ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 4, April 2017, pp 763–773 DOI 10.1002/art.39943 VC 2016, American College of Rheumatology

Long-Term Safety and Efficacy of Fulranumab in Patients With Moderate-to-Severe Osteoarthritis Pain

A Phase II Randomized, Double-Blind, Placebo-Controlled Extension Study

Panna Sanga,1 Nathaniel Katz,2 Elena Polverejan,1 Steven Wang,1 Kathleen M. Kelly,1 Juergen Haeussler,1 and John Thipphawong1

Objective. To evaluate the long-term safety and observed in all efficacy parameters following fulranumab efficacy of fulranumab in patients with knee or hip pain treatment (1 mg every 4 weeks, 3 mg every 4 weeks, and caused by moderate-to-severe chronic osteoarthritis (OA). 10 mg every 8 weeks) as compared with placebo. Similar Methods. In this phase II double-blind, placebo- percentagesofpatientsinbothgroupsexperiencedTEAEs controlled extension study, patients who were randomized (88% taking placebo and 91% taking fulranumab; all in equal proportions to receive subcutaneous doses of phases). Across all fulranumab groups, arthralgia (21%) eitherplaceboorfulranumab(1mgevery4weeks,3mg and OA (18%) (e.g., exacerbation of OA pain) were the every 8 weeks, 3 mg every 4 weeks, 6 mg every 8 weeks, or most common TEAEs. The most common serious TEAEs 10 mg every 8 weeks) in the 12-week double-blind efficacy were the requirement for knee (10%) and hip (7%) arthro- phase and who completed this double-blind efficacy phase plasty, with 80% occurring during the posttreatment were eligible to continue the dosage throughout a 92-week follow-up period. Neurologic-related TEAEs (28%; all double-blind extension phase, followed by a 24-week post- phases) were generally mild-to-moderate. Overall, 81 joint treatment follow-up period. Safety assessments included replacements were performed in 71 patients (8 [11%] evaluation of treatment-emergent adverse events (TEAEs), receiving placebo and 63 [89%] receiving fulranumab); 15 pre-identified AEs of interest, and joint replacements. Effi- patients (21%) had rapid progression of OA (RPOA). All cacy assessments included changes from baseline to the cases of RPOA occurred in fulranumab-treated patients end of the double-blind extension phase in scores on the who were concurrently receiving nonsteroidal antiinflam- patient’s global assessment and the pain and physical matory drugs and occurred in joints with preexisting OA. function subscales of the Western Ontario and McMaster Conclusion. Long-term treatment with fulranumab Universities Osteoarthritis Index. was generally well-tolerated and efficacious. RPOA was Results. Overall, 401 of the 423 patients who com- observed as a safety signal. Future studies are warranted pleted the 12-week double-blind efficacy phase entered the to demonstrate whether the risk of RPOA can be reduced extension study. Long-term sustained improvements were in patients taking fulranumab.

ClinicalTrials.gov identifier: NCT00973141. The incidence of osteoarthritis (OA) is increasing Supported by Janssen Research & Development. 1Panna Sanga, MD, Elena Polverejan, PhD, Steven Wang, due to the increasing age of the population (1–3) and PhD, Kathleen M. Kelly, MD, Juergen Haeussler, MD, John increasing numbers of comorbid conditions, such as obe- Thipphawong, MD: Janssen Research & Development, Titusville, New Jersey; 2Nathaniel Katz, MD, MS: Solutions, Natick, sity (4,5). Based on radiographic studies, the incidence Massachusetts, and Tufts University School of Medicine, Boston, rates of knee OA in people ages 45 years and older in the Massachusetts. US and the European Union are estimated to be 14.1% in Dr. Katz has received consulting fees from Janssen Research & Development (more than $10,000). men and 22.8% in women (6). The prevalence of hip OA Address correspondence to Panna Sanga, MD, Janssen ranges from 3% to 11% in the Western population over Research & Development, 1125 Trenton-Harbourton Road, Titusville, the age of 35 years (7). Knee or hip OA is a major cause of NJ 08560. E-mail: [email protected]. Submitted for publication October 13, 2015; accepted in pain, contributing to limitations in daily functioning and revised form September 20, 2016. reducing quality of life (8,9).

