On October 20, 2014 Janssen Research & Development reported the submission of a supplemental New Drug Application (sNDA) for IMBRUVICA (ibrutinib) to the U.S. Food and Drug Administration (FDA) by its strategic partner Pharmacyclics (Press release Johnson & Johnson, OCT 20, 2014, View Source [SID:1234500852]). If approved, this latest regulatory submission will become the fourth indication for IMBRUVICA, adding the treatment of patients with Waldenström’s macroglobulinemia (WM). WM is a rare type of B-cell lymphoma for which there are no treatment options specifically approved in the U.S. IMBRUVICA received FDA Breakthrough Therapy Designation in February 2013 for patients with WM and is being jointly developed and commercialized by Janssen Biotech Inc. and Pharmacyclics.

“We are committed to bringing our medicines to new patient populations, large and small, who may benefit from them,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. “By understanding the mechanism of disease and how WM was similar to other B-cell malignancies, our collaboration partner Pharmacyclics was able to pursue this submission for WM, which has the potential to make a very meaningful difference to a group of patients who do not have a sufficient number of treatment options available to them today.”

“Waldenström’s macroglobulinemia is considered an orphan disease. Currently, there are no approved treatment options specifically for WM,” said Carl Harrington, President of the International Waldenström’s Macroglobulinemia Foundation. “The potential approval of a WM-specific treatment will make an immense difference in our patients’ lives, offering an FDA-approved option where we previously had none.”

WM (also known as lymphoplasmacytic lymphoma) is a slow-growing, incurable, rare type of B-cell lymphoma[1] for which no established standard of care – or approved therapeutic – exists.[2],[3] In the U.S., there are approximately 1,000 to 1,500 new cases each year and the median age at diagnosis is 60-70 years of age.[1],[4] WM begins with a malignant change to the B cell, a type of white blood cell (lymphocyte), during its maturation so that it continues to reproduce more malignant B cells. WM cells make large amounts of a certain type of antibody (immunoglobulin M, or IgM). Antibodies such as IgM normally help the body to fight infection. Excess IgM causes the blood to thicken and causes many of the symptoms of WM, including excess bleeding, problems with vision and nervous system problems.[5]

The currently approved indications for IMBRUVICA are: 1) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, 2) for the treatment of CLL patients with del 17p, a genetic mutation that occurs when part of chromosome 17 has been lost, and 3) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.[6] Accelerated approval was granted for the MCL indication based on overall response rate (ORR). Improvements in survival or disease-related symptoms have not been established. Continued approval for the MCL indication may be contingent upon verification of clinical benefit in confirmatory trials.6 IMBRUVICA was granted Breakthrough Therapy Designation by the FDA for the MCL, WM and CLL with del 17p indications.

Janssen and Pharmacyclics are continuing an extensive clinical development program for IMBRUVICA, including Phase 3 study commitments in multiple patient populations.

On October 20, 2014 NewLink Genetics reported that they have entered into an exclusive worldwide license agreement with Genentech, a member of the Roche Group, for the development of NLG919, NewLink’s IDO pathway inhibitor (Press release NewLink Genetics, OCT 20, 2014, View Source [SID:1234500850]). The parties also entered into a research collaboration for the discovery of next generation IDO/TDO compounds.

Under the terms of the agreement, NewLink will receive an upfront payment of $150 million. NewLink will be eligible to receive in excess of $1 billion in milestone payments based on achievement of certain predetermined milestones as well as escalating double-digit royalties on potential commercial sales of multiple products by Genentech.

Genentech will fund future research, development, manufacturing and commercialization costs. Genentech will also provide research funding to NewLink for support of the research collaboration. NewLink will continue to pursue development activities associated with NLG919 in combination with its novel HyperAcute vaccine platform.

NewLink will retain the option for co-promotion rights for NLG919 and potential next generation IDO/TDO compounds in the U.S. The completion of the agreement is subject to customary closing conditions, including clearance under the Hart-Scott-Rodino Antitrust Improvements Act.

“This alliance enables us to accelerate and expand development of NLG919 while we continue to advance our other promising clinical and preclinical development programs,” said Dr. Charles Link, Chairman and Chief Executive Officer of NewLink. “Genentech’s oncology development expertise, commercial leadership and history of successful strategic alliances make it an ideal collaborator to bring the potential benefits of NLG919 to patients.”

