CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203214Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`SUMMARY REVIEW OF REGULATORY ACTION
`
`Date:
`
`From:
`
`November 6, 2012
`
`
`
`
`
`
`
`
`
`Badrul A. Chowdhury, MD, PhD
`Director, Division of Pulmonary, Allergy, and Rheumatology
`Products, CDER, FDA
`
`
`Division Director Summary Review
`
`Subject:
`203214
`NDA Number:
`Pfizer Labs
`Applicant Name:
`Date of Submission: October 21, 2011
`PDUFA Goal Date: November 21, 2012 (Original date was August 21, 2012)
`Proprietary Name: Xeljanz
`Established Name:
`Tofacitinib
`Dosage form:
`Tablets
`Strength:
`5 mg and 10 mg
`Proposed Indications: Treatment of adult patients with moderately to severely active
`rheumatoid arthritis who have had an inadequate response to one
`or more disease-modifying anti-rheumatic drugs (DMARDs), to be
`used as monotherapy or in combination with methotrexate or other
`non-biologic DMARDs.
`Approval (5 mg Tablets)
`
`
`
`
`
`
`Action:
`
`
`
`
`
`1. Introduction
`Pfizer submitted this NDA for tofacitinib for the treatment of adult patients with
`moderately to severely active rheumatoid arthritis (RA) who have had an inadequate
`response to one or more disease-modifying anti-rheumatic drugs (DMARDs) to be used
`as monotherapy or in combination with methotrexate or other non-biologic DMARDs.
`Pfizer proposed a recommended starting dose of 5 mg twice-daily, with a qualifier that
`some patients may benefit with an increased dose to 10 mg twice-daily based on clinical
`response. During review of the NDA, the Agency asked Pfizer for additional safety
`analyses for selected events of interest. Pfizer submitted these additional safety analyses
`on August 1 and 10, 2012. These analyses were submitted within the last 3 months of the
`review period and resulted in extension of the PDUFA goal date.
`
`The submitted data support the approval of tofacitinib at a dose of 5 mg twice-daily for
`the treatment of adult patients with moderately to severely active RA who have had an
`inadequate response or intolerance to the non-biologic DMARD methotrexate.
`Tofacitinib can be used either as a monotherapy or in and in combination with
`methotrexate or other non-biologic DMARDs. This summary review will provide an
`overview of the application, with a focus on the clinical efficacy and safety studies.
`
`
`
`Reference ID: 3213226
`
`(b) (4)
`
`

`

`
`
`2
`
`2. Background
`The classes of drugs used for treatment of RA include: nonsteroidal anti-inflammatory
`drugs (NSAIDs) and selective COX-2 inhibitors, corticosteroids, and disease-modifying
`anti-rheumatic drugs (DMARDs). NSAIDs and COX-2 inhibitors are utilized primarily
`for symptomatic relief of pain and are useful co-therapies because of their anti-
`inflammatory and analgesic effects. Corticosteroids are versatile agents with potent anti-
`inflammatory effects, but their use is limited by long-term toxicity. DMARDs are a
`diverse group of therapeutic agents that reduce signs and symptoms of RA as well as
`slow disease progression or produce a disease-modifying effect on joint damage.
`Approved DMARDs and some of their features are listed in Table 1 and Table 2.
`Methotrexate is the most commonly used DMARD because of its proven efficacy and
`well-understood long-term effects. Tumor necrosis factor (TNF)-blockers are commonly
`used DMARDs because of their proven efficacy and safety profile and relatively long-
`term use experience (Table 2). Treatment of RA is typically initiated with NSAIDs or
`low-dose corticosteroids, with introduction of non-biologic DMARDs early in the course
`of the disease to prevent joint damage and bony erosions. Methotrexate is often the
`initial DMARD used as a single agent in patients with low disease activity or without
`features of poor prognosis, and then combined with other DMARDs, commonly biologics
`such as TNF blockers, in patients with high disease activity or with features of poor
`prognosis.1
`
`Table 1. Non-biologic small molecule DMARDs approved for marketing in the United States
`Product Name (Trade Name)
`Mechanism of Action
`Year of First Approval
`[Sponsor]
`in RA
`for RA
`Sulfasalazine (AZULFIDINE)
`Anti-inflammatory
`1950
`[Pfizer]
`and antimicrobial
`Methotrexate sodium (METHOTREXATE SODIUM)
`Anti-metabolite
`[Multiple]
`Hydroxychloroquine (PLAQUENIL)
`Interference with
`[Sanofi-Aventis]
`antigen processing
`Azathioprine (IMURAN)
`Cytostatic
`[Prometheus Labs]
`Penicillamine (CUPRIMINE)
`[Alton]
`Auranofin (RIDAURA)
`[Prometheus Labs]
`Cyclosporine (NEORAL) (SANDIMMUNE)
`[Novartis]
`Leflunomide (ARAVA)
`[Sanofi-Aventis]
`
`Table 2. Biologic large molecule DMARDs approved for marketing in the United States
`Product Name (Trade Name)
`Presentation
`Description
`Claims for adult RA §
`and MOA ‡
`and ROA †
`[Sponsor] {year} *
`Fusion protein consisting of
`Etanercept (ENBREL)
`Vial 25 mg
`TNF-R and human IgG1 Fc
`[Immunex/Amgen] {1998}
`Prefilled syringe 25 or 50 mg/mL
`SureClick Autoinjector 50 mg/mL
`TNF- inhibitor
`
`1 Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, et al. 2012 update of the 2008 American
`College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and
`biologic agents in the treatment of rheumatoid arthritis. Arthritis Care and Res 2012; 64:625-39.
`
`Clinical response
`Major clinical response
`Physical function response
`
`Reference ID: 3213226
`
`1953
`
`1955
`
`1968
`
`1970
`
`1985
`
`Unknown
`
`Unknown
`
`T-cell activation inhibitor
`
`1995, 1990
`
`Anti-metabolite
`
`1998
`
`

