Imbruvica®▼(ibrutinib) Combination Therapy Data From Two Studies and Long-Term Integrated Analysis Presented at ASH 2019 Show Efficacy and Safety in First-Line Treatment of Chronic Lymphocytic Leukaemia

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced combination data from two studies and a long-term integrated analysis evaluating the use of Imbruvica^® (ibrutinib) for the treatment of previously untreated patients with CLL. Results from a 48-month follow-up analysis of the Phase 3 E1912 clinical study reported a statistically significant difference in PFS and OS for ibrutinib plus rituximab compared to a standard chemoimmunotherapy regimen of FCR.¹ Further, the latest integrated analysis from the Phase 3 RESONATE^TM (PCYC-1112) and RESONATE^TM-2 (PCYC-1115/1116) studies investigating the use of single-agent ibrutinib in CLL, reported at up to six years of follow-up, PFS, OS and response rates improved when ibrutinib was used in earlier lines of therapy.² During this extended follow-up, ibrutinib was tolerated across all lines of therapy with 19 percent of patients discontinuing due to adverse events.²

In addition, results presented from the Phase 2 CAPTIVATE study suggested that patients who received ibrutinib plus venetoclax as a time-limited treatment achieved high rates of uMRD in peripheral blood (75 percent of patients) and bone marrow (72 percent of patients).³

These new findings from the E1912, RESONATE/RESONATE^TM-2 and CAPTIVATE studies were presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

“We’re pleased to see follow-up results from the Phase 3 E1912 trial, where the investigational use of ibrutinib plus rituximab is shown to extend OS for previously untreated patients with CLL. In addition, with the integrated analysis of the Phase 3 RESONATE and RESONATE-2 studies, ibrutinib demonstrated an OS benefit in untreated and relapsed patients, with improved outcomes in early lines of therapy,” said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. “We are also excited to see the first MRD data from the fixed-duration regimen of ibrutinib plus venetoclax in the Phase 2 CAPTIVATE trial, reporting a high rate of undetectable MRD at 15 months both in the peripheral blood and bone marrow.”

“The data presented at ASH adds to the robust body of evidence supporting the safety and efficacy of ibrutinib in the first-line, as a monotherapy or in combination with other treatments,” said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. “As chemotherapy is not suitable for all patients there remains a need for non-chemotherapy treatment options and we are committed to exploring various ibrutinib-based combination regimens.”

E1912 extended follow-up of investigational use of ibrutinib plus rituximab compared to FCR in patients with CLL ages 70 or younger (Abstract #33)¹

Longer-term outcomes data from the Phase 3 E1912 clinical trial – designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health – were also presented. As previously reported in earlier data readouts, the study evaluated 354 previously untreated patients with CLL ages 70 years or younger who were randomly assigned to receive ibrutinib and rituximab or six courses of intravenous FCR every 28 days.¹

At a median follow-up of 48 months, 73 percent of patients in the ibrutinib plus rituximab treatment arm remained on ibrutinib with median time on treatment of 43 months.¹ PFS benefits were observed for the ibrutinib plus rituximab arm as compared to the FCR treatment arm (hazard ratio [HR]=0.39; 95 percent confidence interval [CI], 0.26-0.57; p<0.0001).¹ OS benefit also continued to favour the ibrutinib plus rituximab arm (HR=0.34; 95 percent CI, 0.15-0.79; p=0.009).¹

Grade 3 and above treatment-related adverse events (AEs) were observed in 70 percent of patients in the ibrutinib plus rituximab arm versus 80 percent in the FCR arm (odds ratio [OR]=0.56; 95 percent CI, 0.34-0.90; p=0.013).¹

MRD cohort of the Phase 2 CAPTIVATE study on ibrutinib plus venetoclax combination in patients with previously untreated CLL (Abstract #35)³

The Phase 2 CAPTIVATE (PCYC-1142) clinical trial evaluated 164 patients younger than 70 years (median age of 58 years) with previously untreated CLL.³ Patients received ibrutinib monotherapy as lead-in treatment for three cycles, followed by 12 cycles of ibrutinib plus venetoclax combination therapy.³ MRD status was evaluated in peripheral blood (PB) after six, nine, and 12 cycles and in bone marrow (BM) after 12 cycles of ibrutinib plus venetoclax.³

“The new results from the CAPTIVATE study demonstrated the all-oral regimen of ibrutinib monotherapy followed by combined ibrutinib and venetoclax achieved promising rates of undetectable minimal residual disease, an important indicator of deep response, in previously untreated patients with CLL,” said Constantine Tam, M.D., Haematologist and Disease Group Lead, Low Grade Lymphoma and CLL, Peter MacCallum Cancer Centre, Victoria, Australia, and principal study investigator. “We look forward to continuing to explore the efficacy and safety profile of this regimen and its potential to provide a limited-duration option in first-line treatment of CLL.”

