Secondary Efficacy Endpoints
Across all fulranumab treatment groups, no significant differences in worst pain in the past 24 hours were observed as compared with placebo in both the PHN and PTN populations, at the week 12 endpoint (Table 4). When measured by the BPI-SF scale, a significant improvement from baseline in treatment pain relief subscale was observed only for the fulranumab 3 mgQ4 wk group (P=0.04) in the PHN population, but there was no improvement in the PTN population (Table 4). For the NPSI total scores, no improvements were observed from baseline to the end of DB efficacy phase in the fulranumab treatment groups as compared with placebo in either population (Table 4). At the 12-week endpoint, there were no significant differences noted for any of the fulranumab treatment groups compared with placebo as measured by responder analysis (30% responder rate, 50% responder rate, Table S1, Supplemental Digital Content 1, http://links.lww.com/CJP/A363). Approximately half of the PHN (55% for both placebo and fulranumab groups) and PTN (43% for placebo and 48% for the fulranumab 10 mgQ4 wk group) patients reported their status as “not changed” as measured by PGIC. Most of the remaining patients reported improvement in their status (Table S2, Supplemental Digital Content 2, http://links.lww.com/CJP/A364).
Mean trough serum fulranumab concentrations increased in an approximately dose-proportional or slightly greater than dose-proportional manner at doses and dosing regimens ranging from 1 mgQ4 wk to 10 mgQ4 wk (data not shown). Steady-state serum fulranumab concentrations were generally achieved by week 17 to week 21 following 4-weeks maintenance dosing. Mean trough serum fulranumab concentrations were generally maintained at steady state through week 53, when treated with 4-week maintenance dosing. Serum fulranumab concentrations did not appear to be impacted by the concurrent use of other pain medications or by the type of pain (PHN or PTN). A relationship between serum fulranumab concentrations and clinical efficacy was not observed.
Two (2.9%) patients in the fulranumab treatment groups developed antibodies to fulranumab by the end of the study (data not shown). Overall, antibody responses to fulranumab showed low titers (1:10 and 1:40). None of the antibodies developed were able to neutralize the biological effects of fulranumab in vitro.
Overall, fulranumab at all doses was generally well-tolerated. In the PHN population, the overall percentage of patients with TEAEs was similar between placebo (80%) and fulranumab 10 mgQ4 wk group (79%) and the other 2 treatment groups (62% each). In the PTN population, the overall percentage of patients with TEAEs was comparable in the placebo (86%) and 10 mgQ4 wk (78%) groups (Table 5). Osteoarthritis was the only TEAE in the PHN population with a >10% difference in the incidence rate between the 10 mgQ4 wk group and placebo, whereas in the PTN population, both sinusitis and carpal tunnel syndrome occurred with a >10% incidence difference between the 10 mgQ4 wk group and placebo.
The overall percentage of neurological-related TEAEs was similar across all the treatments groups. Most frequently reported neurological-related TEAEs were hypoesthesia (placebo: 1 [2%] patient; 3 mgQ4 wk: 1 [7%] patient; 10 mgQ4 wk: 3 [7%] patients), carpal tunnel syndrome (10 mgQ4 wk: 3 [7%] patients), peripheral neuropathy (1 mgQ4 wk: 1 [8%] patient; 10 mgQ4 wk: 1 [2%] patient), and paresthesia (placebo: 4 [10%] patients; 3 mgQ4 wk: 1 [7%] patient; 10 mgQ4 wk: 1 [2%] patient); events were largely mild to moderate in severity. No patients in fulranumab group and 14% of the patients in placebo group discontinued the treatment due to neurological-related TEAEs. There was no case of serious neurological-related TEAE that led to treatment discontinuation. Neurological TEAEs leading to a neurological consultation were noted in 1 patient each in placebo (paresthesia) and 10 mgQ4 wk (carpal tunnel syndrome and paresthesia) groups.
