The FDA expanded the approved use of Imbruvica (ibrutinib), more than two months ahead of its PDUFA date of April 17, as the first therapy indicated to treat patients with Waldenström's macroglobulinemia (WM), a rare type of B-cell lymphoma. The approval represents the fourth indication for Imbruvica, developed jointly by Pharmacyclics Inc. and Johnson & Johnson (J&J) unit Janssen Biotech Inc.

The oral Bruton's tyrosine kinase, or BTK, inhibitor initially gained accelerated approval in 2013, three months before its PDUFA date, as a single agent to treat patients with mantle cell lymphoma (MCL) who received at least one prior therapy. (See BioWorld Today, Nov. 14, 2013.)

The drug generated just $13.6 million in sales that year, according to Cortellis Competitive Intelligence (CI), but prospects for Imbruvica couldn't be brighter going forward. Last February, the FDA granted accelerated approval to the drug to treat patients with previously treated chronic lymphocytic leukemia (CLL). The drug's use was further expanded in July 2014 to include treatment of CLL patients who carry a deletion in chromosome 17.

Imbruvica's use in CLL generated buzz in June at the American Society of Clinical Oncology (ASCO) meeting in Chicago when Pharmacyclics reported phase III data showing the drug compared favorably to the anti-CD20 antibody Arzerra (ofatumumab, Glaxosmithkline plc), considered the standard of care in elderly CLL patients who can't tolerate chemotherapy.

At the time, Gregory Masters, of ASCO, who moderated a panel that included results from the trial known as RESONATE, predicted ibrutinib "may in fact transform the treatment of CLL, potentially replacing more toxic chemotherapy." (See BioWorld Today, June 5, 2014.)

Gaining label extensions to treat all comers in CLL and to extend treatment as far upstream as possible in other indications is certainly the intention of Pharmacyclics. The approval in WM, which was granted breakthrough therapy designation by the FDA, "continues to talk to the strength of the Imbruvica franchise," Roth Capital Partners analyst Joseph Pantginis wrote in a company note.

Despite the small incidence of WM – an estimated 1,500 patients in the U.S. per year – he "tweaked" the company's price target by $1, to $189, and projected $987 million in 2015 revenues.

In J.P. Morgan's weekly Imbruvica update on Monday, analyst Cory Kasimov noted that captured scripts for Imbruvica, as reported by IMS Health, were up 21.7 percent over the previous week, with the actual number of pills dispensed up 22.3 percent. CLL users take 90 pills per month, Kasimov pointed out, and about 75 percent of the prescriptions were filled for 90-capsule bottles. MCL users are prescribed 120 pills per month.

That growth, relatively early in the CLL launch, suggests the trajectory for Imbruvica. Cortellis CI projects 2019 sales of the drug will surpass $4.6 billion.

APPROVAL 'A PRETTY BIG STATEMENT' ABOUT FDA'S VIEW

WM is a slow-growing form of non-Hodgkin lymphoma that causes B cells to grow within the bone marrow, lymph nodes, liver and spleen. In WM, abnormal B cells also overproduce the protein immunoglobulin M, or IgM, which may lead to excess bleeding and problems with the patient's vision and nervous system.

Approval in WM was based on a clinical study of 63 previously treated participants who received Imbruvica 420 mg once daily, administered orally. The response rate, as assessed by an independent review committee using criteria adopted from the international workshop on WM, was 62 percent (95 percent CI, 48.8, 73.9).

Nearly 51 percent of patients achieved a partial response (PR), although no complete responses were reported. The median time to response was 1.2 months (range, 0.7-13.4 months). The median duration of response has not yet been reached (2.8+ months, 18.8+ months).

The most common side effects associated with the drug include thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection and rash.

Use of Imbruvica to treat WM also was granted priority review and orphan product designation by the FDA. Pharmacyclics plans to begin meeting with physicians today to discuss the approval in WM and to make the drug available for WM patients.

Imbruvica's win in WM was not unexpected. Pharmacyclics CEO Bob Duggan hinted earlier this month during his presentation at the 33rd Annual J.P. Morgan Healthcare Conference in San Francisco that approval was "imminent," adding that the company's goal is to add one or two supplemental approvals per year for the drug. (See BioWorld Today, Jan. 14, 2015.)

Thorsten Graef, vice president of clinical science at the Sunnyvale, Calif.-based biotech, said insights gained from patients with WM are making those label extensions possible.

"The Waldenström's approval is especially important from an academic perspective," Graef told BioWorld Today, noting the indication has baffled the current generation of clinicians much like myeloma did in the years when he was a young doctor. "We did not really understand the rationale," he said, so myeloma was treated without great success until the arrival of drugs such as Velcade (bortezomib, Millennium: The Takeda Oncology Co.) and Revlimid (lenalidomide, Celgene Corp.).

"Waldenström's was roughly in the same position," Graef said. "It's also an orphan indication. There was never too much emphasis on how to understand what is causing the disease and how you can treat this disease."

When researchers began to dig deeper, it became clear that WM most often presents with myeloma-like symptoms, even though the disease is classified as a non-Hodgkin lymphoma. Thus, the disease was treated as a cross between myeloma and CLL, with a variety of drugs "in the mix" – albeit without great effect, Graef said.

"This is an indolent disease," he pointed out. "Patients live with it for a long time and suffer from the clinical features – particularly anemia, which triggers fatigue and takes a toll on daily life."

The approval in WM also was especially meaningful since it includes all patients with the disease, not just refractory patients.

"I think, for the FDA, this was a pretty big statement about how they actually see this drug and what the drug can do for patients," Graef observed.

Additional studies of Imbruvica from J&J and Pharmacyclics – mostly phase III trials with active comparators – are expected to read out this year. Pharmacyclics and Janssen also are seeking to move the drug into combination regimens. Late last year, they inked a deal with London-based Astrazeneca plc to study Imbruvica plus anti-PD-L1 immune checkpoint inhibitor MEDI4736 in hematologic cancers. Other combo trials under way are evaluating Imbruvica with CD20 monoclonal antibody Rituxan (rituximab, Roche AG and Biogen Idec Inc.) and proteasone inhibitor Kyprolis (carfilzomib, Amgen Inc.).

Technically, the WM approval is based on the breakthrough designation rather than complete data from the investigator-sponsored phase II study, which is ongoing at the Dana-Farber Cancer Institute and several other academic centers. Data from the primary endpoint of overall response rate, measured as a reduction of 25 percent or more in disease burden, are expected to report in mid-2016. Co-primary endpoints include major response rates (greater than 50 percent reduction in disease burden) and very good partial response/complete response in symptomatic WM patients with relapsed or refractory disease.

"I think there's a hint that the breakthrough designation actually provided a very good rationale of what you may expect in the label," Graef said.