`

`
`
`Product Name (Trade Name)
`[Sponsor] {year} *
`
`Infliximab (REMICADE)
`[Centocor] {1999}
`
`Presentation
`and ROA †
`SC injection
`Vial 10 mg/mL
`IV infusion
`
`Anakinra (KINERET)
`[Amgen] {2001}
`
`Adalimumab (HUMIRA)
`[Abbott] {2002}
`
`Abatacept (ORENCIA)
`[Bristol Myers Squibb] {2005}
`
`Rituximab (RITUXAN)
`[Genentech and Biogen]
`{2006}
`Golimumab (SIMPONI)
`[Centocor] {2009}
`
`Certolizumab Pegol (CIMZIA)
`[UCB Inc] {2009}
`
`Prefilled syringe 100 mg
`SC injection
`
`Prefiled syringe 40 mg/0.8 mL
`Prefilled syringe 20 mg/0.4 mL
`Humira Pen 40 mg/0.8 mL
`SC injection
`Lyophilized powder 250 mg/vial
`IV infusion
`
`Vial 10 mg/mL
`IV infusion
`
`Prefiled syringe 50 mg/0.5 mL
`SmartJect Autoinjector 50 mg/0.5
`mL
`SC injection
`Lyophilized powder 200 mg/vial
`Prefilled syringe 200 mg/mL
`SC injection
`
`Description
`and MOA ‡
`
`Chimeric IgG1 k mAb
`TNF- inhibitor
`
`Recombinant polypeptide
`IL-1 receptor antagonist
`
`Human IgG1 k mAb
`TNF- inhibitor
`
`Fusion protein consisting of
`CTLA-4 and human IGg1 Fc
`T cell activation inhibitor
`through B7-1 and B7-2
`Chimeric murine/human IgG1
`k mAb
`Anti CD20, B cell depletor
`Humanized IgG1 k mAb
`TNF- inhibitor
`
`Humanized Fab fragment
`TNF- inhibitor
`
`Tocilizumab (ACTEMRA)
`[Genentech/Roche] {2010}
`
`Vial 20 mg/mL
`IV infusion
`
`Humanized IgG1 k mAb
`IL-6 receptor inhibitor
`
`3
`
`Claims for adult RA §
`
`Radiographic response
`Clinical response
`Major clinical response
`Physical function response
`Radiographic response
`Clinical response
`Physical function response
`Radiographic response
`Clinical response
`Major clinical response
`Physical function response
`Radiographic response
`Clinical response
`Major clinical response
`Physical function response
`Radiographic response
`Clinical response
`Physical function response
`Radiographic response
`Clinical response
`Physical function response
`
`
`Clinical response
`Major clinical response
`Radiographic response
`Physical function response
`Clinical response
`Major clinical response
`Radiographic response
`Physical function response
`
`* Year = Year of first approval for RA
`† ROA = Route of administration
`‡ MOA= Mechanism of action
`§ Claims: Clinical response assessed by ACR 20, 50, and 70 response over at least 3-6 month; Major clinical response defined as
`achieving ACR 70 response continuously over 6-month period; Physical function response (or improving physical function) assessed
`by health assessment questionnaire (HAQ) over at least 6-month period; Radiographic response (or inhibiting progression of structural
`damage) assessed radiographically by Total Sharp Score (TSS) and sometimes its components of erosion score (ES) or joint space
`narrowing (JSN) score over 6 or 12 months
`
`
`About tofacitinib:
`All biologic DMARDs approved for the treatment for RA are injectable agents that
`primarily target extracellular cytokines (Table 2). Tofacitinib is an oral, small molecule
`inhibitor of the intracellular tyrosine kinase called Janus kinase (JAK). JAK is critical for
`cytokine receptor binding-triggered signal transduction through STAT to the nuclei of
`cells. The JAK family consists of four members: JAK1, JAK2, JAK3, and TyK2. On
`cytokine binding to its receptor on cell membrane, JAKs are activated, which in turn
`phosphorylate cytokine receptors, creating docking sites for signaling molecules,
`especially for members of the STAT family. The STAT proteins form homo- or hetero-
`dimers and translocate to the nucleus where they induce transcription of target genes.
`Various JAK and STAT proteins are known to be involved in tissues affected in RA,
`therefore, inhibiting the JAK-STAT pathway seems a reasonable target for RA
`treatment.2
`
`
`2 Yamaoka K, Kubo S, Sonomoto K, Maeshima K, and Tanaka Y. JAK inhibitor: tofacitinib, a new disease
`modifying anti-rheumatic drug. Inflam and Reg 2011; 31:349-353.
`
`Reference ID: 3213226
`
`