During the combined DB efficacy and extension phases, 7 patients experienced serious TEAEs (placebo: 2 [10%] patients; 1 mgQ4 wk: 1 [8%] patient; 10 mgQ4 wk: 4 [21%] patients) in the PHN population, whereas 5 patients experienced serious TEAEs (placebo: 2 [9%] patients and 10 mgQ4 wk: 3 [13%] patients) in the PTN population. Moderate bradycardia was reported in 1 patient (2%) in the 10 mgQ4 wk group, whereas hypotension and orthostatic hypotension were reported in 1 patient (2%) each in the 10 mgQ4 wk group, which were mild to moderate in severity.
There were no TEAEs indicative of hepatic or acute renal failure during the study. No clinically significant changes from baseline in total neuropathy score-nurse and MMSE were observed. Five joint replacements occurred during the study, 2 in the placebo and 3 in the fulranumab 10 mgQ4 wk groups. All cases of joint replacement were reviewed by the independent adjudication committee (IAC). Four of the joint replacement cases were determined by the IAC to be from normal progression of osteoarthritis; 1 case in the fulranumab 10 mgQ4 wk group was determined to be RPOA. None of the joint replacement cases were assessed by the IAC to be either osteonecrosis or RPOA with features of osteonecrosis. The single case adjudicated as RPOA occurred in a patient on fulranumab using regular concurrent nonsteroidal anti-inflammatory drugs, and who had a prior history of osteoarthritis in the affected joint before joint replacement. The majority of the joint replacements (n=3) were assessed as not related to study drug; 1 (RPOA) was assessed as possibly related and 1 was considered to have insufficient data for assessment of relationship.
Injection-site evaluations (investigator-assessed, after each injection) of mild rating were noted across all the groups. No clinically significant changes in laboratory parameters, vital signs, or ECGs were noted in any patient during the study. There were no deaths in the study.
NGF plays an important role in the generation of pain and hyperalgesia in several acute and chronic pain states through the sensitization of nociceptive neurons.23,24 A new class of analgesic drugs, the anti-NGFs, is a potential option in treatment of conditions where the current therapeutics are deemed ineffective. This paper reports the safety and analgesic efficacy of fulranumab, an anti-NGF compound, in the treatment of PHN and PTN. No significant reduction was achieved in either neuropathic populations versus placebo in average daily pain score at both time points (week 4 or week 8) of the 12-week DB efficacy phase (except for PHN patients at week 4 [P=0.02] in the 10 mg group).
This study was planned to generate long-term data on fulranumab treatment in the PTN and PHN patient population. However, the planned enrollment of 200 patients was not achieved due to the clinical hold, resulting in enrollment of only 111 patients, which is a limitation of this study. Approximately 75% of PHN and PTN patients were able to complete the 12-week DB efficacy phase and ∼66% of patients could enter DB extension phase. LOCF may not be the best method to use to measure the change from baseline in average pain intensity (primary endpoint) as an overly optimistic result may be obtained for the study drug. In our study, BOCF method was also used and the results were comparable. It is advised to explore other imputation strategies as part of the sensitivity analyses.
Similar to the primary efficacy results (analyzed by NRS scale), there were no significant differences observed for any of the fulranumab treatment groups compared with placebo as measured by responder analysis, most bothersome symptom from NPSI, PGIC, and BPI-SF, except a significant improvement from baseline in treatment pain relief subscale (P=0.04) observed in the BPI-SF for PHN group (3 mgQ4 wk). The NPSI total score measures the overall pain intensity and is correlated to numerical pain scales, whereas individual subscales may assess distinct dimensions of neuropathic pain.20 There were no significant differences in any of the subscales including burning spontaneous pain, pressing spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia subscales (data not shown).
