Proof of Concept Trial of Tanezumab for the Treatment of Symptoms Associated With Interstitial Cystitis

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1 Proof of Concept Trial of Tanezumab for the Treatment of Symptoms Associated With Interstitial Cystitis R. J. Evans,*, R. M. Moldwin, N. Cossons, A. Darekar, I. W. Mills and D. Scholfield From the Department of Urology, Wake Forest University, Winston-Salem, North Carolina (RJE), The Arthur Smith Institute for Urology, The North Shore-Long Island Jewish Healthcare System, New Hyde Park, New York (RMM), and Pfizer, Ltd., Sandwich, United Kingdom (NC, AD, IWM, DS) Abbreviations and Acronyms AE adverse event ECG electrocardiogram FAS full analysis set GRA global response assessment IC interstitial cystitis ICSI Interstitial Cystitis Symptom Index IV intravenous MVV mean voided volume NGF nerve growth factor NRS numerical rating scale OA osteoarthritis PPS pentosan polysulfate sodium PVR post-void residual rfas restricted FAS Submitted for publication July 7, Study received institutional review board approval. Supported by Pfizer, Inc. Supplementary material for this article can be obtained at * Correspondence: Department of Urology, Wake Forest University, 140 Charlois Blvd., Winston-Salem, North Carolina (telephone: ; FAX: ; revans@ wfubmc.edu). Financial interest and/or other relationship with Pfizer, Ortho-McNeil, Watson, Allergan, Astellas and the Interstitial Cystitis Association. Financial interest and/or other relationship with Pfizer, Taris, Lipella and Ortho-McNeil. Financial interest and/or other relationship with Pfizer. For other articles on a related topic see pages 1946 and Purpose: In this randomized, double-blind, placebo controlled phase 2 study we investigated tanezumab, a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for interstitial cystitis pain. Materials and Methods: Patients with interstitial cystitis received a single intravenous dose of 200 g/kg tanezumab or placebo. Patients recorded daily pain scores (on an 11-point numerical rating scale) 7 days before attending study visits and completed a urinary symptom diary for 3 of those days. Patients also completed the Interstitial Cystitis Symptom Index questionnaire and a global response assessment. The primary end point was change in average daily numerical rating scale pain score from baseline to week 6. Secondary end points included global response assessment, Interstitial Cystitis Symptom Index score, micturition and urgency episode frequency per 24 hours, and mean voided volume per micturition. The incidence of adverse events was also assessed. Results: A total of 34 patients received tanezumab and 30 received placebo. At week 6 tanezumab produced a significant reduction from baseline in average daily pain score vs placebo (treatment difference [LS mean, 90% CI] was 1.4 [ 2.2, 0.5]). A significantly higher proportion of patients on tanezumab responded as improved in the global response assessment and tanezumab also significantly reduced urgency episode frequency vs placebo. Tanezumab had no significant effect on Interstitial Cystitis Symptom Index score, micturition frequency or mean voided volume per micturition. The most common adverse events were headache (tanezumab 20.6%, placebo 16.7%) and paresthesia (tanezumab 17.6%, placebo 3.3%). Conclusions: Tanezumab has shown preliminary efficacy in the treatment of pain associated with interstitial cystitis. Key Words: tanezumab; nerve growth factor; cystitis, interstitial; antibodies; pain INTERSTITIAL cystitis is characterized by increased urinary frequency, urgency, nocturia and chronic pain. 1,2 The Rand Interstitial Cystitis Epidemiology study estimated that 3 to 8 million women in the United States have IC symptoms, suggesting that IC may be a substantial burden on public health. 3 The etiology of IC is unknown but likely involves a process of bladder epithelial dysfunction, mast cell degranulation and neurogenic inflammation. 4 Studies have suggested that in IC there is a defect in the urothelium allowing irritants to leak into the bladder wall causing inflammation, tissue /11/ /0 Vol. 185, , May 2011 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro

2 TANEZUMAB FOR TREATMENT OF INTERSTITIAL CYSTITIS 1717 irritation and injury, mast cell degranulation and afferent nerve depolarization. 5,6 Afferent nerve depolarization would result in the release of nociceptive neurotransmitters, leading to further mast cell degranulation and activation of nerve terminals. 4 During degranulation mast cells release proinflammatory agents including NGF. NGF is a neurotrophin which is essential for the differentiation and survival of sensory and sympathetic neurons during development. However, in adults it has been suggested that NGF, through the sensitization of nociceptive neurons, is important in the generation and potentiation of pain following tissue injury and inflammation. 7 Inhibition of NGF signaling reduces pain-like behavioral responses in a number of animal models of visceral pain Tanezumab is a humanized anti-ngf monoclonal antibody that binds with high affinity and specificity to NGF, preventing it from interacting with receptors on nociceptive neurons. We investigated the use of tanezumab for the treatment of moderate to severe IC pain in a phase 2 trial. The primary objective was to evaluate the efficacy, safety and tolerability of single dose 200 g/kg IV tanezumab for the treatment of IC pain, and the secondary objective was to evaluate tanezumab for the treatment of other IC symptoms. MATERIALS AND METHODS Study Population Participants had moderate to severe IC defined as scores of 13 or greater on the Pelvic Pain and Urgency/Frequency symptom questionnaire 11 and 7 or more on the O Leary- Sant ICSI. 12 Exclusion criteria were IC symptoms for less than 6 months, PVR volume greater than 200 ml and history of allergic or anaphylactic reaction to mabs or IgG fusion proteins. Patients remained on existing nonprohibited oral medications as background therapy for IC symptoms provided these had been administered for 3 or more months before screening. In the event of inadequate pain relief or worsening IC symptoms patients were permitted to take acetaminophen. Study Design This study was conducted in compliance with the Declaration of Helsinki and all International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and amendments were reviewed and approved by the institutional review boards of each participating study center. Each subject provided written informed consent before study participation. This was a randomized, placebo controlled, double-blind, multicenter, parallel group, proof of concept study. The study was conducted between March 2008 and April 2009 in 23 study centers across the United States. After screening patients were enrolled in a 2-week run-in period during which they recorded daily pain scores (measured using a 0 to 10 NRS more than 7 days before the randomization visit) and daily urinary symptoms for 3 of those days. Patients who had completed 5 or more days of the daily symptom diary with a mean average daily pain NRS score of 4 or more and those with a mean micturition frequency of 8 or more per 24 hours were eligible for randomization. Patients were stratified according to baseline mean average daily pain score (4 to less than 7 and 7 or greater) and randomized using an automated tele-randomization system to receive a single IV dose of 200 g/kg tanezumab or placebo. Patients were followed for 16 weeks after treatment with study visits at weeks 2, 4, 6, 10 and 16. At each visit patients received a symptom diary and were instructed to record average daily NRS pain score each day for the 7 days before the subsequent study visit and urinary symptoms for 3 of those days. Efficacy Assessments The primary efficacy end point was the change from baseline to week 6 in average daily NRS pain score. Secondary efficacy end points included change in average daily NRS pain score at weeks 2, 4, 10 and 16, and GRA, ICSI score and micturition diary variables. The GRA questionnaire, measuring patient reported overall response to treatment compared with the start of the trial, was completed at weeks 6 and 16 or at early termination. Patients who responded as moderately or markedly improved were defined as treatment responders. The ICSI, a 4-question composite symptom score of urgency, frequency, nocturia and pain 12 was completed at all post-screening visits or at early termination. Micturition variables, including micturition and urinary urgency episode frequency per 24 hours and MVV per micturition, were derived from urinary symptom data