`

`
`
`4
`
`
`In kinase assays, tofacitinib inhibits JAK1 and JAK3 and, to a lesser extent, JAK2 and
`TyK2. In the immune system, JAK1, JAK2, and TyK2 are ubiquitously expressed,
`whereas JAK3 expression is restricted to hematopoietic cells. JAK1 knockout mice
`display perinatal lethality (thought to be related to neuroapoptosis due to lack of gp130
`signaling), and JAK1 inhibition would be expected to enhance susceptibility to infections
`related to defective signaling by class II cytokine receptors and receptors that use the
`gp130 subunit. JAK3 pairs with JAK1 to mediate signal transduction activity through the
`common gamma chain family of cytokines, including IL-2, -4, -7, -9, -15, and -21, which
`are integral to lymphocyte activation, proliferation, and function (Figure 1). JAK3
`knockout mice display T and B cell lymphopenia without effects on myeloid lineage
`cells. Autosomal recessive JAK3 deficiency in humans results in a form of severe
`combined immunodeficiency disease (SCID) that is characterized by a lack of circulating
`T cells and NK cells, but a normal number of B cells.3 JAK2 has a pivotal role in the
`signal transduction required in definitive erythropoiesis and JAK2 knockout mice are
`embryonically lethal due to a lack of erythropoiesis. TyK2 knockout mice are viable
`with no overt abnormalities, but do show reduced CD4+ cell differentiation to Th1 cells.
`
`
`Figure 1. Schematic of JAK1/3-Stat5 signaling pathway
`
`
`
`
`
`
`3 Vijayakrishnan L, Venkataramanan R, and Gulati P. Treating inflammation with the Janus Kinase
`inhibitor CP-690,550. Trends Pharmacol Sci 2011; 32:25-34.
`
`Reference ID: 3213226
`
`