763 764 SANGA ET AL

Available therapies for reducing OA pain include randomization. Other key inclusion and exclusion criteria are pharmacologic agents (e.g., acetaminophen, nonsteroidal described in the previous report (28). antiinflammatory drugs [NSAIDs], opioids, antidepressants The protocol and informed consent documents were reviewed and approved by an independent ethics committee or such as duloxetine, topical ointments, and intraarticular institutional review board at each study site. The study was con- injections), nonpharmacologic interventions (e.g., educa- ducted in accordance with the ethical principles of the Declaration tion, exercise, and lifestyle modifications), surgical ap- of Helsinki and in accordance with the Good Clinical Practice proaches (arthroplasty), and psychological counseling guidelines of the International Conference on Harmonisation, as (7,10–12). Existing pharmacologic treatments are associated well as applicable regulatory requirements, and in compliance with the study protocol. All participants provided written with various side effects, including gastrointestinal, cardio- informed consent to participate in the study. vascular (13,14), neurologic, and narcotic (15,16). In addi- Study design. This phase II, randomized, double-blind, tion, currently available pharmacologic treatments do not placebo-controlled extension study was conducted at 85 sites in always provide sufficient pain relief, often do not improve Canada, Korea, Poland, and the US from September 2009 to functional status, and are contraindicated in some patients August 2011. The planned study included a 3-week screening phase, a 12-week double-blind efficacy phase, a 92-week double- (17–19). In many patients, the limited efficacy of these drugs blind extension phase, and a 26-week posttreatment follow-up and the higher occurrence of adverse events (AEs) limit phase (total of 104 weeks of treatment). All treatments were their tolerability and reduce compliance (20–23). Poor tol- stopped on December 23, 2010, when the US Food and Drug erability in some patients even results in refusal to continue Administration (FDA) placed ongoing fulranumab studies on pharmacologic therapy despite pain at levels sufficient to clinical hold because of the concern that the entire class of anti- NGF antibodies may be associated with potential treatment- require joint replacement (21). Given the limitations of emergent AEs (TEAEs) leading to joint destruction. At the time current therapies, there is an unmet need for alternative of the clinical hold, the longest fulranumab exposure in the study therapies that provide better efficacy, tolerability, and func- was 73 weeks. tionality in the long-term management of the signs and During the 12-week double-blind efficacy phase, patients symptoms of OA. were randomized (1:1:1:1:1:1) to 1 of the following treatments: placebo or 1 of 5 fulranumab regimens (1 mg every 4 weeks, 3 mg Regulatory authorities have recently recommended every 8 weeks, 3 mg every 4 weeks, 6 mg every 8 weeks, and the demonstration of maintained efficacy of new pharma- 10 mg every 8 weeks), as subcutaneous injections into the thigh cologic agents beyond the 12 weeks previously required or abdomen (28). Patients continued on their randomized dose (24,25). Long-term (.6 months) efficacy studies of ex- throughout the double-blind extension phase. During the 12- isting pharmacologic agents ( in general) are week double-blind efficacy phase, patients were required to main- tain their concurrent pain medications without changes; however, rare, and very few long-term placebo-controlled studies they were allowed to change their concurrent pain medications as have demonstrated sustained analgesic efficacy in OA clinically needed during the double-blind extension phase. Dos- (26,27). Fulranumab, a human anti–nerve age reductions of the study drug were allowed in patients who (anti-NGF) , was previously shown experienced new or worsening neurologic-related TEAEs. How- to have significant efficacy for improving pain and physical ever, if neurologic symptoms persisted for 3 months, the patients were withdrawn from the study drug. functioning and, was generally well tolerated in patients Efficacy assessments. Efficacy end points included with moderate-to-severe chronic OA in a 12-week double- changes over time from baseline in scores on the pain and physical blind efficacy phase study (28). In the present study, we function subscales of the Western Ontario and McMaster Univer- focused on the double-blind extension phase of the previ- sities Osteoarthritis Index (WOMAC; version 3.1) (29,30) and the patient’s global assessment (PGA) (31,32). Scores for individual ously described primary study(28).Wedescribeherein items of WOMAC 3.1 were recorded using an NRS of 0–10 (with the long-term safety and efficacy of fulranumab as adjunc- higher scores corresponding to greater pain/difficulty/stiffness). tive therapy to standard therapy for pain in patients with The PGA is a single-item assessment of each patient’s perception moderate-to-severe knee or hip pain caused by OA. of his or her OA status (11-point NRS, from 0 5 very good to 10 5 very bad). During the double-blind extension phase, the average PGA scores were recorded every 4 weeks, and the PATIENTS AND METHODS WOMAC pain and physical function subscale scores were re- corded every 8 weeks. Patients. The patient population in this study consisted Safety assessments. Safety assessments included evalu- of men and women ages 40–80 years with OA of the hip or knee ations of TEAEs, clinical laboratory test results, vital signs, physi- who were receiving stable analgesic regimens of NSAIDs and/or cal examination findings, 12-lead electrocardiogram (EKG), and immediate-release or long-acting opioids and were entering the injection sites. Neurologic safety was assessed at every visit using double-blind phase of the initial trial (28). For the current study, an abbreviated neurologic examination, the Total Neuropathy patients were required to have a mean OA pain intensity score of Score–nurse (TNSn) (33), and the Mini-Mental State Examina- $5 (using an 11-point Numerical Rating Scale [NRS]), as aver- tion (34). The TNSn was administered at all study visits as a aged over the last 3 days of pain scores assessed before screening tool. It consisted of targeted questioning of patients in LONG-TERM SAFETY AND EFFICACY OF FULRANUMAB 765