collected at all post-screening visits. The dose of tanezumab and primary time for analysis were chosen by quantitative modeling of dose concentration response characteristics from a previously conducted trial of tanezumab in patients with OA. Although maximal efficacy was expected at week 6, the observation period of up to 16 weeks after treatment allowed the assessment of safety and tolerability over more than 5 half-lives for tanezumab clearance. Safety Assessments AEs were documented at each study visit. Safety assessments included vital signs and an ECG. Previous studies suggest that an anti-ngf antibody is unlikely to cross the blood-brain barrier and that the effects of tanezumab are limited to the peripheral nervous system. 13,14 A full neurological examination was performed by the study investigator at each study visit (including mental status, cranial nerves, motor, sensory, coordination, gait and reflexes). If an AE suggestive of new or worsening peripheral neuropathy or dysesthesia, paresthesia, allodynia, hypoesthesia or hyperesthesia was reported, or if the investigator detected clinically significant abnormalities, the patient was referred to a neurologist. PVR urine volume assessments were performed using a transabdominal ultrasound at visits 1, 3, 5 and 7. Statistical Analyses To achieve the planned sample size of 48 patients and accounting for a 25% estimated dropout rate, approximately 64 patients were to be recruited into the study. The

3 1718 TANEZUMAB FOR TREATMENT OF INTERSTITIAL CYSTITIS sample size was selected to provide a 90% CI of width 1.5 around the mean difference in the change in average daily pain score from baseline to week 6 for tanezumab vs placebo with 80% probability (assuming a SD of 2.8). As is suitable for an exploratory study, an estimation approach rather than a formal hypothesis testing approach was used as it requires fewer subjects while ensuring that appropriate efficacy conclusions can be made. Changes from baseline to week 6 in average daily pain score were analyzed using an ANCOVA model. Conclusions were based on adjusted mean treatment differences and corresponding CIs. A clinically significant treatment difference for the primary end point was considered to be a change from baseline in average daily NRS pain score of 1 or more point over placebo when the accompanying 90% CI does not overlap zero. Similar analyses were used to analyze ICSI score and the micturition diary variables. The GRA results were analyzed using proportional odds analysis. Odds ratios and corresponding 90% CIs of the estimated odds of patients responding after treatment with tanezumab vs placebo were calculated. The proportion of treatment responders based on a 30% or greater and 50% or greater reduction from baseline in average daily pain NRS score was also analyzed using logistic regression with the results presented as ORs and 90% CIs. Efficacy analyses were based on the rfas which included all randomized patients who had provided diary data for 4 or more days within the predefined diary windows at baseline and at the post-randomization visit. A sensitivity analysis was also conducted on the FAS, which only required diary data for 1 or more days after randomization. RESULTS Patient Disposition Overall 64 patients were randomized and received treatment. Of these patients 52 (81.3%) completed the study (fig. 1). Patients were mostly female (89%), 21 to 85 years old, with an average daily pain NRS score of 6.4 in the tanezumab group and 5.9 in the placebo group. Efficacy At week 6 tanezumab produced a clinically significant reduction from baseline in average daily pain score vs placebo (fig. 2). The upper limit of the 90% CI does not contain zero, implying statistical significance at the 1-sided 5% level of significance. Similar results were obtained from the analyses of the FAS. Overall 57% of patients on tanezumab vs 35% of those on placebo had a 30% or greater reduction in pain score from baseline, and 36% (tanezumab) vs 9% (placebo) had a 50% or greater reduction. Based on a definition of 50% or greater reduction from baseline in pain score, OR (90% CIs) showed that the odds of responding to treatment were more than 7-fold greater for patients on tanezumab vs placebo (7.6 [1.6, 36.0]). For the mean change from baseline to week 6 in ICSI score there was no significant difference for tanezumab vs placebo (mean difference [90% CIs] vs placebo, 1.5 [ 3.7, 0.8]). Figure 1 The GRA analysis showed that at week 6 a higher proportion of patients on tanezumab responded as improved compared with those on placebo (OR 5.1). In particular more patients on tanezumab responded as moderately and markedly improved (tanezumab 40.0% vs placebo 11.8%, table 1). At week 6 tanezumab produced a significant reduction from baseline in urgency episode frequency per 24 hours vs placebo (table 2). However, tanezumab had no significant effect vs placebo on mean change from baseline in micturition frequency per 24 hours or MVV per micturition. The number of patients who used acetaminophen during the study (48.4% vs 46.4%) and the number of acetaminophen doses per patient in the rfas (mean [SD] 11.7 [27.5] vs 9.7 [22.1]) was similar for tanezumab vs placebo. Safety Overall 23 (67.6%) patients on tanezumab and 18 (60.0%) on placebo experienced an AE. Two (5.9%) patients on tanezumab had a serious AE (vertigo, drug exposure during pregnancy) compared with 4 (13.3%) on placebo (cholelithiasis, ovarian mass, urosepsis and urinary tract infection, transient ischemic attack). Headache was the most frequently reported AE in the tanezumab group (20.6% vs placebo 16.7%). Paresthesia (tanezumab 17.6%, placebo 3.3%) and hyperesthesia (tanezumab 8.8%, placebo 0.0%) were the most common AEs of abnormal peripheral sensation reported for tanezumab. All of the abnormal peripheral sensation AEs were mild to moderate in severity and most had resolved by the end of the study. There were 3 patients on tanezumab and 2 on

4 TANEZUMAB FOR TREATMENT OF INTERSTITIAL CYSTITIS 1719 Figure 2. Data for rfas, adjusted for baseline pain severity score, amitriptyline, PPS and hydroxyzine use, age, gender and body mass index. Boldface indicates clinically significant results. placebo who had a clinically significant worsening from baseline in the neurological examination. Overall 3 patients (2 on tanezumab, 1 on placebo) with a clinically significant worsening from baseline in the neurological examination and/or an AE of abnormal peripheral sensation were examined by a Table 1. Summary of GRA analysis No. Placebo (%) No. Tanezumab (%) Wk 6:* Markedly improved 1 (5.9) 5 (20.0) Moderately improved 1 (5.9) 5 (20.0) Slightly improved 5 (29.4) 7 (28.0) No change 6 (35.3) 5 (20.0) Slightly worse 3 (17.6) 2 (8.0) Moderately worse 0 (0.0) 1 (4.0) Markedly worse 1 (5.9) 0 (0.0) OR (90% CI) 5.1 (1.7, 15.0) Wk 16: Markedly improved 0 (0.0) 4 (21.1) Moderately improved 2 (15.4) 5 (26.3) Slightly improved 5 (38.5) 2 (10.5) No change 5 (38.5) 5 (26.3) Slightly worse 0 (0.0) 1 (5.3) Moderately worse 1 (7.7) 2 (10.5) Markedly worse 0 (0.0) 0 (0.0) OR (90% CI) 2.7 (0.8, 9.8) Data for rfas. * Placebo group 17 patients, tanezumab group 25 patients. Placebo group 13 patients, tanezumab group 19 patients. neurologist. For all 3 patients the neurological consultation demonstrated that there was no evidence of new or worsened peripheral neuropathy. There were no apparent trends in vital signs and ECG assessments from weeks 1 to 16, at week 6 or in changes from baseline. In addition, no vital signs or ECG result was recorded as an AE. There were no clear trends in the PVR urine volume of patients on tanezumab or placebo. In addition, no patient in either treatment group reported urinary retention. Urinary tract infections were reported by 2 (6.7%) patients on placebo and 1 (2.9%) on tanezumab. DISCUSSION IC is a multifactorial condition in which patients have widely differing clinical phenotypes. Nickel et al proposed that the clinical phenotypes of patients with IC could be categorized into 6 domains (urological, psychosocial, organ specific, infection, neurological/systemic and tenderness). 15 Although there are several options for the treatment of IC targeted at 1 or more these domains, few address the core issue of IC related pain. Current therapies for IC including PPS, hydroxyzine and amitriptyline have demonstrated efficacy in clinical trials However, the response to these treatments varies. PPS produced low response rates for refractory cases in a trial funded by the National Institutes of Health, 20 sug-

5 1720 TANEZUMAB FOR TREATMENT OF INTERSTITIAL CYSTITIS Table 2. Mean changes from baseline to week 6 Placebo Group Tanezumab Group No. pts Urgency episodes/24 hrs: Mean change (SE) 1.1 (1.6) 1.0 (1.5) Difference vs placebo (90% CI) 2.1 ( 4.3, 0.0) Micturitions/24 hrs: Mean change (SE) 0.1 (1.3) 0.7 (1.2) Difference vs placebo (90% CI) 0.6 ( 1.1, 2.3) MVV (ml): Mean change (SE) 3.2 (17.9) 0.4 (15.6) Difference vs placebo (90% CI) 2.8 ( 25.9, 20.3) Data for rfas. gesting that it may not be effective in many patients with IC, particularly those with severe symptoms. In addition, PPS can take 6 to 9 months before symptom relief is noted. Hydroxyzine has produced inconsistent response rates and has sedative properties which can restrict its use. 20,21 Amitriptyline has been associated with an increased incidence of side effects related to its anticholinergic activity. 22 In this study tanezumab demonstrated preliminary efficacy in reducing pain in patients with moderate to severe IC who were continuing to take their preexisting IC medications. An analysis of treatment response demonstrated that the odds of having a 50% or greater reduction from baseline in pain were more than 7 times higher for patients on tanezumab vs placebo. The improvement in pain symptoms was reflected in the GRA, which showed 5 times higher odds of improvement for tanezumab vs placebo. In addition, tanezumab significantly reduced urgency episode frequency but had no significant effect on the other micturition end points. Tanezumab also had no significant effect on ICSI score vs placebo, which may relate to the ICSI questionnaire containing 2 frequency related questions and, thus, is consistent with the results for the diary measure of frequency (micturition frequency per 24 hours). Tanezumab was generally safe with no discontinuations due to AEs. One patient experienced a serious AE (exposure during pregnancy) that the investigator considered treatment related. AEs of abnormal peripheral sensation were more common with tanezumab than placebo, but all of these AEs were mild to moderate in severity and most had resolved by the end of the study. For the patients who underwent neurological evaluation none of the AEs were considered related to peripheral neuropathy. There were no clear trends in PVR for patients on tanezumab vs placebo and no reports of urinary retention in either group. Limitations of this study were the small sample size for assessing secondary end points, limited exposure of patients to tanezumab (single dose) and short followup (16 weeks). These factors were particularly limiting in assessing the effect of tanezumab on the micturition end points, which have a large behavioral component that may not have been impacted during the 6-week period. Further analysis in a longer, multiple dose, dose ranging study would enable a more thorough investigation of the effects of tanezumab on urinary symptoms associated with IC. Through May 24, 2010, 16 subjects participating in 1 of 13 phase 3 studies of OA of the hip or knee experienced progressively worsening OA associated with radiographic evidence of bone necrosis that required total joint replacements. The affected joints included the knee, hip or shoulder (predominately unilateral involvement) with more than half of the cases occurring in a joint other than the index joint under evaluation in the study. These 16 events led the Food and Drug Administration to put the OA clinical program for tanezumab on clinical hold on June 22, 2010 until more information can be obtained to determine the true incidence and causality of these events. On July 19, 2010 the Food and Drug Administration also added phase 2 studies with tanezumab in chronic low back pain and diabetic peripheral neuropathy to the clinical hold. CONCLUSIONS This study has demonstrated positive proof of concept for the treatment of pain associated with IC following a single dose of 200 g/kg IV tanezumab. Furthermore, tanezumab reduced urgency episode frequency and provided overall patient reported treatment benefit. Additional multiple dose studies are required to fully understand the effect of tanezumab on IC symptoms. ACKNOWLEDGMENTS Editorial support provided by Michelle Jenvey, UBC Scientific Solutions, and funded by Pfizer, Inc. REFERENCES 1. Driscoll A and Teichman JM: How do patients with interstitial cystitis present? 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