`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 205-552/S-17
`
`
`Imbruvica
`
`ibrutinib capsules, 140 mg
`
`Pharmacyclics LLC.
`
`August 2, 2017
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
` For the treatment of patients with chronic graft-versus
`host disease (cGVHD) after failure of one or more
`lines of systemic therapy.
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`NDA 205-552/S17
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Approval Letter
`Approvable Letter
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`
`NDA 205-552/S-17
`NDA 205-552/S-17
`
`
`APPLICA TI0N NUMBER:
`
`SUMMARY REVIEW
`
`SUMMARY REVIEW
`
`
`
`
`
`

`

`Date
`
`Ann. T. Farrell, M.D., Division Director
`From
`
`Subject
`,7 ,
`,
`r ,,
`,
`, Summary Review
`NDA/BLA #
`205552-017
`
`PDUFA Goal Date
`
`Au st 2, 2017
`
`Proprietary Name /
`Established
`S .
`
`Name
`
`Imbruvrca/ibrutinib/PCI-32765
`
`Dosa _e Forms / Stren_ h
`
`140 mo hard elatin ca n sules
`
`Proposed Indication(s)
`
`Treatment of patients with chronic graft-versus host
`disease (cGVHD) after failure of one or more lines of
`s stemic therau
`
`Action/Recommended Action for Approval
`
`Material Reviewed/Consulted
`
`0ND Action Packa ' e, includin- :
`
`— M
`
`edical Officer Review
`
`Re ate Health Pro'ectManaer
`
`Sn lement #
`
`Applicant Name
`Pharmacyclics
`Date of Submission
`Feb
`.
`2, 2017
`
`-—=—
`
`CDTL Review
`
`OSE/DMEPA
`C0A Staff
`
`Mills/LaShawn Griffiths
`
`A alew, M.D.
`
`Anselo deClaro, M.D.
`
`Leeza Rahimi, Pharm.D.lYelena Maslov, Phaim. D.
`Ebony Dashiell-Aje / Selena Daniels/Elecktra
`Pa ado oulos, MD.
`
`Reference ID: 41 33540
`
`

`

`Signatory Authority Review Template
`
`
`
`1. Introduction
`
`
`On November 13, 2013 Pharmacyclics, Inc. received approval for Imbruvica
`(ibrutinib). Ibrutinib (PCI-32765) is an irreversible inhibitor of Bruton’s tyrosine kinase
`(Btk). Imbruvica is approved for treatment of patients with the following diseases:
`
`
`Mantle cell lymphoma (MCL) who have received at least one prior
`therapy
`Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) who
`have received at least one prior therapy
`Chronic lymphocytic leukemia)/Small lymphocytic lymphoma (SLL) with 17p
`deletion
`Waldenströms Macroglobulinemia
`Marginal zone lymphoma
`
`
`
`This submission provides for a new indication for the treatment of patients with
`chronic graft versus host disease (cGVHD), which is a serious and life-threatening
`condition occurring following hematopoietic stem cell transplant.
`2. Background
`
`
`There are no currently approved treatments for chronic graft versus host disease.
`Corticosteroids are the mainstay for the first-line treatment of cGVHD. There are no
`approved therapies for the treatment of cGVHD after failure of 1 or more lines of
`therapy.
`
`From the CDTL review:
`The primary basis for the application is clinical trial PCYC-1129-CA, titled “A
`Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or
`Refractory Chronic Graft Versus Host Disease” [Clinicaltrials.gov Identifier
`NCT02195869].
`
`Formal meetings occurred between the Agency and the Applicant on 3 November
`2015 and 31 August 2016 to discuss the development program and registration plans
`for Imbruvica to support an indication for the treatment of patients with chronic graft-
`versus-host disease.
`
`FDA granted Breakthrough Therapy Designation for Imbruvica for the treatment of
`patients with cGVHD after failure of 1 or more lines of systemic therapy on 22 June
`
`Reference ID: 4133540
`
`