Figure 1. Flow chart showing the study design and disposition of the study patients. Fulranumab was administered at a dosage of 1 mg every 4 weeks, 3 mg every 8 weeks, 3 mg every 4 weeks, 6 mg every 8 weeks or 10 mg every 8 weeks. Patients who completed the double-blind (DB) extension phase or discontinued treatment because of clinical hold (directed by the US Food and Drug Administration; see Patients and Meth- ods for details) entered the 26-week posttreatment follow-up phase. AE 5 adverse event; LOE 5 lack of efficacy; LF 5 lost to follow-up; WC 5 withdrew consent; sponsor 5 sponsor discontinued the cohort/study; ID 5 investigator decision. order to identify and quantify treatment-emergent impairment of information and to attribute causality based on clinical data. sensory and motor function, autonomic symptoms, and pin and The IAC consisted of 5 external clinical experts from rheuma- vibration sensibilities, and to facilitate neurologic evaluation, lon- tology, orthopedic surgery, and radiology, who had extensive gitudinal monitoring, and trigger further neurologic consultations clinical experience with patients with RPOA and ON. if needed. Changes from baseline in any TNSn subscore of .2or The IAC reviewed clinical information (including total TNSn score .3 (scale of 0–4) were reviewed by the site radiographic images, pathology reports, and surgical notes, investigator; all changes assessed to be clinically significant by the where available) for all patients who had joint replacements as site investigator were referred to a neurologist for further assess- well as for patients who had a sustained increase in pain that ment. Antidrug antibodies were also measured up to 6 months was not explained by another diagnosis, but did not undergo after the last dose of study drug. joint replacement and had radiographs taken because of the Due to concerns about joint safety during the study, all change in symptoms. Based on the assessment of joint joint replacement surgery information was collected both ret- radiographs, magnetic resonance images (MRIs) when avail- rospectively and prospectively from the time of the clinical able, and other clinical data (including pathology reports when hold until the end of the posttreatment follow-up phase. An available), the IAC adjudicated each case as one of the follow- independent data monitoring committee was appointed before ing: ON RPOA, RPOA with a component of, or advancing to, the start of the study to review all unblinded safety data. After ON (RPOA plus ON), normal progression of OA (NPOA), or the 2010 clinical hold for the joint safety issue, a separate insufficient information. The IAC assessed case attributions Independent Adjudication Committee (IAC) blinded with based on blinded structural and clinical evidence and applied regard to treatment group was established by the sponsor to the following attributes: definitely related, probably related, develop definitions of rapid progression of OA (RPOA) and possibly related, not related, or insufficient information. Each osteonecrosis (ON) (Supplementary Table 1, available on the adjudicator was asked to grade each case on her or his own, Arthritis & Rheumatology web site at http://onlinelibrary.wiley. and the final grading by each member was done following com/doi/10.1002/art.39943/abstract), consistent with the litera- group discussions. It was required that at least 3 of the 5 IAC ture and the adjudicators’ experience, as well as to review sus- members agree on the assessment of the case for a given cate- picious cases to render diagnoses based on radiologic gory to be designated as the collective IAC final assessment. 766 SANGA ET AL

Table 1. Demographic and baseline clinical characteristics in the double-blind extension analysis set, by treatment group* Fulranumab