`

`3. Chemistry, Manufacturing, and Controls
`The proposed commercial drug product, Xeljanz tablets, contains 5 mg and 10 mg
`tofacitinib (equivalent to 8 mg and 16 mg tofacitinib citrate, respectively) and standard
`compendial excipients. The drug product will be packaged as bottles containing 60
`tablets and 180 tablets. The drug substance tofacitinib citrate is
`
`(hm)
`
`The drug substance is highly soluble, but has low permeability (BCS
`class 3). Pfizer followed Quality by Design (QbD) principles in their development of the
`manufacturing process for the drug substance and the drug product. The drug product of
`immediate—release tablets is manufactured with a
`M0
`
`The drug substance is manufactured by Pfizer Ireland Pharmaceuticals, Ringaskiddy,
`Ireland. The drug product is manufactured and packaged in Frieburg, Germany, and is
`also being packaged in Puerto Rico. All manufacturing and testing facilities associated
`with this application have acceptable inspection status. The various DMFs associated
`with the manufacture of the product are adequate or do not require review due to
`adequate information in the NDA. An expiry of 24 months is proposed and supported by
`submitted data.
`
`4. Nonclinical Pharmacology and Toxicology
`Pfizer conducted a complete and adequate toxicology program that included general
`toxicology studies in rodent and non-rodent species, reproductive and embryofetal
`development studies, and carcinogenicity studies. The target organs of toxicity in rats
`included: lymph nodes (lymphocyte depletion and atrophy), thymus (lymphocyte
`depletion and atrophy), spleen (lymphocyte depletion and atrophy), bone marrow
`(cellular decrease), changes in hematology (decreased white blood cells and red blood
`cells), adrenal gland (cortical vacuolation), gastrointestinal tract (stomach, duodenum,
`jejunum), liver (increased liver enzymes and hypertrophy), and lung Gristiocytosis
`thought to be a result of immunosuppression). In general, the longer the duration of the
`toxicity study in rats, the more severe the toxicities were (e.g., shorter term studies
`showed lymphoid depletion, but the chronic study resulted in atrophy of the lymph
`organs). The toxicities in monkeys included severe immunosuppression resulting in
`infections and a decrease in immunosurveillance, resulting in lymphomas from
`lymphocryptovirus infection, and hematological changes similar to those described for
`rats. The target organs of toxicity in monkeys consisted of the spleen (viral inclusions and
`lymphocyte hyperplasia), thymus (lymphocyte hyperplasia), lymph nodes (lymphocyte
`hyperplasia), bone marrow (erythroid hyperplasia), and stomach (viral inclusions,
`inflammation-secondary infections). Shorter duration studies in the monkey resulted in
`general lymphocyte depletion of the lymph organs, whereas longer duration of treatment
`resulted in lymphocyte hyperplasia in these organs. The proposed human doses were
`covered by the NOAELs (no observed adverse effect levels) from animal studies; the
`limiting toxicities were thought to be monitorable in a clinical setting. Tofacitinib had no
`effects on fertility in male rats; however, fertility was reduced in female rats due to
`decreased corpora lutea and implantation sites and increased early resorptions and pre—
`and post-implantation losses. Tofacitinib was teratogenic (visceral and skeletal
`abnormalities) in rats and rabbits; maternal toxicity was evident in rats but not rabbits.
`
`Reference ID: 321 3226
`
`

`

`
`
`6
`
`There were no effects on peri- and post-natal development in rats. The submitted data
`support pregnancy category C classification for tofacitinib. The carcinogenicity study
`showed no increased incidence of tumors in a 6-month transgenic mouse study. In a 2-
`year rat study, the findings were sex-specific and included interstitial cell adenomas in
`testis in males, benign thymomas in females, and malignant hibernomas in females.
`
`
`
`5. Clinical Pharmacology and Biopharmaceutics
`Pfizer submitted a complete and adequate clinical pharmacology program for tofacitinib.
`The absolute oral bioavailability of tofacitinib is 74%. Following oral administration of
`tofacitinib, peak plasma concentration is reached within 30 to 60 minutes with
`elimination half-life of about 3 hours. Clearance mechanisms of tofacitinib include
`hepatic metabolism (about 70%) and renal excretion of the parent molecule (about 30%).
`The metabolism of tofacitinib is primarily mediated by CYP3A4 with a minor
`contribution from CYP2C19. The plasma concentration of tofacitinib is affected in
`patients with hepatic impairment and renal impairment, and when given together with
`drugs that inhibit or induce CYP3A4. The recommended dose of tofacitinib is 5 mg QD
`for the following intrinsic and extrinsic factors: moderate or severe renal impairment;
`moderate hepatic impairment; co-administration with strong CYP3A4 inhibitors (e.g.,
`ketoconazole); and co-administration with moderate CYP3A4 and strong CYP2C19
`inhibitors (e.g., fluconazole). Tofacitinib is not recommended in patients with severe
`hepatic impairment or in combination with cyclosporine because of the risk of increased
`immunosuppression. Co-administration with strong CYP3A4 inducers (e.g., rifampin)
`reduces tofacitinib levels to inefficacious levels. Inhibitors of p-glycoprotein are not
`likely to substantially alter tofacitinib exposure. There is no substantial impact of food,
`age, weight, and gender on tofacitinib exposure. A thorough QT study was conducted for
`tofacitinib and reviewed by the QT study interdisciplinary review team. No significant
`QTc prolongation effect of tofacitinib at the doses tested was detected.
`
`
`
`6. Clinical Microbiology
`There are no outstanding clinical microbiology issues.
`
`
`
`7. Clinical and Statistical – Efficacy
`a. Overview of the clinical program
`Some characteristics of the studies that form the basis of the review and regulatory
`decision for this application are shown in Table 3. The design and conduct of these
`studies are briefly described below, followed by efficacy findings and conclusions.
`Safety findings are discussed in the following section.
`
`
`Reference ID: 3213226
`
`