`

`2016. Orphan drug designation was granted on 23 June 2016 for ibrutinib for the
`treatment of chronic graft-versus-host disease….
`
`The Applicant also submitted the results of a drug interaction trial (PCI-
`32765LYM1003) that evaluated the potential interaction between a moderate CYP3A
`inhibitor (erythromycin) and a strong CYP3A inhibitor (voriconazole) in patients with a
`B-cell malignancy, as well as a summary report of physiologically based
`pharmacokinetic (PBPK) simulations (16-031-Hu-PO-PBPK) that evaluated the
`potential interaction between the strong CYP3A4 inhibitor posaconazole and ibrutinib
`to support changes to the current labeling recommendations.
`3. CMC/Device
`
`
`No issues were identified precluding approval.
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`No issues were identified precluding approval.
`
`Pharmacology-Toxicology team reviewed the study report for PCYC-1132-NT to
`address FDAAA PMR 2060-3: Determine the effect of a broad range of
`concentrations of ibrutinib on the potential to inhibit platelet function by conducting in
`vitro studies. Assessment methods should include evaluation of effects on platelet
`aggregation, including GPIb-mediated aggregation. Evaluation should include
`samples from subjects with and without concomitant conditions associated with
`platelet dysfunction (e.g., severe renal dysfunction, use of a concomitant
`anticoagulant, and use of aspirin).
`
`Findings from PCYC-1132-NT included:
`Ibrutinib demonstrated inhibition of collagen-induced platelet aggregation, with
`
`IC50 values at 4.6 μM (2026 ng/mL), 0.8 μM (352 ng/mL), and 3 μM (1321
`ng/mL) in blood samples from healthy donors, donors taking warfarin, and
`donors with severe renal dysfunction, respectively.
`Ibrutinib did not show meaningful inhibition of platelet aggregation for ADP,
`arachidonic acid, ristocetin, and TRAP-6.
`
`
`Despite the study, the mechanism for bleeding events with ibrutinib remains not well
`understood.
`
`Based on the above results, PMR 2060-3 is fulfilled.
`
`
`
`
`Reference ID: 4133540
`
`

`

`5. Clinical Pharmacology/Biopharmaceutics
`No issues were identified precluding approval. The Applicant submitted the results of
`a drug interaction trial (PCI-32765LYM1003) that evaluated the potential interaction
`between a moderate CYP3A inhibitor (erythromycin) and a strong CYP3A inhibitor
`(voriconazole) in patients with a B-cell malignancy, as well as a summary report of
`physiologically based pharmacokinetic (PBPK) simulations (16-031-Hu-PO-PBPK)
`that evaluated the potential interaction between the strong CYP3A4 inhibitor
`posaconazole and ibrutinib to support changes to the current labeling
`recommendations. Labeling recommendations were made based on this study and
`the clinical study in patients with cGVHD.
`
`
`
`6. Microbiology
`N/A
`7. Clinical/Statistical-Efficacy
`The clinical team reviewed the application. The following text is from the CDTL
`review:
`
`Trial Design
`The trial was an open-label, multi-center, single-arm trial of patients with cGVHD after
`failure of first line corticosteroid therapy and requiring additional therapy. With a
`sample size of 40 subjects, and an expected overall cGVHD response rate of 50%,
`the study was expected to have at least 90% power to demonstrate that the lower
`bound of the 95% confidence interval of the response rate is greater than 25%. The
`responses were assessed by investigators using the 2005 National Institute of Health
`(NIH) Consensus Panel Response Criteria with two modifications (added “not
`evaluable” for organs with non-cGVHD abnormalities, and organ score change from 0
`to 1 was not considered disease progression) to align with the updated 2014 NIH
`Consensus Panel Response Criteria.
`
`Patient Population
`A total of 45 subjects were enrolled, and 43 subjects were treated. The primary
`analysis population was an all-treated population which included 42 subjects who
`received at least 1 dose of ibrutinib at the recommended dose of 420 mg once daily,
`excluding one subject who had evidence of recurrence of underlying malignancy
`(AML) at the start of study drug.
`
`The median age was 56 years (range, 19 to 74 years), 52% were male, and 93%
`were Caucasian. The most common underlying malignancies leading to
`transplantation were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
`The median time since cGVHD diagnosis was 14 months, the median number of prior
`cGVHD treatments was 2 (range, 1 to 3 treatments), and 60% of patients had a
`Karnofsky performance score of ≤ 80. The majority of patients (88%) had at least 2
`
`Reference ID: 4133540
`
`