1 mg every 3 mg every 3 mg every 6 mg every 10 mg every Total Placebo 4 weeks 8 weeks 4 weeks 8 weeks 8 weeks (n 5 401) (n 5 59) (n 5 70) (n 5 69) (n 5 68) (n 5 69) (n 5 66) No. (%) female 236 (59) 33 (56) 42 (60) 40 (58) 44 (65) 43 (62) 34 (52) Race, no. (%) White 340 (85) 49 (83) 60 (86) 62 (90) 57 (84) 57 (83) 55 (83) Black or African American 41 (10) 6 (10) 5 (7) 5 (7) 10 (15) 8 (12) 7 (11) Asian 15 (4) 3 (5) 3 (4) 2 (3) 1 (2) 2 (3) 4 (6) American Indian 2 (0.5) 1 (2) 1 (1) 0 0 0 0 or Alaska native Multiple 2 (0.5) 0 1 (1) 0 0 1 (1.4) 0 Other 1 (0.2) 0 0 0 0 1 (1.4) 0 Age, years No. (%) ,65 257 (64) 38 (64) 46 (66) 44 (64) 44 (65) 46 (67) 39 (59) No. (%) $65 144 (36) 21 (36) 24 (34) 25 (36) 24 (35) 23 (33) 27 (41) Mean 6 SD 61.0 6 9.13 61.0 6 8.29 60.8 6 9.19 60.7 6 8.80 60.8 6 9.67 60.9 6 9.33 62.2 6 9.59 BMI at baseline, 31.5 6 5.80 31.8 6 7.18 30.5 6 5.39 31.5 6 5.23 31.5 6 5.35 32.4 6 5.96 31.2 6 5.70 mean 6 SD kg/m2 Pain score at baseline, 6.8 6 1.19 7.0 6 1.13 7.0 6 1.47 6.7 6 1.15 6.7 6 1.09 6.8 6 1.07 6.8 6 1.18 mean 6 SD Stratum 1, baseline opioid use, no. (%) No opioids 272 (68) 39 (66) 47 (67) 48 (70) 47 (69) 47 (68) 44 (67) Use opioids 129 (32) 20 (34) 23 (33) 21 (30) 21 (31) 22 (32) 22 (33) Stratum 2, baseline body weight, no. (%) ,85 kg 165 (41) 24 (41) 30 (43) 28 (41) 29 (43) 28 (41) 26 (39) $85 kg 236 (59) 35 (59) 40 (57) 41 (59) 39 (57) 41 (59) 40 (61) Joint studied, no. (%) Hip 94 (23) 8 (14) 16 (23) 19 (28) 17 (25) 20 (29) 14 (21) Knee 307 (77) 51 (86) 54 (77) 50 (72) 51 (75) 49 (71) 52 (79)

* BMI 5 body mass index.

Statistical analysis. All efficacy and safety analyses the 26-week posttreatment follow-up phase. The top 3 were performed on the intent-to-treat analysis set, which included reasons for withdrawal from the double-blind extension all patients who had received at least 1 dose of fulranumab or pla- phase were sponsor discontinuation of the study due to the cebo. During the double-blind extension phase, descriptive statis- tics over time and corresponding data were produced for all FDA clinical hold (53%), patient’s choice (13%), and AEs efficacy parameters. No prespecified statistical modeling was (11%). Two patients (one with paresthesia of the fingers of applied for efficacy assessments after week 16. As an exploratory the right hand and the other with a tingling sensation in analysis, a mixed model for repeated measures was fit based on both arms) had neurologic symptoms (mild and possibly measurements at weeks 5, 9, 13, 17, 25, 33, 41, and 49 using an related to fulranumab treatment) that persisted for 3 unstructured covariance matrix. All safety evaluations were sum- marized descriptively. The combined safety results were presented months, but both of them recovered upon cessation of for all phases of the study (double-blind efficacy plus double-blind fulranumab treatment. Most patients (86%) completed the extension plus posttreatment follow-up). posttreatment follow-up phase. The demographic and base- line disease characteristics of the patients who entered the double-blind phase have been published elsewhere (28). RESULTS Table 1 shows the baseline characteristics of the patients Patient disposition and baseline characteristics. who entered the double-blind extension phase. A total of 468 patients were randomized into the study. Of Extent of treatment exposure. Although the study the 423 patients who completed the 12-week double-blind was planned for a 2-year treatment period (double-blind efficacy phase, 401 (95%) elected to enter the double-blind efficacy plus double-blind extension), due to the clinical extension phase (Figure 1). All of them entered the post- hold, the median duration of drug exposure in the treatment follow-up phase. Another 4 patients entered the fulranumab groups ranged from 365 days to 393 days (Sup- posttreatment follow-up phase directly from the double- plementary Table 2, available on the Arthritis & Rheumatol- blind efficacy phase. Thus, a total of 405 patients entered ogy web site at http://onlinelibrary.wiley.com/doi/10.1002/ LONG-TERM SAFETY AND EFFICACY OF FULRANUMAB 767

Figure 2. Mean change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, the WOMAC physical function score, and the patient’s global assessment (PGA) score in the intent-to-treat analysis set. art.39943/abstract). Placebo-treated patients tended to stop scores for the 1 mg every 4 weeks, 3 mg every 4 weeks, and therapy sooner than fulranumab-treated patients: 71–87% 10 mg every 8 weeks fulranumab groups compared with of patients received at least 6 injections of fulranumab com- placebo (Figure 2). Numerical separations from placebo pared with 64% receiving placebo, and 41–56% patients for scores on the WOMAC pain and physical function sub- received at least 12 doses of fulranumab compared with scales and PGA were noted for the 1 mg every 4 weeks, 41% receiving placebo (Supplementary Table 2). Most 3mgevery4weeks,and10mgevery8weeksfulranumab patients (.98%) in all treatment groups did not require groups at weeks 33 and 41 (Figure 2). Based on the explor- dosage adjustments during the study. atory mixed model for repeated measures, the statistical Efficacy analysis. Due to the clinical hold, the significance at the 2-sided level of 0.1 was achieved by the efficacy end points could be summarized only up to week 3 mg every 4 weeks and 10 mg every 8 weeks groups at 49; there was sparse efficacy data available between weeks weeks 33 and 41. 49 and 73. Long-term improvements were observed in Safety analysis. Overall, 421 of the 466 patients WOMAC pain and physical function subscales and PGA in the intent-to-treat group (90%) experienced at least 1 768 SANGA ET AL