The NRS scale used to access the average pain intensity (primary efficacy endpoint), despite having practical advantages in terms of not requiring any physical materials and widespread acceptance in clinical practice, has its own limitations. The scores are subjective and can be influenced by many social, cognitive, and contextual factors. The variability seen between the efficacy results as measured by NRS and BPI treatment pain relief subscales may be explained by these factors. In addition, the sensitivity of pain relief and that of pain intensity have been reported to mostly correlate but are not always similar.25
Fulranumab has demonstrated significant analgesic activity in patients with pain associated with chronic osteoarthritis of the knee or hip and pain associated with painful diabetic neuropathy,18,19 but failed to show analgesic activity in either of the neuropathic populations enrolled in this study. The reasons for differences observed in the responses to fulranumab in different patient populations are not well-understood. In this study, the PHN and PTN were monophasic in etiology (caused by an isolated insult like viral or traumatic). One hypothesis for the differential effect may be that NGF released from unhealthy axons causes pain by acting on intact axons or terminals. In painful diabetic neuropathy, which is chronic, there are both dying and intact axons, whereas in monophasic neuropathies the injured axons either die or heal, and pain may be less dependent on NGF. Another possible reason is that the patients included in the current study were particularly refractory to any drug therapy and had chronic and longer-lasting pain, although there is no evidence either way to support this possibility. Overall efficacy results for both PHN and PTN are consistent with an earlier study of a similar anti-NGF class treatment (tanezumab) used for PHN.26 Serum fulranumab concentrations did not appear to be impacted by concurrent use of pain medications or by the type of neuropathic pain (PHN or PTN). As robust efficacy was not observed, it is difficult to assess correlation between serum fulranumab concentrations and clinical efficacy. The lack of correlation could be due to the lack of efficacy and may be buried in the noise of placebo effect.
Fulranumab was generally well-tolerated at all 3 doses evaluated in the study. During the combined DB phases (efficacy and extension safety), the overall rate of TEAEs was similar among placebo and fulranumab treatment groups. No apparent dose relationship was observed. No deaths were reported. During the DB efficacy phase for PHN and PTN, a low incidence of serious TEAEs and the TEAEs leading to discontinuation was observed. The majority of patients were withdrawn from the DB extension phase due to sponsor’s decision to discontinue the study as a result of the FDA clinical hold. The most common neurological-related TEAEs were those related to hypoesthesia, carpal tunnel syndrome, peripheral neuropathy, and paresthesia. These findings are consistent with a study evaluating efficacy and safety of fulranumab in painful diabetic peripheral neuropathy patients wherein similar neurological-related TEAEs (neuropathic pain, neuropathy, paresthesia, and carpal tunnel syndrome) were reported.19 Few TEAEs of clinical interest (bradycardia, hypotension, neurological, and motor-related TEAEs) were reported in this study, consistent with previous safety information on fulranumab.18,19 No changes were noted on vital signs assessed (blood pressure, pulse rate measures, ECGs).
Events of RPOA and osteonecrosis resulting in rapid joint destruction leading to joint replacement surgery were identified as specific safety concerns by the FDA in clinical studies of anti-NGF drugs in development.27 In 2010, FDA placed all anti-NGF therapies (including fulranumab) on clinical hold for all indications except cancer pain.28 However, the clinical hold was lifted in 2012 with a recommendation for a close safety surveillance.27 One case of RPOA leading to joint replacement was reported in this study, although 7 patients enrolled had a history of OA. No case of osteonecrosis was reported in the study. The safety findings observed in this study were consistent with previous studies of fulranumab18,19 and other anti-NGFs in pain therapy such as tanezumab.26
Larger clinical studies involving more patients are needed to fully characterize the efficacy of fulranumab, ideally with an active comparator. In addition, clinical studies evaluating long-term safety and tolerability of this potentially new class of analgesic drug are required.
This study failed to show that fulranumab at a dose up to 10 mg once every 4 weeks, compared with placebo, was efficacious in reducing pain in patients with PHN or PTN. There was some evidence of pain reduction only at the highest dose of fulranumab (10 mgQ4 wk) at the 4-week time point. The limitation of the study is the small sample size. Overall, fulranumab at all doses was generally well-tolerated in PHN and PTN patients in this study.