`

`organs involved at baseline, with the most commonly involved organs being mouth
`(86%), skin (81%), and gastrointestinal tract (33%). The median daily steroid dose
`(prednisone or prednisone equivalent) at baseline was 0.3 mg/kg/day, and 52% of
`patients were receiving ongoing immunosuppressants in addition to systemic
`corticosteroids at baseline. Prophylaxis for infections were managed per institutional
`guidelines with 79% of patients receiving combinations of sulfonamides and
`trimethoprim and 64% receiving triazole derivatives.
`
`Efficacy Results
` The best overall response rate (complete response[CR] + partial
`response[PR]) was 28/42 (66.7%) [95% CI: (50.5, 80.4)] in the all-treated
`population. The lower bound of the 95% CI exceeded 25% (the pre-specified
`threshold of efficacy, p < 0.0001); therefore, the primary objective of the study
`was met.
` Nine (21.4%) out of 42 subjects achieved CR and 19 (45.2%) subjects had PR.
` The median time to best overall response was 12.3 weeks with a range of 4.2
`to 42.1 weeks.
` The rate of sustained response in all-treated population for ≥ 20 weeks was
`47.6% [95% CI: (32.5, 62.7)].
` Median duration of response (DOR) was not reached. DOR for 23 (82%)
`subjects was censored.
` Responses were observed across all organs involved for cGVHD (skin, mouth,
`gastrointestinal tract, and liver).
` Eighteen of 42 patients (43%) had at least one LSS summary score
`measurement that was at least 7 points lower than their baseline LSS score.
`The percentage of subjects with at least 7 point reduction from baseline in Lee
`cGVHD symptom Scale score was 60.7% for the responder (17 of 28 subjects)
`and was 7.1% for the non-responders (1 of 14 subjects) over the duration of
`the study.
`
` agree with the conclusions of the clinical and statistical review team recommending
`approval for this application.
`
`
` I
`
`8. Safety
`The most common treatment-emergent adverse drug reactions were fatigue, bruising,
`diarrhea, muscle spasms, stomatitis, hemorrhage, nausea and pneumonia. Only two
`new safety issues were identified during the review of this portion of the application:
`fall and sepsis.
`
`
`Reference ID: 4133540
`
`

`

`9. Advisory Committee Meeting
`This application was not taken to an Oncologic Drugs Advisory Committee meeting
`because there were no issues with the trial design, conduct, endpoints or data
`analysis.
`Pediatrics
`10.
`This product has orphan designation therefore is exempt from the requirement to
`conduct studies in pediatric patients.
`
`
`Other Relevant Regulatory Issues
`11.
`Financial Disclosure information was provided and reviewed. The information
`provided did not suggest any integrity issue.
`
`The Office of Scientific Investigation review did not uncover serious issues which
`would interfere with the regulatory use of the data.
`12.
`Labeling
`All disciplines made recommendations for labeling. The recommendations were
`discussed during internal labeling negotiations.
`
`DHP review team requested that the COA staff review the Lee Symptom Scale (LSS),
`a patient reported outcome measure, which was used as a secondary endpoint in the
`clinical trial. Office of Hematology and Oncology Products has typically considered
`placing secondary endpoint information in labeling if the division believed the
`information could be helpful to the practitioner. The DHP review team decided that
`information from LSS would be helpful for the practitioner as LSS is used as part of
`the cGVHD assessment at patient visits. LSS has been in use since initial publication
`in 2002. Since 2004, publications have referenced the LSS when reporting on
`cGVHD. The DHP review team consulted the COA staff to understand the potential
`issues with regard to labeling.
`
`The COA staff did not recommended that the LSS data be placed in labeling and
`referred to the published PRO guidance. The issues noted are:
`
`
`1) Whether patient reported data from an open-label single arm trial should be placed
`in labeling
`
`Single arm, open-label trial design is necessary when enrolling patients who have no
`alternative treatments and whose condition is not under control. This situation exists
`for the patients enrolled in the trial described above and whose disease condition is
`the subject of this application.
`
`Patient reported outcome data from an open-label single arm trial has been placed in
`approved labeling and has been the primary evidence for the indication.
`
`Reference ID: 4133540
`
`