Table 2. TEAEs and peripheral neurologic adverse events during all phases of study in the intent-to-treat analysis set, by treatment group Fulranumab

1 mg every 3 mg every 3 mg every 6 mg every 10 mg every Placebo 4 weeks 8 weeks 4 weeks 8 weeks 8 weeks Total (n 5 78) (n 5 77) (n 5 76) (n 5 79) (n 5 78) (n 5 78) (n 5 388) No. (%) of patients with TEAEs 69 (88) 66 (86) 72 (95) 74 (94) 72 (94) 68 (87) 352 (91) No. (%) of patients with 13 (17) 11 (14) 14 (18) 26 (33) 20 (26) 25 (32) 96 (25) serious TEAEs No. (%) of patients with $5% TEAEs* Arthralgia 12 (15) 15 (19) 14 (18) 22 (28) 17 (22) 14 (18) 82 (21) Osteoarthritis† 11 (14) 9 (12) 9 (12) 14 (18) 17 (22) 19 (24) 68 (18) Paresthesia 4 (5) 3 (4) 10 (13) 12 (15) 16 (21) 10 (13) 51 (13) Upper respiratory tract infection 4 (5) 8 (10) 12 (16) 12 (15) 6 (8) 11 (14) 49 (13) Back pain 8 (10) 7 (9) 8 (11) 7 (9) 9 (12) 9 (12) 40 (10) Nasopharyngitis 6 (8) 9 (12) 9 (12) 9 (11) 4 (5) 9 (12) 40 (10) Pain in extremity 4 (5) 6 (8) 8 (11) 5 (6) 11 (14) 9 (12) 39 (10) Headache 7 (9) 7 (9) 14 (18) 7 (9) 5 (6) 5 (6) 38 (10) Knee arthroplasty 3 (4) 5 (6) 4 (5) 13 (16) 6 (8) 10 (13) 38 (10) Peripheral edema 4 (5) 6 (8) 4 (5) 10 (13) 9 (12) 8 (10) 37 (10) Carpal tunnel syndrome 1 (1) 4 (5) 3 (4) 9 (11) 6 (8) 8 (10) 30 (8) Hypoesthesia 3 (4) 4 (5) 3 (4) 7 (9) 6 (8) 9 (12) 29 (7) Hip arthroplasty 4 (5) 3 (4) 2 (3) 5 (6) 8 (10) 8 (10) 26 (7) Hypertension 6 (8) 5 (6) 5 (7) 3 (4) 6 (8) 6 (8) 25 (6) Muscle strain 1 (1) 5 (6) 3 (4) 3 (4) 8 (10) 6 (8) 25 (6) Joint swelling 1 (1) 4 (5) 2 (3) 7 (9) 6 (8) 5 (6) 24 (6) Musculoskeletal pain 2 (3) 7 (9) 6 (8) 1 (1) 5 (6) 4 (5) 23 (6) Nausea 3 (4) 3 (4) 4 (5) 5 (6) 5 (6) 5 (6) 22 (6) Diarrhea 3 (4) 9 (12) 4 (5) 3 (4) 3 (4) 2 (3) 21 (5) Muscle spasms 1 (1) 6 (8) 3 (4) 4 (5) 5 (6) 2 (3) 20 (5) Constipation 3 (4) 4 (5) 6 (8) 1 (1) 3 (4) 6 (8) 20 (5) Cough 1 (1) 5 (6) 5 (7) 3 (4) 5 (6) 2 (3) 20 (5) Contusion 4 (5) 4 (5) 2 (3) 3 (4) 3 (4) 3 (4) 15 (4) Fatigue 4 (5) 4 (5) 2 (3) 3 (4) 3 (4) 3 (4) 15 (4) Sinusitis 9 (12) 4 (5) 4 (5) 2 (3) 2 (3) 1 (1) 13 (3) No. of patients with peripheral 1191825272321 neurologic AEs Paresthesia 5 4 13 15 21 13 13 Hypoesthesia 4 5 4 9 8 12 7 Muscle weakness 0 3 1 3 1 0 2 Burning sensation 1 0 0 0 3 4 1 Hyporeflexia 1 0 3 0 0 1 1 Dysesthesia 0 0 0 0 0 3 1 Motor dysfunction 0 0 0 1 0 0 ,1 Peripheral neuropathy 1 0 0 1 0 0 ,1 Sensory disturbance 1 0 0 0 0 0 0

* The individual treatment-emergent adverse events (TEAEs) that are listed are based on events in all study groups for all phases combined. † For example, exacerbation of osteoarthritis pain.

TEAE during the study (all phases). The incidence of Overall, 28% of patients in the fulranumab TEAEs was similar in the placebo group (88% [n 5 69]) groups had neurologic-related TEAEs, compared with and the overall fulranumab groups (91% [n 5 352]) 14% patients in the placebo group. The most common (Table 2). The most frequently reported TEAEs ($10% ($5% of patients) neurologic-related TEAEs in the of patients) among all fulranumab-treated patients were fulranumab groups were paresthesia (13%), carpal tun- arthralgia (21%), OA (18%) (e.g., exacerbation of OA nel syndrome (CTS) (8%), and hypoesthesia (7%) pain), paresthesia (13%), and upper respiratory tract (Table 2). Only 3% of patients in the fulranumab groups infection (13%), whereas among the placebo-treated discontinued the treatment due to neurologic-related patients, these were arthralgia (15%), OA (14%), and TEAEs in the combined double-blind phase (paresthe- sinusitis (12%). sia, CTS, dystonia, numbness of feet, decreased Achilles LONG-TERM SAFETY AND EFFICACY OF FULRANUMAB 769

Table 3. IRs for joint replacement and RPOA, by treatment group* Fulranumab

1 mg every 3 mg every 3 mg every 6 mg every 10 mg every Placebo 4 weeks 8 weeks 4 weeks 8 weeks 8 weeks (n 5 78) (n 5 77) (n 5 76) (n 5 79) (n 5 78) (n 5 78) No. of patients with 89 8 171217 $1 joint replacement IR for joint replacement secondary to RPOA 100 96 91 189 141 206 No. (%) of patients 0 2 (2.6) 2 (2.6) 4 (5.1) 2 (2.6) 5 (6.4) with RPOA No. of joints identified 02 2 5 2 5 with RPOA IR for RPOA 0 21 22 43 23 57

* The cutoff date was July 10, 2011 for joint replacement. IRs 5 incidence rates (per 1,000 person- years); RPOA 5 rapid progression of osteoarthritis. tendon reflex, lumbar radiculopathy, and muscle weak- and 3 taking fulranumab), radiculopathy (n 5 2; both ness). Two patients had serious neurologic-related taking fulranumab), peripheral sensorimotor neuropa- TEAEs during the double-blind extension phase, which thy (n 5 6; all taking fulranumab), or mixed neuropathy led to treatment discontinuation (CTS in 1 patient (n 5 3; 1 taking placebo and 2 taking fulranumab). All receiving fulranumab 3 mg every 4 weeks and syncope of these were documented to have recovered after cessa- in 1 patient receiving fulranumab 10 mg every 8 weeks; tion of therapy, except for 3 patients with peripheral both serious TEAEs were considered severe). The syn- neuropathies. Of these, 2 patients withdrew consent cope case resolved on the same day and was considered (one on day 140 and the other on day 176) while the to be unrelated to the study drug; however, treatment TEAE was still present, but continued follow-up during was discontinued due to the sponsor’s decision to dis- the posttreatment follow-up phase until study comple- continue treatment on day 421. tion. One patient continued the study drug despite the During the posttreatment follow-up phase, 7 TEAE but was later withdrawn due to noncompliance fulranumab-treated patients (4 receiving 6 mg every 8 with the protocol. The most frequent (.10 patients) weeks and 3 receiving 10 mg every 8 weeks) and no neurologic AEs in the fulranumab-treated groups that placebo-treated patients experienced neurologic-related did not resolve until the end of the study was CTS TEAEs. These neurologic-related TEAEs included a (n 5 11 [3.1%]) burning sensation (2 patients [10 mg every 8 weeks] at A total of 109 patients (23%) reported serious 92 days and 177 days after treatment cessation, respec- TEAEs: 13 taking placebo (17%) and 96 taking tively), CTS (2 patients [6 mg every 8 weeks] at 97 days fulranumab (25%) (Table 2). The most frequently and 157 days after treatment cessation, respectively), occurring serious TEAEs ($5%) in fulranumab groups paresthesia (2 patients [6 mg every 8 weeks] at 30 days were knee arthroplasty (n 5 38 [10%]) and hip arthro- and 196 days after treatment cessation, respectively), plasty (n 5 26 [7%]). Of these, 25% were joint replace- hypoesthesia (1 patient [10 mg every 8 weeks] at 30 days ments for reasons that were not secondary to RPOA; after treatment cessation), and muscle weakness (1 these were advanced and long-term candidates for joint patient [6 mg every 8 weeks] at 196 days after treatment replacements. cessation). None of the AEs were serious or led to Additional cases of joint replacement were discontinuation. reported after the end of the follow-up phase. A total of Approximately one-third of the neurologic- 71 patients reported having at least 1 joint replacement related TEAEs (n 5 40 [8%]) led to neurologic con- (total of 81 joint replacements) (Table 3). Among the 81 sultations (for placebo, 6%; for fulranumab, 3% taking joint replacement surgeries, 46 involved the knee joint, 1 mg every 4 weeks, 9% taking 3 mg every 8 weeks, 11% 33 involved the hip joints, and 2 were in shoulder joint. taking 3 mg every 4 weeks, 10% taking 6 mg every 8 Twenty-five of the joint replacements were in nonindex weeks, and 10% taking 10 mg every 8 weeks). Of these, joints (10 hip, 13 knee, and 2 shoulder joints); the rest 15 patients with neurologic TEAEs that lasted more involved the index joints. Figure 3 describes the time to than 15 days were confirmed to have neuropathy, which joint replacement surgery in placebo- and fulranumab- was diagnosed as either CTS (n 5 4; 1 taking placebo treated groups. The incidence rate for all joint 770 SANGA ET AL

Figure 3. Kaplan-Meier plots showing time to joint replacement surgery in each treatment group. Pbo 5 placebo. replacements was 139 per 1,000 person-years in the 10 mg every 8 weeks (4%) groups with at least 1 neuro- fulranumab group and 98 per 1,000 person-years in the logic examination had a change in total and subscale placebo group. All joint-related AEs (71 patients with scores on the TNSn as compared with the other joint replacements and 5 who had not undergone joint fulranumab groups and placebo (0–1%) during the replacement surgery) were reviewed by the IAC. In the double-blind efficacy phase, while more patients receiv- majority of patients with joint replacement, the proce- ing fulranumab at a dosage of 3 mg every 4 weeks dure was determined by the IAC to be related to normal (12%) had a change in total and subscale scores on the progression of OA (n 5 56 [79%]) followed by RPOA TNSn as compared with the other fulranumab groups (n 5 15 [21%]) (Table 3). None of the cases assessed by and placebo (3–7%) during the double-blind extension the IAC were either ON or RPOA with features of ON. phase. There was no change in the TNSn suggestive of All cases adjudicated as RPOA occurred in patients sympathetic dysfunction seen in this study. receiving fulranumab and concurrent NSAIDs who had No TEAEs that were indicative of hepatic or a history of OA in the affected joint. acute renal failure occurred during the study. Most The mean 6 SD age of the patients with joint injection-site reactions of redness, tenderness, swelling, replacements was 61 6 9.01 years. A total of 58% were or induration were also mild or moderate. No clinically women, and 56% had a BMI of $30. The median num- meaningful changes were observed in laboratory test ber of injections received before surgery was 11 (range results, vital signs, or EKG findings. There were no 1–17). Small changes from baseline were noted in the deaths during the study. total and subscale scores on the TNSn. An equal proportion of patients in the DISCUSSION fulranumab and placebo groups (4% and 5%, respec- tively) had at least 1 neurologic consultation during the The anti-NGF class is a potential option for double-blind efficacy phase, while a higher percentage patients who have had an ineffective response to avail- of patients receiving fulranumab at a dosage of 3 mg able pharmaceutical analgesics. This class has demon- every 4 weeks (16%) had at least 1 neurologic consulta- strated superior efficacy in the management of pain and tion more than the other fulranumab groups and the improvement of physical functioning as compared with placebo group (6–10%) in the double-blind extension placebo, NSAIDs, and opioids, as well as superior toler- phase (29 patients had objective findings). More ability as compared with opioids (26,35). We report patients in the fulranumab 6 mg every 8 weeks (3%) and herein the findings of our study of the long-term safety LONG-TERM SAFETY AND EFFICACY OF FULRANUMAB 771

