IMBRUVICA® (ibrutinib) Data Demonstrates Efficacy in Previously Untreated and Relapsed/Refractory High-Risk Chronic Lymphocytic Leukemia Patients

SUNNYVALE, Calif., Jan. 5, 2015 /PRNewswire/ -- Pharmacyclics, Inc. (NASDAQ: PCYC) today announced that treatment with single-agent IMBRUVICA^® (ibrutinib) in treatment-naive and previously treated patients with chronic lymphocytic leukemia (CLL) resulted in a significant response rate, with 92% of high-risk CLL patients with deletion 17p (del 17p) or tumor protein 53 (TP53 aberrations) achieving an objective response. These high-risk patients typically do not respond well to standard therapies. These results were published in The Lancet Oncology. IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

"Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options," said Mohammed Farooqui*, D.O., Staff Clinician, Laboratory of Lymphoid Malignancies, National Heart, Lung, and Blood Institute and lead author of the publication.

When functioning normally, the TP53 gene produces a protein called p53, which acts as a tumor suppressor and regulates cell division by preventing cells from growing and dividing too quickly.¹ If TP53 is damaged or a copy of the gene is lost, it can result in aberrations which cause cells to grow in an uncontrolled way, resulting in early disease relapse and poor survival rates.^2,3 In addition, CLL patients with deletion of the short arm of chromosome 17 are considered to have the poorest prognosis.⁴ These mutations often occur together and are present in approximately 7-11.5% of treatment-naive CLL patients.^2,5,6

"This study is important as it is the largest prospective cohort of del 17p CLL patients treated with single-agent IMBRUVICA as first-line therapy," said Danelle James, M.D., M.S., Vice President, Clinical Development, Pharmacyclics. "These positive IMBRUVICA results are very exciting and reinforce the effectiveness and tolerability of IMBRUVICA in patients with del 17p CLL, while demonstrating its potential utility in earlier lines of treatment for this difficult-to-treat, high-risk group of CLL patients."

The Phase II, open-label, single-center study enrolled 51 CLL patients at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD. Thirty-five patients had previously untreated disease and 16 patients had relapsed or refractory CLL. The primary endpoint of the study was overall response rate (ORR) after 24 weeks, and secondary endpoints included safety, overall survival, progression-free survival (PFS), best response and nodal response. Forty-seven of the 51 patients (92%) enrolled in this study had del 17p CLL and four patients carried the TP53 aberration but did not have the del 17p mutation.

At the time of analysis, the median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Ninety-two percent (n=44) of patients achieved an objective response (95% CI, 84-100), 50% achieved a partial response (PR; n=24) and 42% achieved a PR with lymphocytosis (n=20). The ORR rate and depth of responses increased over time.

The estimated PFS at 24 months for all patients on an intention-to-treat basis was 82% (95% CI, 71-94). Forty-two of the 51 patients enrolled in the study (82%) continued on IMBRUVICA treatment without disease progression. After eight weeks on therapy, IMBRUVICA was associated with a > 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%) and spleen (79%) in patients. After 24 weeks of therapy, the rates of tumor burden reduction (> 50%) increased to 83%, 93% and 95%, respectively.

Most non-hematologic adverse events were Grade 1 or 2. The most common adverse events (AEs; occurring in > 30% of all patients) potentially related to IMBRUVICA treatment were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%) and muscle spasms (31%). The most common nonhematologic Grade 3 adverse event was pneumonia in three patients (6%). No bleeding events > Grade 3 occurred. The most frequent Grade 3 or 4 hematologic AEs in this study were neutropenia (24%), anemia (14%) and thrombocytopenia (10%). Nine patients (18%) discontinued treatment; reasons for discontinuation included disease progression in five patients (10%) and three deaths (6%).

About Chronic Lymphocytic Leukemia (CLL)
The prevalence of CLL is approximately 115,000 patients in the United States,⁷ with approximately 16,000 newly diagnosed patients every year.⁸ As this orphan disease frequently progresses following first-line therapy, patients are faced with fewer treatment options and often are prescribed multiple lines of therapy as they relapse or become resistant to treatments.⁹

In CLL, the genetic mutation del 17p occurs when part of chromosome 17 has been lost or deleted. CLL patients with del 17p have poor treatment outcomes.⁴ Del 17p is reported in approximately 7-10% of treatment-naïve CLL/SLL cases,¹⁰ and approximately 20% to 40% of relapsed/refractory patients harbor the mutation.¹¹

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).¹² BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.^12,13 IMBRUVICA blocks signals that tell malignant B-cells to multiply and spread uncontrollably.¹²

IMBRUVICA is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, and for the treatment of CLL patients with del 17p,¹² a genetic mutation that occurs when part of chromosome 17 has been lost.

IMBRUVICA is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. 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.¹²

IMBRUVICA is being studied alone and in combination with other treatments in several blood cancers including: chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); Waldenstrom's macroglobulinemia (WM); diffuse large B-cell lymphoma (DLBCL); follicular lymphoma (FL); marginal zone lymphoma (MZL); multiple myeloma (MM); and, other B-cell malignancies. Over 4,600 patients have been treated in clinical trials of IMBRUVICA conducted in 35 countries by more than 800 investigators. Currently, 13 Phase III trials have been initiated with IMBRUVICA and 55 trials are registered on www.clinicaltrials.gov. The overall clinical development program covers all lines of therapy and various combinations of treatments.

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway, and is the only product to have received three Breakthrough Therapy Designations.