`

`
`
`7
`
`Table 3. Relevant clinical studies
`Study ID
`Study Characteristics
`and Year *
`-Patient age
`-Response to past treatment
`-Concurrent background treatment
`-Study duration
`Dose Ranging Efficacy and Safety
`-Over 18 years
`1025
`-Inadequate response to methotrexate
`2007-2008
`-Methotrexate background
`Dose-
`-6 months
`ranging
`Study 2
`
`1035
`2007-2009
`Dose-
`ranging
`Study 1
`
`-Over18 years
`-Inadequate response to a biologic or
`a non biologic DMARD
`-No background treatment
`-6 months
`
`Definitive Efficacy and Safety – Monotherapy
`-Over 18 years
`1045
`-Inadequate response to a biologic or
`Study I
`a non-biologic DMARD
`“Solo”
`2009-2010
`-No background treatment
`-6 months
`Definitive Efficacy and Safety – Background DMARD
`-Over 18 years
`1046
`Study II
`-Inadequate response to a non-
`“Sync”
`biologic DMARD
`2009-2011
`-Non-biologic DMARD background
`-12 months
`-Over 18 years
`-Inadequate response to methotrexate
`-Methotrexate background
`-12 months
`
`1064
`Study III
`“Standard”
`2009-2011
`
`Treatment
`groups †
`
`N ‡ Primary efficacy
`variables §
`
`Region % ¶
`
`Tof 1 mg BID
`Tof 3 mg BID
`Tof 5 mg BID
`Tof 10 mg BID
`Tof 15 mg BID
`Tof 20 mg QD
`Placebo
`Tof 1 mg BID
`Tof 3 mg BID
`Tof 5 mg BID
`Tof 10 mg BID
`Tof 15 mg BID
`Ada 40 mg
`Placebo
`
`Tof 5 mg BID
`Tof 10 mg BID
`Placebo 5 mg
`Placebo 10 mg
`
`Tof 5 mg BID
`Tof 10 mg BID
`Placebo 5 mg
`Placebo 10 mg
`
`71
`68
`71
`75
`75
`80
`69
`54
`52
`50
`61
`57
`53
`59
`
`244
`245
`61
`61
`
`318
`318
`79
`80
`
`ACR20 at wk 12
`
`ACR20 at wk 12
`
`ACR20 at mo 3
`HAQ-DI at mo 3
`DAS28<2.6 at mo 3
`
`ACR20 at mo 6
`HAQ-DI at mo 3
`DAS28<2.6 at mo 6
`
`US (24%)
`EU (44%)
`L Am (32%)
`ROW (0%)
`
`US (22%)
`EU (48%)
`L Am (22%)
`ROW (8%)
`
`US (25%)
`EU (34%)
`L Am (27%)
`ROW (14%)
`
`US (17%)
`EU (25%)
`L Am (14%)
`ROW (44%)
`
`ACR20 at mo 6
`HAQ-DI at mo 3
`DAS28<2.6 at mo 6
`
`US (15%)
`EU (56%)
`L Am (12%)
`ROW (18%)
`
`US (17%)
`EU (24%)
`L Am (14%)
`ROW (45%)
`
`US (42%)
`EU (46%)
`L Am (5%)
`ROW (7%)
`
`204
`Tof 5 mg BID
`201
`Tof 10 mg BID
`56
`Placebo 5 mg
`52
`Placebo 10 mg
`204
`Ada 40 mg
`ACR20 at mo 6
`321
`Tof 5 mg BID
`-Over 18 years
`1044
`mTSS at mo 6
`319
`Tof 10 mg BID
`-Inadequate response to methotrexate
`Study IV
`HAQ-DI at mo 3
`81
`Placebo 5 mg
`-Methotrexate background
`“Scan”
`2009-open
`DAS28<2.6 at mo 6
`79
`Placebo 10 mg
`-24 months (12 month interim)
`Definitive Efficacy and Safety – Background DMARD – Inadequate TNF responder
`-Over 18 years
`Tof 5 mg BID
`133
`ACR20 at mo 3
`1032
`Study V
`-Inadequate response to a TNF
`Tof 10 mg BID
`134
`HAQ-DI at mo 3
`“Step”
`inhibitor
`Placebo 5 mg
`66
`DAS28<2.6 at mo 3
`2009-2011
`-Methotrexate background
`Placebo 10 mg
`66
`-6 months
`Open Label Long Term Extension (LTE) Safety
`Tof 5 mg BID
`“Roll-over” from studies 1045, 1046,
`1024
`Tof 10 mg BID
`1064, 1044, and 1032 above
`Tof 5 mg BID
`“Roll-over” from Japanese Phase 2
`Tof 10 mg BID
`study and study 1044 (Japanese only)
`* Study ID shown (from top to bottom) as Pfizer’s study number, as referred to in the tofacitinib product label, and as
`identified by Pfizer at the May 9, 2012, AAC meeting. Year shows when study subject enrollment started – completed.
`† Tof = Tofacitinib oral tablets; Ada = adalimumab sc injection
`‡ Number randomized
`§ ACR20 = Proportion of patients achieving 20% improvement from baseline in American College of Rheumatology
`defined criteria; HAQ-DI = Change from baseline in Health Assessment Questionnaire Disability Index; DAS28<2.6 =
`Percentage achieving Disease Activity Score for 28-joint counts in patients with ESR less than 2.6; mTSS = Change
`
`1041
`
`
`
`
`
`
`
`
`
`Reference ID: 3213226
`
`

