CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
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`APPLICATION NUMBER:
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`205552Orig2s000
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`OFFICE DIRECTOR MEMO
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`

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`Office Director Decisional Memo
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`NDA 205552/Original-2_lmbmvin (ibmtinb)
`
`Summary Review for Regulatory Action
`
`_——
`
`From
`Richard Pazdur, MD
`
`Subject
`Office Director Decisional Memo
`NDA/BLA #
`NDA 205552 0 ‘. inal-2 for CLL indication
`
`m'im— Pharmac clics, Inc.
`Date of Submission
`28 June 2013
`
`PDUFA Goal Date
`28 February 2014
`Proprietary Name I Established
`Imbruvicalibrutinib
`
`(USAN) names
`Dosa eformslStren th
`Proposed Indication(s)
`
`Cao ules, 140m
`Treatment of patients with chronic lymphocytic leukemia (CLL) who
`have received at least one . rior thera .
`AcceleratedA oval
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`Material Reviewed/Consulted
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`Division Director Review
`
`Ann Farrell, MD
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`Marathe, PhD, Pin Zhao PhD
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`Regulatory Project Manager Review
`Clinical Review
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`Pharmacology Toxicology Review
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`ONDQA—CMC and Biophannaceutic
`Reviews
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`Clinical Pharmacology Review
`
`Nicole Verdun, MD/ R. Anoelo de Claro, MD
`Yun Wan, PhD/ Lei Nie, PhD
`
`Shwu-Luan Lee, PhD, Haw-Jyh (Brian) Chiu,
`PhD, George Ching-Jey Chang, PhD,
`Mararet E. Brower, PhDI Haleh Saber, Pth John Lei
`
`CMC: Donghao (Robert) Lu, PhD (Dmg substance)l Xiao-Hong Chen,
`PhD (Drug product)l
`BiophaIm: John Duan, PhD [Angelica Dorantes, PhD
`Microbiology: Bryan Riley, PhD
`ONDQA: Ramesh Sood, PhD Tertia Review
`
`Elimika Pfuma, PhannD, PhD, Julie Bullock, PharmD, Rosane Charlab
`Orbach, PhD, Bahru Habtemanam, PhannD, Yu7Jiuo Pan, PhD, Anshu
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`Page 1 of 4
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`Reference ID: 3452802
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`Office Director Decisional Memo
`NDA 205552/Original-2_Imbruvica (ibrutinib)
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`
`
`Introduction
`1.
`On June 28, 2013, Pharmacyclics Inc. submitted NDA 205552 for two indications: (1) for the treatment of
`patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and (2) for the
`treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
`The application was administratively split into NDA 205552/Original-1 for the MCL indication and NDA
`205552/Original-2 for the CLL indication. NDA 205552/Original-1 received accelerated approval for the
`treatment of patients with MCL who have received at least one prior therapy on November 13, 2013. The
`subject of this review is NDA 205552/Original-2 for the CLL indication.
`
`Imbruvica (ibrutinib) is a first-in-class Bruton’s tyrosine kinase inhibitor, which targets the B-cell antigen
`receptor (BCR) signaling pathway.
`
`The primary basis for the application is the result from clinical trial PCYC-1102-CA, an open-label, single-arm
`trial of Imbruvica monotherapy in 48 patients with CLL who have received at least one prior therapy.
`
`
`2. Background
`CLL is the most common form of leukemia in adulthood. The National Cancer Institute estimates that 15,680
`men and women (9,720 men and 5,960 women) will be diagnosed with CLL in 2013. CLL is a
`lymphoproliferative neoplasm characterized by an accumulation of monoclonal mature B-cells (CD5+CD23+)
`in the blood, bone marrow, and secondary lymphatic organs.
`
`Current treatments for CLL are not curative, and relapse, toxicity, and resistance to therapy provide for an
`unmet medical need. Among patients who relapse or who are refractory to first line treatment, the choice of
`subsequent therapy depends on age, duration of response to prior therapy, ability to tolerate treatment,
`disease related manifestations, and the presence of molecular poor-risk features.
`
`The following treatments are FDA-approved for the treatment of CLL: Chlorambucil (1957),
`Cyclophosphamide (1959), Fludarabine (1991), Alemtuzumab (2007), Bendamustine (2008), Ofatumumab
`(2009, accelerated approval), Rituximab (2010), and Obinutuzumab (2013).
`
`3. CMC/Device
`CMC sections were addressed in the NDA 205552 (Original-1) review. There are no major labeling changes
`proposed for the CMC sections with NDA 205552 (Original-2).
`
`
`4. Nonclinical Pharmacology/Toxicology
`Nonclinical Pharmacology and Toxicology sections were addressed in the NDA 205552 (Original-1) review.
`There are no major labeling changes proposed for the Nonclinical Pharmacology and Toxicology sections with
`NDA 205552 (Original-2).
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`Clinical Pharmacology reviewed the MCL and CLL indications together in the NDA 205552 (Original-1)
`review, and issued a brief addendum for NDA 205552 Original-2. There are no major labeling changes
`proposed for the Clinical Pharmacology sections with NDA 205552 (Original-2).
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`Page 2 of 4
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`Reference ID: 3452802
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`Office Director Decisional Memo
`NDA 205552/Original-2_Imbruvica (ibrutinib)
`
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`6. Clinical Microbiology
`The application did not include clinical microbiology information. Refer to Section 3 of NDA 205552 (Original-
`1) review for product quality microbiology information.
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`7. Clinical - Efficacy
`The approval in CLL is based on the results of a multi-center, single-arm trial of 48 patients with previously
`treated CLL. The median age was 67 years (range, 37 to 82 years) and 71% were male. All patients had a
`baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years and the median
`number of prior treatments was 4 (range, 1 to 12 treatments). Ibrutinib was administered orally at 420 mg
`once daily until disease progression or unacceptable toxicity.
`
`The efficacy results demonstrated a 58.3% overall response rate (95% CI: 43.2, 72.4) as assessed by an
`independent review committee. No complete responses were observed. The response duration ranged from
`5.6 to 24.2+ months; the median was not reached.
`
`As a condition of this accelerated approval, the sponsor is required to submit results of randomized clinical
`trial(s.) In January 2014, Pharmacyclics notified FDA of the early stopping of the RESONATE trial by the Data
`Monitoring Committee (DMC) based on favorable results of a planned interim analysis. RESONATE, a phase
`3 clinical trial, randomized patients to either ibrutinib or ofatumumab. Patients entered on this trial had
`previously treated CLL or small lymphocytic lymphoma (SLL) and were not considered candidates for
`treatment with purine analogue-based treatments. The trial was reported to demonstrate an improvement in
`progression-free survival and overall survival.
`
`8. Clinical - Safety
`The safety profile of ibrutinib for patients with previously treated CLL was consistent with observations in the
`mantle cell lymphoma clinical trial. The most common adverse reactions reported in the CLL clinical trial
`(occurring in greater than or equal to 20% of patients) were thrombocytopenia, diarrhea, bruising,
`neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia,
`constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness.
`
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`9. Advisory Committee Meeting
`The NDA for this new molecular entity was not presented to the Oncologic Drugs Advisory Committee
`because the application did not raise significant efficacy or safety issues for the proposed indication.
`
`
`10. Pediatrics
`Imbruvica is exempt from the pediatric study requirements in 21 CFR 314.55. The FDA Office of Orphan
`Products Development granted Orphan Drug Designation for ibrutinib for the treatment of CLL on April 6,
`2012. Imbruvica has not been evaluated in pediatric patients.
`
`
`11. Recommendations/Risk Benefit Assessment
` Recommended Regulatory Action: Accelerated Approval
`
` Risk Benefit Assessment
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`Page 3 of 4
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`Reference ID: 3452802
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`Office Director Decisional Memo
`NDA 205552/Original-2_Imbruvica (ibrutinib)
`
`
`Relapsed CLL is a serious and life-threatening illness. The efficacy and safety results in clinical trial
`PCYC-1102-CA demonstrate an acceptable benefit-risk profile for Imbruvica for the treatment of patients
`with previously treated CLL.
`
`The response rate of 58.3% (95%CI: 43.2%, 72.4%) in a patient population with relapsed CLL, with a
`duration of response ranging from 5.6 to 24.2+ months support approval. However, verification of clinical
`benefit of Imbruvica in the CLL population is necessary due to the small number of patients treated, none
`of the patient achieved a complete response, and time-to-event endpoints such as PFS or overall survival
`cannot be adequately interpreted in single-arm trials. Therefore, the sponsor will be required to verify
`clinical benefit under accelerated approval regulations. During the review, the Applicant notified the
`Agency regarding early stopping of the RESONATE trial (PCYC-1112-CA), a Phase 3, randomized
`controlled trial of ibrutinib or ofatumumab in patients with previously treated CLL due to significant
`improvements in PFS and overall survival in the ibrutinib arm. Although the results have not been
`submitted to the Agency, a subsequent submission is planned for this trial and may serve as the
`demonstration of clinical benefit.
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`The risk-benefit profile of Imbruvica was discussed in the reviews of Drs. Farrell, De Claro, and Verdun
`and I concur with their recommendation to grant accelerated approval for this NDA.
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` Recommendation for Postmarketing Risk Evaluation and Management Strategies
`A REMS to assure safe use of ibrutinib is not recommended.
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` Recommendation for other Postmarketing Requirements and Commitments: See action letter.
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`Page 4 of 4
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`Reference ID: 3452802
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TAMY E KIM
`02/11/2014
`
`RICHARD PAZDUR
`02/11/2014
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`Reference ID: 3452802
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`