and analgesic efficacy of fulranumab when used as an FDA in clinical studies of anti-NGF drugs in develop- adjunct to nonopioid or opioid OA analgesics. Approxi- ment (36). The available literature suggests that RPOA mately 90% of patients had as many as 12 months of is a part of the natural spectrum of OA progression exposure to fulranumab. (37). Patients with RPOA have OA that progresses at a Fulranumab (at 3 mg every 4 weeks and 10 mg much faster rate than routine OA does, with significant every 8 weeks) provided continued effective relief of joint space narrowing and/or osteolysis occurring in , 1 pain associated with knee and hip OA as early as week year (38,39). The incidence rate of RPOA in the general 4, which was maintained up to week 53. The results of population has not been well-described; however, an pain reduction were further corroborated by improve- incidence rate of 15.2–18.2% has been reported in ments in physical function noted in scores on the patients awaiting joint replacement surgery (40,41). WOMAC physical function subscale and PGA following Most of the available data on RPOA are based on hip fulranumab treatment. Numerical separation of scores OA; high incidence rates of RPOA in the knee have not on the WOMAC pain and physical function subscales been reported and have not been seen in large cohorts and PGA observed in the fulranumab 3 mg every 4 of knee OA patients. Although not identified as RPOA, weeks and 10 mg every 8 weeks groups versus placebo rapid destruction of hip joints has been described with throughout the study suggests sustained efficacy of long- the use of potent NSAIDs such as indomethacin (42). term treatment with fulranumab (28). The sawtooth pat- All cases of RPOA in the current study, irrespec- tern seen in the PGA scores for the lower dosage groups tive of whether these were in the target joint, appeared (those administered every 8 weeks) also suggests that to be associated with combination therapy with dosing every 8 weeks does not result in sustained effi- fulranumab and NSAIDs in patients with preexisting cacy and that dosing every 4 weeks is preferred. OA, which is consistent with previous findings (43). Sustained efficacy in comparison to placebo has not pre- Published studies have also demonstrated an increased viously been described for the existing pharmacologic risk of RPOA for the combination of and a therapies for OA. long-term NSAID as compared with tanezumab mono- The overall safety profile of fulranumab demon- therapy (44,45). Consistent with this, all cases of RPOA strated that the proportion of patients reporting TEAEs observed in the present study occurred in patients among the fulranumab-treated groups (86–95%) was receiving combined therapy of fulranumab and NSAID similar to that in the placebo group (88%). The types of use and in patients with a history of OA in the affected TEAEs seen during this long-term extension study were joint. However, due to the small number of RPOA cases not different from those observed during a 4-dose per treatment group, a drug or dosage effect for RPOA monotherapy study in a similar OA population (28). could not be evaluated. Future studies are warranted to A number of clinical events were specifically demonstrate whether limiting the use of concomitant monitored a priori as “events of interest” during the long-term NSAIDs and using only lower doses of study, which included bradycardia, hypotension, neuro- fulranumab may reduce the risk of RPOA. logic signs or symptoms, renal failure, and hepatic fail- Limitations of this study were that the study ure. A study-mandated discontinuation was in effect for design did not support a statistical analysis of the dose neurologic-related TEAEs (paresthesia, CTS, and hypo- or dosing frequency response and lacked an active com- esthesia) if 3 monthly doses were missed. Of the parator. Placebo-treated patients tended to stop therapy remaining TEAEs, no other events of interest during sooner than fulranumab-treated patients. Most of the this study were serious or led to discontinuation. Fur- joint safety information (radiographs, pathology reports, thermore, although most patients with neurologic- etc.) were collected retrospectively. In addition, since related TEAEs were documented to recover after stop- the study was shortened due to the clinical hold, not all ping the study drug, future studies will exclude patients patients were able to complete all of the planned with active or recent CTS. There were no dose-related treatments that would otherwise have provided clearer trends with regard to vital signs (blood pressure, pulse insight into the long-term tolerability and efficacy of rate measures, EKGs), AEs, or individual items on the fulranumab. autonomic questionnaire element of the TNSn that In this long-term, placebo-controlled study, would suggest that there was any effect of fulranumab fulranumab was generally well-tolerated in patients with on the sympathetic nervous system. chronic OA knee or hip pain, with the exception of A joint-related safety signal, RPOA, resulting in RPOA emerging as a safety signal. Long-term (up to 1 rapid joint destruction leading to joint replacement sur- year) efficacy of fulranumab therapy versus placebo was gery was identified as a specific safety concern by the observed for 3 dosages: 1 mg every 4 weeks, 3 mg every 772 SANGA ET AL

4 weeks, and 10 mg every 8 weeks. Dosing every 4 weeks The authors independently collected the data, interpreted the results, is preferred, since it showed a better long-term efficacy and had the final decision to submit the manuscript for publication. Writing assistance was provided by Dr. Shruti Shah (SIRO Clinpharm profile than did dosing every 8 weeks. Despite the Pvt. Ltd.), and editorial support was provided by Dr. Harry Ma monthly dosing regimen and long half-life of (Janssen Research & Development). Publication of this article was not fulranumab, patients experienced pain relief within a contingent upon approval by Janssen Research & Development. short period of time. Additional long-term studies com- paring fulranumab therapy with current standard-of- ADDITIONAL DISCLOSURES care treatment are warranted to demonstrate sustained Author Katz is an employee of Analgesic Solutions. efficacy and to assess the safety/tolerability of lower doses of fulranumab without concomitant use of long- REFERENCES term NSAIDs. 1. Jones G. Osteoarthritis: where are we for pain and therapy in 2013? Aust Fam Physician 2013;42:766–9. ACKNOWLEDGMENTS 2. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of The authors thank the study participants, without primary health care. Ann Rheum Dis 2001;60:91–7. whom this study would never have been accomplished. We also 3. Hotez PJ, Alvarado M, Basanez~ MG, Bolliger I, Bourne R, thank the following investigators for their participation in the Boussinesq M, et al. 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