`

`
`In 2012 the FDA approved Kineret for “the treatment of neonatal-onset multisystem
`inflammatory disease (NOMID)” based primarily on a single-arm, open-label extension
`trial using a PRO instrument which included some PROXY reporting due to the
`median age of patients as patients less than 8 cannot typically report for themselves.
`The other supporting evidence was laboratory parameter changes. All of the statistics
`were descriptive.
`
`In Dr. Janet Maynard’s Clinical review she wrote:
`“..the natural history of NOMID generally involves progressive decline in these
`domains due to uncontrolled inflammation… while validated outcome measures for
`NOMID do not exist, the endpoints chosen for Study 03-AR-0298 correspond well to
`recently agreed standards for assessment of patients with autoimmune disease”.
`“These standards emphasize the assessment of a treatments affect on daily
`symptoms, acute phase reactants, quality of life, and disease-specific organ
`inflammation. The primary statistical methods of Study 03-AR-0298 were descriptive.
`“While this trial was open-label, it was adequate given the marked efficacy of the
`product and the limitations of evaluating an ultra-rare orphan disease.”
`
`Symptoms were collected using the DSSS instrument and calculated as the sum of
`the severity of five key NOMID symptoms (fever, headache, rash, joint pain, and
`vomiting). It was recorded daily by the patient or caregiver.
`
`
`2) Amount of missing data
`In Dr. Wroblewski’s review of the LSS she notes:
`
`FDA Analysis of the Lee Symptom Scale Results
`The clinical review team requested an additional efficacy dataset from the Applicant
`for the Lee Symptom Scale which include baseline and individual scores for each of
`the 30 items on the scale. The clinical review team conducted independent analyses
`of the LSS from the dataset.
`
`Robustness of Data
`Overall, there was very little missing data. There were a total of 170 Lee Symptom
`Scale assessments in 42 patients. There were 26/5100 (0.5%) items missing.
`
`Over time patients did drop out of the study and therefore were not assessable for
`either the primary endpoint or any secondary endpoints.
`
`
`3) What does a single time point - seven point improvement on an overall score mean
`
`From Dr. Wroblewski’s review:
`
`
`Reference ID: 4133540
`
`

`

`Lee et al proposed that a 6-7 point decrease (on normalized 1-100 scale) in the LSS
`overall summary score from baseline. A response in a patient reported outcome could
`be classified as a response versus no response (no improvement or worsening) as
`measured by change from baseline and subsequent measurements. The definition or
`threshold of improvement for the Lee Symptom scale is based on the reliability of the
`measure. A distribution based analysis was used to define improvement as a change
`of 6 to 7 points (0.5 standard deviation) on the total chronic GVHD symptom score.
`For normally distributed data, for patient reported measures a change of 0.5 standard
`deviation can be considered as clinically meaningful.
`
`Reviewer Comment: The proposed threshold of 6-7 point change based on
`distribution methods is an acceptable threshold. Future work with the LSS instrument
`could include anchor-based analyses methods.
`
`The 2014 NIH cGVHD Consensus states that a 0.5 standard deviation may be
`considered clinically meaningful for normally distributed data and a distribution
`analysis was used to define improvement as change of 6-7 on the total cGVHD
`symptom score.
`o The original 7 point benchmark was defined by Lee et al. in the initial
`paper on LSS in 2002 using the standard distribution method and is
`what was accepted by the NIH Consensus as clinically meaningful.
`o
`In a separate publication by Inamoto et al, a LSS overall score of 6.1
`was presented as clinically meaningful.
`o The benchmark of 6-7 on overall LSS is well known in community.
`o Determination of the 6-7 benchmark has consistently been based on 0.5
`standard deviation of a baseline distribution method (literature).
`o Using the benchmark of 7 as context for the descriptive findings of the
`LSS is reasonable in this study.
`
`
`The 7 point change is an accepted threshold and is currently accepted benchmark for
`comparison of this product with other treatments tried to date.
`
`Labeling needs to be relevant for the practitioner and use if possible those tools that
`are commonly used.
`
`Durability is important. The language in the proposed label will report the LSS
`symptom bother improvement and provide some information on sustained response.
`
`
`4) Use of a composite score which does not reflect what the actual patient reported
`changes occurred
`
`The comment refers to the fact that most of the reported improvements were in the
`skin and eyes and mouth items. Patients with cGVHD have a very heterogeneous
`presentation across multiple organs. From Dr. Wroblewski’s review she wrote:
`
`
`Reference ID: 4133540
`
`

`

`There is not one consistent presentation of the signs and symptoms of cGVHD. The
`LSS encompasses the most commonly affected organs and related cGVHD
`symptoms and is comprehensive in capturing the relevant symptoms for patients with
`cGVHD. The LSS has been validated and is widely used in the transplantation
`community.
`
`The items on the LSS composite index were identified as the core issues that most
`impacted the patients’ lives, an approach that minimizes noise from potential
`treatment-related toxicities or symptoms that might result more commonly from other
`unrelated causes.
`
`At baseline, patients enrolled in this study had involvement: skin (81%), mouth (86%),
`gastrointestinal (33%), lungs (10%), platelet (5%) and liver (17%). So it is not
`surprising that the majority of the improvement seen in this trial were the organs that
`were most commonly involved.
`
`5) Limitations due to the term “bother” not describing adequately what is a considered
`covered by the term “symptom” and additional concerns regarding terminology and
`what is covered in the subscale.
`
`It should be noted that, by design, the LSS measures symptom bother as
`distinguished from symptom intensity. The degree to which patients report that they
`are bothered by a symptom represents a global assessment incorporating not only the
`intensity of the symptom and its frequency, but also the degree to which it causes
`emotional disturbance or interferes with functioning.
`
`Because “bother” may better describe what LSS reports and therefore will use the
`term bother in labeling.
`
`The Division acknowledges that the LSS could be improved and for that reason, the
`information regarding the LSS results from the trial will be limited.
`
`
`
`Decision/Action/Risk Benefit Assessment
`13.
` Recommended regulatory action
`Approval
`
`Fulfillment of PMR 2060-3
`
` 
`
` Risk Benefit Assessment
`cGVHD is a serious complication of hematopoietic stem cell transplant. The
`first line treatment is corticosteroids. If steroids are not successful in managing
`the disease, there are no other agents approved to treat the disease. Imbruvica
`was successful in achieving an improvement in the disease for approximately
`
`Reference ID: 4133540
`
`

`

`2/3 of those enrolled and was durable. Only two new safety issues were
`identified fall and sepsis.
`
` 
`
` Recommendation for Post marketing Risk Management Activities
`None other than routine surveillance
` Recommendation for other Post marketing Study Requirements/
`Commitments
`
`Because cGVHD is complex and the submitted data is from a single arm trial, a
`PMR will be issued to provide data from a randomized controlled trial. For
`wording of the PMR, please see the approval letter.
`
`
`
`
`
`
`
`Reference ID: 4133540
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ANN T FARRELL
`08/02/2017
`
`Reference ID: 4133540
`
`