ 531 are much earlier stage, but showing signs of promise for now in the Imbruvica-resistant patients. LOXO-305 was in a dosing trial that enrolled 10 CLL patients, and the company said it stimulated a disease response in patients resistant and intolerant to Imbruvica.
ArQule had final Phase 1 data showing an 89% response rate in nine CLL patients who have undergone previous treatment for the disease. Eight of those had developed the Imbruvica-resistant mutation, and a response was seen in seven of those.
That was enough, it seems, to lure Merck to the negotiating table. The pharma's surprise offer of $20 per share values the company at more than a 100% premium, a dramatic turn from two years ago when ArQule's stock traded at less than $1.