Results showed uMRD – defined as less than one CLL cell per 10,000 leukocytes (MRD<0.01 percent) by flow cytometry – was achieved at any time after baseline in PB for 75 percent of patients (122 of 163 patients) and in BM for 72 percent (111 of 155 patients).³ The high rates of uMRD in BM were consistent across high-risk subgroups, including in patients with del(17p); del(17p) or TP53 mutation; del(11q); complex karyotype; and unmutated IGHV status. In patients with uMRD in PB with matched BM samples, 93 percent of patients had uMRD in both PB and BM. With median follow-up of 14.7 months, three patients (2 percent) experienced disease progression.^3,4

The most common AEs of any grade (in 20 percent of patients or greater) were diarrhoea (31 percent) and arthralgia (22 percent) during treatment with ibrutinib alone; and diarrhoea (60 percent), neutropenia (40 percent), nausea (34 percent), upper respiratory tract infection (24 percent), and fatigue (20 percent) during treatment with ibrutinib plus venetoclax. AEs leading to dose reductions occurred in 20 percent of patients overall. AEs leading to discontinuation were infrequent, occurring in 7 percent of patients overall (ibrutinib: 5 percent; venetoclax: 4 percent).^3,4

Results from the MRD-guided, randomised treatment discontinuation cohort and fixed-duration cohort of the CAPTIVATE clinical trial are being further evaluated and will be presented at a future medical meeting.

Ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialised by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

#ENDS#

About ibrutinib

Ibrutinib is a once-daily, first-in-class Bruton's tyrosine kinase (BTK) inhibitor that is administered orally.⁵ Ibrutinib blocks the BTK protein; the BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.⁶ By blocking BTK, ibrutinib may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.⁷

Ibrutinib is currently approved in Europe for:⁵

• Chronic lymphocytic leukaemia (CLL): As a single agent or in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy
• Mantle cell lymphoma (MCL): As a single agent for the treatment of adult patients with relapsed or refractory MCL
• Waldenström’s macroglobulinemia (WM): As a single agent for the treatment of adult patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemo-immunotherapy, and in combination with rituximab for the treatment of adult patients

Ibrutinib is approved in more than 95 countries for at least one indication, and to date, has been used to treat more than 170,000 patients worldwide across its approved indications.⁸

The most common adverse reactions seen with ibrutinib include diarrhoea, neutropenia, haemorrhage (e.g., bruising), musculoskeletal pain, nausea, rash, and pyrexia.⁵

For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.

About chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is typically a slow-growing blood cancer of the white blood cells.⁹ The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year and is about 1.5 times more common in men than in women.¹⁰ CLL is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.¹¹

The disease eventually progresses in the majority of patients, and they are faced with fewer treatment options with each relapse. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.

About the Janssen Pharmaceutical Companies of Johnson & Johnson

At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at www.janssen.com/emea. Follow us at www.twitter.com/janssenEMEA for our latest news. Janssen-Cilag, Janssen Biotech, Inc. and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding ibrutinib. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2018, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

References

¹ Shanafelt TD, Wang V, Kay NE, Hanson CA, O'Brien SM, Barrientos JC, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre S. Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients with Chronic Lymphocytic Leukemia (CLL): Extended Follow-up from the E1912 Trial. ASH 2019 Oral Presentation. Abstract #33.

² Barr PM, Tedeschi A, Munir T, Hillmen P, Woyach J, Byrd JC, Ghia P, Mulligan S, Dai S, Amaya-Chanaga C, Dean JP. Using Ibrutinib in Earlier Lines of Treatment Results in Better Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Results from the MRD Cohort of the Phase 2 CAPTIVATE Study. ASH 2019 Poster Presentation. Abstract #3054.

³ Tam CS, Siddiqi T, Allan JN, Kipps TJ, Flinn IW, Kuss BJ, Opat S, Barr PM, Tedeschi A, Jacobs R, Badoux XC. Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic. ASH 2019 Oral Presentation. Abstract #35

⁴ Tam CS, Siddiqi T, Allan JN, Kipps TJ, Flinn IW, Kuss BJ, Opat S, Barr PM, Tedeschi A, Jacobs R, Badoux XC. Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Results from the MRD Cohort of the Phase 2 CAPTIVATE Study. Abstract #35. Available at: https://ash.confex.com/ash/2019/webprogram/Paper121424.html. Last accessed December 2019.

⁵ Imbruvica Summary of Product Characteristics, November 2019. Available at: https://www.ema.europa.eu/documents/product-information/imbruvica-epar-product-information_en.pdf Last accessed December 2019

⁶ Turetsky, A, et al. Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor. Scientific Reports. volume 4, Article number: 4782 (2014).

⁷ de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.

⁸ Data on File - IMBRUVICA. 170K Patients on IMBRUVICA - EMEA-SR-0731

⁹ American Cancer Society. What is chronic lymphocytic leukemia? Available at:https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html Last accessed December 2019.

¹⁰ Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116:3724–34.

¹¹ Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl.5):v78-v84.

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