Pharmacyclics Inc. gained a $75 million milestone payment from Johnson & Johnson (J&J) unit Janssen Biotech Inc. for progress with the oral Bruton’s tyrosine kinase inhibitor ibrutinib, and the future looks even brighter for the compound, if the FDA grants approval.

U.S. regulators accepted the new drug application (NDA) for the priority review compound as a treatment for two B-cell malignancy indications: previously treated mantle cell lymphoma (MCL) and previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

The FDA’s move triggered Sunnyvale, Calif.-based Pharmacyclics’ latest milestone payment in the deal.

Ibrutinib also has made its way, along with about two dozen other applicants, into the FDA’s newish breakthrough therapy category, which means the same benefit as fast-track status as well as other advantages, though many drug developers are still in the process of finding out exactly what those are. (See BioWorld Today, Feb. 14, 2013.)

By the time Pharmacyclics submitted the NDA for ibrutinib in July, more than 1,600 patients had been treated with the compound, and seven Phase III studies had been started with Janssen, along with 31 trials registered with the National Institutes of Health.

Helped by its breakthrough status and hoped-for quick approval, ibrutinib could mimic the growth-via-label-expansion model of Rituxan (rituximab, Biogen Idec Inc. and Roche AG), as the drug might be used for maintenance and in older CLL patients intolerant to current standard therapy. Other indications could include diffuse large B-cell lymphoma, in which a Phase III trial is under way, along with indolent non-Hodgkin’s lymphoma, myeloma and more.

Though J&J typically does not disclose FDA decision deadlines for its compounds and Pharmacyclics could not be reached, analyst Michael Yee, of RBC Capital Markets, estimated the action date would fall in late February 2014. “However, we believe this drug will likely be approved fairly quickly by end,” Yee wrote in a research report.

The cystic fibrosis drug Kalydeco (ivacaftor, Vertex Pharmaceuticals Inc.) was approved in about three months, Yee noted, adding that, “as we predicted, consensus for ibrutinib has moved upward, and we estimate 2014 end-user sales are at $175 million to $210 million, and [between] $550 million and $600 million for 2015.” (See BioWorld Today, Jan. 31, 2013.)

Last June, Pharmacyclics reported updated Phase Ib/II data showing that the compound, also known as PCI-32765, did not produce any new safety signals, and hematologic toxicities were uncommon in CLL and SLL tests. Progression-free survival (PFS) with a median follow-up of 17.5 months was 87.7 percent in the relapsed/refractory 420-mg cohort, and high-risk relapsed/refractory patients with 17 p deletion and IgVH unmutated status turned out to have an estimated 18-month PFS of greater than 70 percent and 80 percent, respectively.

At the end of the year, more Phase II data indicated that in patients naïve to Velcade (bortezomib, Millennium: The Takeda Oncology Co.) and in those exposed to it, ibrutinib yielded high and durable responses and was generally well tolerated in patients with MCL. More data followed in CLL and SLL. (See BioWorld Today, April 3, 2012.)

In April of this year, Pharmacyclics enrolled the fifth patient in its Phase III monotherapy trial, RESONATE-2, using ibrutinib vs. chlorambucil in elderly patients with newly diagnosed CLL/SLL, which rang the bell on a fourth $50 million milestone from Janssen. The randomized, multicenter, open-label study is testing the targeted therapy in patients 65 years or older with treatment-naïve CLL/SLL. Pharmacyclics “benefits from a number of these large milestones, which help fund most all of their share of the clinical studies,” Yee wrote, and $625 worth remains.

Earlier this month, ibrutinib’s antitumor mechanism of action in MCL was examined in Blood. A study showed that the lymphocytes that increase in peripheral blood during ibrutinib treatment are MCL cells rather than normal cells, suggesting that ibrutinib inhibits MCL cell adhesion and migration in the lymph node or tissues. The cells showed decreases in markers of activation and growth as treatment continued.

In June, after Pharmacyclics unveiled Phase Ib, dose-escalation data from a non-Hodgkin’s lymphoma (NHL) trial at the American Society of Clinical Oncology meeting, Needham & Co. analyst Alan Carr wrote in a research report that key opinion leaders “appear excited about the potential availability of the three most advanced agents for B-cell malignancies,” including ibrutinib, idelalisib (PI3K inhibitor, Gilead Sciences Inc., another ASCO star) and ABT-199 from Abbvie Inc., which targets Bcl-2. ABT-199 has had its problem, though. Development was suspended near the beginning of this year, after a CLL patient died of tumor lysis syndrome, the same problem that has bedeviled Revlimid (lenalidomide, Celgene Corp.). (See BioWorld Today, Feb. 19, 2013.)