“We are intrigued by the biology of the IDO and TDO compounds and are very interested in the potential to combine them with Genentech’s portfolio of novel therapies,” said James Sabry, Senior Vice President and Global Head of Genentech Partnering. “We are delighted to have initiated this significant partnership with NewLink. We hope this collaboration will lead to new therapies for people with cancer.”

October 17, 2014 Pharmacyclics reported that the European Commission (EC) has granted marketing approval for IMBRUVICA (ibrutinib) throughout the 28 member states of the European Union (EU) (Press release Pharmacyclics, OCT 17, 2014, View Source [SID:1234500842]). IMBRUVICA, a first-in-class, oral, once-daily, non-chemotherapy treatment, now is approved to be marketed in Europe for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), or adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, or in first line CLL patients in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemotherapy.

IMBRUVICA is being jointly developed and commercialized in the U.S. by Pharmacyclics and Janssen Biotech, Inc. (Janssen). Janssen affiliates will hold the marketing authorization and will market IMBRUVICA in EMEA (Europe, Middle East, Africa), as well as the rest of the world, outside the U.S.

The EC approval was based on data from the Phase II study (PCYC-1104) in MCL, the Phase III RESONATE study (PCYC-1112-CA) in CLL and small lymphocytic lymphoma (SLL) and the Phase Ib/II study (PCYC-1102) in CLL/SLL. This approval is based on the IMBRUVICA Marketing Authorization Application (MAA) submitted to the European Medicines Agency (EMA) last year. The EMA is an agency of the EU that administers a centralized procedure for the scientific evaluation of medicines developed by pharmaceutical companies for use in the 28 countries of the EU. In addition to EU markets, a worldwide regulatory filing program for ibrutinib currently is underway.

“We are very pleased that patients with CLL and relapsed or refractory MCL in the European Union will have a first-in-class, oral, single-agent, non-chemotherapy treatment option in IMBRUVICA,” said Bob Duggan, Chairman & CEO of Pharmacyclics. “This approval underscores the compelling safety and efficacy benefits of IMBRUVICA, including statistically significant improvement in overall survival and progression-free survival in CLL and the overall robustness of the data in MCL.”

IMBRUVICA is approved in the U.S. for three indications: for the treatment of patients with MCL and CLL who have received at least one prior therapy, and for the treatment of CLL patients with deletion of the short arm of chromosome 17 (del 17p), including treatment-naive and previously treated del 17p CLL patients. Accelerated approval was granted for the MCL indication based on overall response rate (ORR). Improvements in survival or disease-related symptoms have not been established in MCL. Continued approval for the MCL indication may be contingent upon verification of clinical benefit in confirmatory trials.

The following results are included in the IMBRUVICA Summary of Product Characteristics (SmPC) from EU commission review.

MCL Study Efficacy Results
In a multi-center, single-arm, open-label Phase II study (PCYC 1104), the efficacy of ibrutinib in 111 patients with relapsed or refractory MCL were evaluated. An ORR of 68% was observed, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow up of 15.3 months, the estimated median response duration was 17.5 months, and the estimated median progression-free survival (PFS) was 13.9 months.1

CLL Study Efficacy Results
RESONATE (PCYC-1112) is a Phase III, randomized, multi-center, open-label, international, head-to-head study of single-agent, orally-administered ibrutinib versus the intravenously administered monoclonal antibody ofatumumab, targeting the CD-20 antigen. The study enrolled 391 previously treated patients with CLL/SLL.2

At a median follow-up of 9.4 months, single-agent ibrutinib demonstrated a statistically significant improvement in PFS, overall survival (OS), and ORR, regardless of baseline characteristics, as compared with patients treated with ofatumumab.

The PFS results represent a 78% reduction in the risk of progression or death in patients treated with ibrutinib compared to ofatumumab. The OS results represent a 57% reduction in the risk of death in patients receiving ibrutinib versus those in the ofatumumab arm. The efficacy was similar across all of the subgroups examined, including in patients with and without del 17p, a pre-specified stratification factor.

As noted in the market application and reported in The New England Journal of Medicine publication, the RESONATE results were observed despite a total of 57 patients who were initially randomized to ofatumumab crossing over to receive IMBRUVICA prior to the analysis.

MCL and CLL Study Safety Results
The most commonly occurring adverse reactions ( > 20%) were diarrhea, musculoskeletal pain, upper respiratory tract infection, bruising, rash, nausea, pyrexia, neutropenia, and constipation. The most common grade 3/4 reactions ( > 5%) were anemia, neutropenia, pneumonia, and thrombocytopenia.