The authors acknowledge Dr Shweta Vadnerkar PhD (SIRO Clinpharm Pvt Ltd) and Ubhayabharathi Gurunath MSc (SIRO Clinpharm Pvt Ltd) for providing writing assistance, Drs Wendy Battisti PhD and Ellen Baum PhD, MBA (Janssen Research & Development, LLC) for additional editorial support for the development of this manuscript. In addition, the authors would like to thank Dr Jose Pinheiro PhD (Janssen Research & Development, LLC) for proposing and performing the dose-response analysis, Dr Norman Bohider PhD for contributing to the original study design, and Dr Steven Wang PhD (Janssen Research & Development, LLC) for providing direction regarding data interpretation.
The authors also thank the study participants of the 3 studies, without whom the studies would never have been accomplished and also thank the following investigators for their participation in the study: United States of America: Atkinson S, MD; Finger Lakes Clinical Research, Rochester, New York, Bhatia P, MD; Neuro Pain Medical Center, Fresno, CA, Blatt K, MD; The Medical Research Network, LLC, New York, NY, Blue E, MD; TriValley Primary Care (TVPC), Pennsburg, PA, Cato JR, MD; Heritage Medical Associates, PC, Nashville, TN, Chamely AA, MD; Sunrise Clinical Research, Inc., Tamarac, FL, Chen DW, MD; Brockton, MA, Chipman H, MD; Journey Research, Inc., Oldsmar, FL, Cutler B, MD; Neurology Clinical Research, Inc., Sunrise, Florida, DeGarmo RG, DO; DeGarmo Institute of Medical Research, Greer, SC, DeSantis MC, MD; Clinical Trials of America, Inc., Hickory, NC, Drass MJ, MD; Aliegheny Pain Management, Altoona, PA, Dunteman E, MD; A & A Pain Institute of St. Louis, St. Louis, MO, Elliot SK, MD; Medical Research Center, LLC, Evansville, IN, Reyes HS, MD; Medical Research Center, LLC, Evansville, IN, Ellis JS, MD; Clinical Trials of Texas, Inc., San Antonio, TX, Christine LT, MD; San Antonio, TX, Hooft RP, MD; Mountain West Clinical Trials, Eagle, Idaho, Hootz SE, MD; Neurological Clinic of Texas P.A., Dallas, TX, Isaradisaikul D, MD; Neurological Clinic of Texas P.A., Dallas, TX, Huynh B, MD; ClinRx Research, LLC, Plano, TX, Kemp SE, MD; Clinical Trials of America, Inc, Shreveport, LA, Marco R, MD; Shreveport, LA, Markman JD, MD; University of Rochester, Rochester, NY, Markovitz PJ, MD, PhD; Mood and Anxiety Research, Inc.,Fresno, CA, Micheal PA, MD; Fresno, CA, O’laughin TJ, MD; Fresno, CA, Mezhebovsky I, MD; Boston Clinical Trials, Boston, MA, Nicholson B, MD; Lehigh Valley Health Network, Allentown, Pennsylvania, Nash ML, MD, FAHA, CPI; NeuroStudies.net/Dekalb Neurology Associates, L.L.C., Decatur, GA, Nunez M, MD; Comprehensive Clinical Development, Inc., St. Petersburg, Florida, Pappas JE, MD; Kentucky Medical Research Center, Lexington, KY, Petersen D, MD; Valley Medical Center, PLLC, Lewiston, ID, Radnovich R, DO; Injury Care Medical Center, Boise, ID, Rao HT, MD; The Neurological Institute, P.A., Charlotte, NC, Rapo SE, MD; Clinical Research Center of Cape Cod, Inc., Hyannis, MA, USA Rederich GJ, MD; Redondo Beach, CA, Schmidt LM, DO; Genova Clinical Research, