The FDA gave drug developers a shot of good news Wednesday afternoon with the approval of Imbruvica (ibrutinib), the oral Bruton’s tyrosine kinase (BTK) inhibitor developed by Pharmacyclics Inc. and Johnson & Johnson unit Janssen Biotech Inc., as a single agent to treat patients with mantle cell lymphoma (MCL) who received at least one prior therapy.

Approval in the initial indication came more than three months before the drug’s PDUFA date of Feb. 28, 2014.

BTK is a key signaling molecule of the B-cell receptor signaling complex that plays an important role in the survival of malignant B cells. Imbruvica blocks signals that stimulate malignant B cells to grow and divide uncontrollably.

Inked just two years ago, the potential $975 million deal for ibrutinib, then known as PCI-32765, included $150 million up front at a time when shares of Pharmacyclics (NASDAQ:PCYC) were trading at less than $13 and the company had $112 million in the bank after a $56 million registered direct offering. Milestone payments were tied to development, regulatory filings and approval – not sales figures. Partner Janssen picked up 60 percent of product development costs. With the drug approved, the companies will split commercial costs and profits equally, with Pharmacyclics taking the lead and booking sales in the U.S. (See BioWorld Today, Dec. 12, 2011.)

Following Imbruvica’s approval Wednesday, investors sent shares of Pharmacyclics to more than $129 before closing the day at $123.82 for a gain of $4.15. The company’s market cap has passed $9 billion, and in its third quarter financials reported last week, cash holdings were $560. 1 million as of Sept. 30.

Imbruvica is the third drug approved in MCL, following Velcade (bortezomib, Millennium: The Takeda Oncology Co.) in 2006 and Revlimid (lenalidomide, Celgene Corp.) earlier this year. The drug is the second approved through the FDA’s breakthrough therapy designation, following by one week the approval of Roche AG subsidiary Genentech Inc.’s Gazyva (obinutuzumab), formerly GA101, in combination with chlorambucil to treat previously untreated chronic lymphocytic leukemia (CLL). (See BioWorld Today, Nov. 4, 2013.)

In February, Pharmacyclics, of Sunnyvale, Calif., and Janssen, of Raritan, N.J., were among the first companies to gain the breakthrough therapy designation for the drug candidate in MCL. (See BioWorld Today, Feb. 14, 2013.)

Pharmacyclics completed its new drug application (NDA) submission in late June for MCL and a second indication of previously treated CLL/small lymphocytic lymphoma (SLL), which remains under review, with a decision expected by the PDUFA date. In August, the FDA accepted the application for priority review, with Pharmacyclics pocketing a $75 million milestone payment from Janssen. (See BioWorld Today, Aug. 30, 2013.)

Despite the breakthrough drug designation – designed potentially to allow approvals on the basis of a single clinical trial – more than 1 ,600 patients had been treated with ibrutinib by the time Pharmacyclics submitted the NDA.

Nevertheless, Craig Tendler, vice president of late development and global medical affairs for oncology at Janssen, said ibrutinib’s development provided the company with terrific insights into the breakthrough drug designation process. Early discussions with the FDA “helped us on a development path that was very streamlined and focused,” he said, with the agency providing critical guidance on what data to collect and report as part of its filing.

“With other drugs in our pipeline, we are trying to look at how to generate the same kind of data early on, have a discussion with FDA and determine whether we have a population of patients where there is high unmet need, whether what we’re seeing is quite different than what’s available in the market and whether there’s a strong scientific rationale that supports what we’re seeing in the clinic,” Tendler told BioWorld Today.

The FDA also granted accelerated approval and orphan drug designation to Imbruvica. Approval, based on the overall response rate, was predicated on the results of a multicenter, international, single-arm Phase II study of 1 1 1 patients with previously treated MCL that showed a 65.8 percent overall response rate (95 percent CI: 56.2, 74.5); 17 percent of patients achieved a complete response and 49 percent achieved a partial response. The median duration of response was 17.5 months (95 percent CI: 15.8, not reached).

“As an oncologist, I can tell you I’m very excited about the data,” Jesse McGreivy, Pharmacyclics’ chief medical officer, told BioWorld Today, adding that Imbruvica moves cancer therapies significantly farther down the road toward greater efficacy with less risk. “We are, as I see it, in a renaissance of improving treatment in oncology.”

Global Peak Sales Could Reach $6.5 Billion

On a conference call, Pharmacyclics officials said the label contained no black box warnings and no contraindications. Safety data during the drug’s pivotal trial showed the most common Grade 3 or 4 nonhematological adverse reactions (>/= 5 percent) included pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue and skin infections.

Five percent of patients had Grade 3 or higher bleeding events, and treatment-emergent Grade 3 or 4 cytopenias were reported in 41 percent of patients. As is customary for many drug approvals, the drug’s prescribing information includes warnings against hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies and embryo-fetal toxicity.

Pharmacyclics officials said sales teams from both companies are trained and product is ready, with marketing efforts beginning immediately. The recommended dose in MCL is 560 mg (four 140-mg capsules) orally once daily, priced at $10,900 for a 30-day supply. Pharmacyclics and Janssen also put patient assistance programs in place.

Pricing in CLL, where the companies are seeking approval of a lower dose, is expected to be approximately $8,200 per month.

Expecting a strong launch in MCL, Roth Capital Partners analyst Joseph Pantginis raised his price target on Pharmacyclics to $151, from $144.

“While we believe the approval of ibrutinib was widely expected, this is still a strong win for the company,” Pantginis wrote in a company update, projecting Pharmacyclics would see fourth quarter revenues of at least $2 million from the drug.

J.P. Morgan analyst Cory Kasimov was equally enthused, reiterating an “overweight” rating on Pharmacyclics’ stock.

“Importantly, approval ahead of [the American Society of Hematology annual meeting] (Dec. 7-10, New Orleans) will enable PCYC/JNJ to have a significant commercial presence at the [conference],” he wrote in a company alert. “With no panel, no black box, and no contraindications in the label, we see today’s news as a clear positive given increasing concern around these issues post the Iclusig [ponatinib, Ariad Pharmaceuticals Inc.] developments in CML.” (See BioWorld Today, Oct. 10, 2013, and Nov. 1, 2013.)

Indeed, MCL is likely the tip of the iceberg for Imbruvica, which could mimic the growth-via-label-expansion model of Rituxan (rituximab, Biogen Idec Inc. and Roche AG) – also the game plan for second-generation Gazyva. In addition to its use as a maintenance drug and in older patients intolerant to conventional therapy, other potential 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.

According to Cortellis Competitive Intelligence, 37 trials – including eight Phase III studies – examining ibrutinib are planned or under way by Pharmacyclics, Janssen or investigators at the National Institutes of Health, MD Anderson Cancer Center, Dana Farber Cancer Institute or Ohio State University.

Kasimov modeled peak U.S. sales of $350 million for Imbruvica in MCL, assuming a 20 percent market share in the indication. With approval in additional indications and territories, he projected worldwide peak sales of approximately $6.5 billion.

In a first glance at Pharmacyclics following the approval, RBC Capital Markets analyst Michael Yee characterized the approval in MCL only as “a relative short time disappointment vs. Wall Street expectations for simultaneous approval in both indications with a broad label.”

He added, however, that the FDA was likely awaiting the RESONATE-1 readout in January 2014 before rendering a final decision on CLL, “with approval more likely coming soon than not.”