INDICATIONS
IMBRUVICA is indicated to treat people with:

• Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
• Chronic lymphocytic leukemia (CLL) with 17p deletion (a genetic mutation that occurs when part of chromosome 17 has been lost).
• Mantle cell lymphoma (MCL) who have received at least one prior therapy
  • Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Patients taking IMBRUVICA for CLL should take 420 mg taken orally once daily (or three 140 mg capsules once daily).

Patients taking IMBRUVICA for MCL should take 560 mg taken orally once daily (or four 140 mg capsules once daily).

Capsules should be taken orally with a glass of water. Capsules should be taken whole. Do not open, break, split or chew the capsules.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA^®.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five % of patients with MCL and 26% of patients with CLL had Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE).

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23 to 29%), thrombocytopenia (5 to 17%), and anemia (0 to 9%) occurred in patients treated with IMBRUVICA.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation.

Second Primary Malignancies - Other malignancies (5 to 10%) including carcinomas (1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (4 to 8%).

Embryo-Fetal Toxicity - Based on animal studies, IMBRUVICA may cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while taking IMBRUVICA^®.

The most common adverse reactions include thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, pyrexia, vomiting, and decreased appetite.

In MCL, fatal and serious cases of renal failure have occurred. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.

For additional important safety information, please see Full Prescribing Information at http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Patient Access to IMBRUVICA
Patients who are prescribed IMBRUVICA can receive access support through a variety of programs:

• The YOU&i Start™ program enables eligible patients who are experiencing insurance coverage delays to access free product for a limited time.
• The YOU&i Access™ Instant Savings Program helps commercially insured, eligible patients who have difficulties with out-of-pocket expenses for IMBRUVICA. Eligible patients may receive support to reduce their monthly out-of-pocket costs to $25 per month.
• The YOU&i Access Service Center assists patients with all access-related administration issues.
• The Johnson & Johnson Patient Assistance Foundation (JJPAF), an independent, non-profit organization to which Pharmacyclics makes donations, allows patients who are deemed uninsured and eligible, and who qualify based on financial need, access to IMBRUVICA.

For more information about these comprehensive patient access programs, call or visit 1-877-877-3536 or www.IMBRUVICA.com.

About Pharmacyclics
Pharmacyclics, Inc. (NASDAQ: PCYC) is a biopharmaceutical company focused on developing and commercializing innovative small-molecule drugs for the treatment of cancer and immune mediated diseases. The company's mission is to build a viable biopharmaceutical company that designs, develops and commercializes novel therapies intended to improve quality of life, increase duration of life and resolve serious medical healthcare needs and to identify and control promising product candidates based on exceptional scientific development and administrative expertise, develop its products in a rapid, cost-efficient manner, and to pursue commercialization and/or development partners when and where appropriate.

Pharmacyclics markets IMBRUVICA and has three product candidates in clinical development and several preclinical molecules in lead optimization. The company is committed to high standards of ethics, scientific rigor, and operational efficiency as it moves each of these programs to commercialization. Pharmacyclics is headquartered in Sunnyvale, CA. To learn more, visit www.pharmacyclics.com. Follow us on Twitter @pharmacyclics at http://twitter.com/pharmacyclics.

Safe Harbor StatementThis announcement may contain forward-looking statements made in reliance upon the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements, among others, relating to our future capital requirements, including our expected liquidity position and timing of the receipt of certain milestone payments, and the sufficiency of our current assets to meet these requirements, our future results of operations, our expectations for and timing of ongoing or future clinical trials and regulatory approvals for any of our product candidates, and our plans, objectives, expectations and intentions. Because these statements apply to future events, they are subject to risks and uncertainties. When used in this announcement, the words "anticipate", "believe", "estimate", "expect", "expectation", "goal", "should", "would", "project", "plan", "predict", "intend", "target" and similar expressions are intended to identify such forward-looking statements. These forward-looking statements are based on information currently available to us and are subject to a number of risks, uncertainties and other factors that could cause our actual results, performance, expected liquidity or achievements to differ materially from those projected in, or implied by, these forward-looking statements. Factors that may cause such a difference include, without limitation, our need for substantial additional financing and the availability and terms of any such financing, the safety and/or efficacy results of clinical trials of our product candidates, our failure to obtain regulatory approvals or comply with ongoing governmental regulation, our ability to commercialize, manufacture and achieve market acceptance of any of our product candidates, for which we rely heavily on collaboration with third parties, and our ability to protect and enforce our intellectual property rights and to operate without infringing upon the proprietary rights of third parties. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, performance or achievements and no assurance can be given that the actual results will be consistent with these forward-looking statements. For more information about the risks and uncertainties that may affect our results, please see the Risk Factors section of our filings with the Securities and Exchange Commission, including our Form 10-K for the year ended December 31, 2013 and quarterly reports on Form 10-Q. We do not intend to update any of the forward-looking statements after the date of this announcement to conform these statements to actual results, to changes in management's expectations or otherwise, except as may be required by law.

*Disclaimer: Dr. Farooqui served as principal investigator of this National Institutes of Health-sponsored clinical study. He has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. Dr. Farooqui does not have a financial interest in either company. The National Heart, Lung, and Blood Institute at the National Institutes of Health has received research funding from Pharmacyclics in conjunction with this clinical trial.

IMBRUVICA is a registered trademark of Pharmacyclics, Inc.

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⁹ Veliz M, Pinilla-Ibarz J. Cancer Control. Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia. January 2012, Vol. 19, No. 1.
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¹¹ Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010: 481-8.
¹² IMBRUVICA Prescribing Information, July 2014.
¹³ Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed December 2014.

SOURCE Pharmacyclics, Inc.

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