`

`
`
`8
`
`Study ID
`and Year *
`
`Treatment
`groups †
`
`N ‡ Primary efficacy
`variables §
`
`Region % ¶
`
`Study Characteristics
`-Patient age
`-Response to past treatment
`-Concurrent background treatment
`-Study duration
`from baseline in van der Heijde modified Total Sharp Score;
`¶ % As randomized; US: United States; EU = European continent for dose ranging studies, European continent and
`Canada for pivotal studies; L Am = Latin America - Americas excluding US and Canada; ROW = Rest of the world
`
`
`
`b. Design and conduct of the studies
`All studies were randomized, double-blinded, placebo-controlled (studies 1035 and 1064
`also had active treatment arms), and conducted in patients 18 years of age and older with
`moderate to severe active RA diagnosed according to the American College of
`Rheumatology (ACR) criteria. Tofacitinib at various doses was given either as
`monotherapy or in combination with methotrexate in patients with various histories of
`response to previous treatments as shown in Table 3. In all studies, placebo treatment
`duration was less than active treatment duration. In studies 6 months in duration, at
`month 3 placebo non-responder patients (studies 1025 and 1035) were advanced to
`tofacitinib 5 mg, and all placebo-treated patients (studies 1045 and 1032) were advanced
`to tofacitinib 5 mg or 10 mg in a blinded fashion. In studies 12 months or longer in
`duration (studies 1046, 1064, and 1044), at month 3 placebo non- responder patients and
`at month 6 all placebo-treated patients were advanced to tofacitinib 5 mg or 10 mg in a
`blinded fashion. The primary efficacy variables in the various studies are listed in Table
`3. In the definitive studies (studies 1045, 1046, 1064, 1044, and 1032), primary efficacy
`variables were evaluated in a step-down order as follows: ACR20 response rate, change
`in mTSS (study 1044 only), change from baseline in HAQ-DI, and percentage achieving
`DAS-28<2.6. Statistical significance was tested for the 10 mg dose followed by the 5 mg
`dose. Safety assessment in all studies included recording of adverse events, vital signs,
`physical examination, and clinical laboratory measures.
`
`The efficacy variables relevant to this submission were ACR response criteria, the Health
`Assessment Questionnaire-Disability Index (HAQ-DI), and the van der Heijde modified
`Total Sharp Score (mTSS), and the Disease Activity Score 28 (DAS-28). These are
`described below. An understanding of these endpoints will help the interpretation of the
`study results described in the subsequent section.
`
`The American College of Rheumatology (ACR) response is a composite endpoint with
`seven components that are used to calculate the proportion of patients achieving a target
`percentage of improvement from baseline.4,5 The ACR criteria have been used
`extensively in clinical trials in RA as a measure of efficacy of a therapeutic agent. The
`ACR 20 response is calculated as at least 20% reduction in tender joint count of 68 joints,
`and at least 20% reduction in swollen joint count of 66 joints, and at least a 20%
`reduction in at least 3 of the following 5 measures: patient global assessment of arthritis
`
`4 DT Felson, Anderson JJ, Boers M, et al. ACR preliminary definition of improvement in Rheumatoid
`Arthritis. Arthritis & Rheum 1995; 38:727-735.
`5 Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis classification criteria. Arthritis &
`Rheum 2010; 62:2569-2581.
`
`Reference ID: 3213226
`
`

`

`
`
`9
`
`on a visual analog scale, physician global assessment of arthritis on a visual analog scale,
`patient assessment of pain on a visual analog scale, patient assessment of physical
`functioning (e.g., health assessment questionnaire), and acute phase reactant (ESR or
`CRP). The ACR 50 and ACR 70 are similarly calculated using the higher 50% and 70%
`levels of improvement, respectively. The Agency has accepted ACR 20 response as an
`acceptable demonstration of efficacy of a therapeutic agent supporting a “clinical
`response” claim, and ACR 70 response lasting for 6 months as supportive of a claim of a
`“major clinical response.”
`
`Stanford Health Assessment Questionnaire-Disability Index (HAQ-DI) assesses a
`patient’s level of functional ability and includes questions regarding fine movements of
`the upper extremities, locomotor activities of the lower extremities, and activities that
`involve both upper and lower extremities. There are 20 questions in 8 categories of
`functioning intended to represent a comprehensive set of functional activities, including
`dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. Patients are
`asked to grade their status on a scale from 0 (no difficulty) to 3 (unable to do) for each
`question. The 8 category scores are averaged into an overall HAQ-DI score on a scale
`from 0 (no disability) to 3 (completely disabled). The HAQ-DI has been validated for
`use in RA, with a minimal clinically important difference (MCID) of 0.25 units (for a
`given patient) or 0.22 units (based on group means).6 The Agency has accepted a
`“physical function response” claim based on HAQ-DI.
`
`The van der Heijde modified Total Sharp Score (mTSS) is an accepted radiographic
`scoring system for RA joint damage.7 X-rays of the hands and feet are graded based on
`joint space narrowing (Grades 0 to 4, 15 joints per hand, 6 joints per foot) and erosions
`(Grades 0 to 5, 16 joints per hand, 6 joints per foot). For the hands, joint space narrowing
`scores and erosion scores are summed separately, and the joint space narrowing score
`ranges from 0 to 168 and the erosion score ranges from 0 to 280 and their sum, the total
`radiographic score, ranges from 0 to 448. Although the theoretical maximum score is
`448, the actual scores seen in RA clinical trials are much smaller because a given patient
`has only a fraction of joints affected by structural damage, as assessed by radiographic
`criteria. The smallest detectable difference on a per-individual basis has been identified
`for the van der Heijde modification of the Sharp score as approximately 5 units.8 The
`Agency has accepted a “radiographic response” claim based on the mTSS.
`
`Disease Activity Score 28 (DAS-28) is a composite index of RA disease activity which
`incorporates the number of tender and swollen joints (out of 28 possible), a patient global
`assessment of disease activity (0-100 mm visual analog scale), and ESR.9 An alternative
`
`6 B Bruce and JF Fries. The Health Assessment Questionnaire (HAQ). Clin Exp Rheumatol 2005; 23
`(Suppl 39):S14-S18
`7 S Boini and F Guillemin. Radiographic scoring methods as outcome measures in rheumatoid arthritis:
`properties and advantages. Ann Rheum Dis 2001; 60:817-827
`8 K Bruynesteyn et al., Determination of the minimal clinically important difference in rheumatoid arthritis
`joint damage of the Sharp/van der Heijde and Larsen/Scott scoring methods by clinical experts and
`comparison with the smallest detectable difference.Arthritis & Rheum 2002; 46:913-920
`9 J Fransen and PLCM van Riel. The Disease Activity Score and the EULAR Response Criteria. Clin Exp
`Rheumatol 2005; 23 (Suppl 39): S93-S99
`
`Reference ID: 3213226
`
`

`

`
`
`10
`
`equation is available for use with CRP. These variables are summed and weighted
`mathematically into a single numerical value ranging from 0 to 10. The ACR response
`criteria and DAS-28 are conceptually similar, but differ with number of joints counted
`(e.g. DAS-28 does not include the joints of the feet), and physician global assessment,
`patient pain, and health assessment score, which are incorporated into the ACR response
`criteria but not in DAS-28. Another difference is that the DAS-28 measures disease
`activity at a given time point, whereas the ACR response criteria are calculated as
`improvement in the variables over a set period of time. A DAS-28 score >5.1 is
`indicative of high disease activity, and <3.2 of low disease activity. A score of <2.6 has
`been accepted by the Agency to describe an even lower threshold of disease activity.
`
`
`c. Efficacy findings and conclusions
`The submitted data show efficacy for tofacitinib for clinical response and improvement in
`physical function at the proposed doses of 5 mg and 10 mg twice-daily. Balancing
`efficacy and safety (safety discussed in section 8 below), 5 mg twice-daily is
`recommended as the optimum dose with no recommendation for dose escalation.
`
`In the following sections, dose selection and dosing regimen for tofacitinib are discussed
`first, followed by a discussion of the efficacy data for the proposed claims of clinical
`response, physical function response, radiographic response, and closing with summary
`comments on efficacy.
`
`Dose selection and dose ranging:
`Pfizer conducted 5 dose-finding studies: 1025, 1035, 1039, 1040, and 1019. Dose
`selection was primarily based on study 1025, which assessed probability of achieving an
`efficacy target effect based on ACR response at week 12, and a safety surrogate of
`hemoglobin threshold for >2 g/dL decrease from baseline or an absolute level of <8 g/dL
`set at placebo-adjusted incidence of no more than 5% through week 24 of exposure.
`Pfizer carried 5 mg and 10 mg twice-daily doses to phase 3 studies based on results of
`study 1025 and supportive data from study 1035 (Figure 2 and Table 4). This decision is
`reasonable, but has some shortcomings as noted below.
`
`
`
`Figure 2. ACR response and anemia in study 1025
`
`
`
`Reference ID: 3213226
`
`

`

`
`
`11
`
`
`Table 4. ACR response rates (% patients with ACR response) at primary analysis time point
`Study *
`Time
`Treatment †
`ACR 20
`ACR 50
`ACR 70
`P vs placebo
`%
`%
`%
`ACR 20
`47
`23
`4
`0.219
`56
`29
`21
`0.021
`56
`37
`18
`0.017
`58
`28
`12
`0.011
`56
`44
`24
`0.018
`56
`36
`24
`0.015
`36
`17
`6
`
`31
`11
`6
`0.356
`45
`25
`12
`0.022
`61
`39
`14
`<0.001
`72
`46
`25
`<0.001
`72
`51
`26
`<0.001
`39
`21
`4
`0.070
`24
`10
`3
`
`
`Week 12 Tof 1 mg BID
`1025
`
`Tof 3 mg BID
`
`
`Tof 5 mg BID
`
`
`Tof 10 mg BID
`
`
`Tof 15 mg BID
`
`
`Tof 20 mg QD
`
`
`Placebo
`
`Week 12 Tof 1 mg BID
`1035
`
`Tof 3 mg BID
`
`
`Tof 5 mg BID
`
`
`Tof 10 mg BID
`
`
`Tof 15 mg BID
`
`
`Ada 40 mg
`
`
`Placebo
`
`* Study ID shown as Pfizer’s study number
`† Tof = Tofacitinib oral tablets; Ada = adalimumab sc injection
`
`
`From an efficacy standpoint, more emphasis was placed on the ACR 70 results as the
`dose response curve was steeper for the target effect with 10 mg twice daily being
`approximately double that of the 5 mg twice-daily dose (80% vs 40%). However, ACR
`20 results show that the 5 mg twice-daily dose provided approximately 60% response,
`which is within range of the response seen with biological DMARDs. The 3 mg twice-
`daily dose also provided acceptable ACR responses (Table 4). There was little
`consideration given to other dose-related adverse events besides hemoglobin decrease. In
`particular, total lymphocyte subset count or function or adverse events related to
`lymphocytes were not considered in this model. Tofacitinib binds with higher affinity to
`JAK1 and JAK3, which affects lymphocytes. JAK2, which effects erythropoiesis, has
`lesser binding affinity for tofacitinib. From a dose frequency standpoint, the only dose
`frequency tested was twice-daily, except one dose of 20 mg once-daily in study 1025,
`with rationale of patient convenience and limited data suggestin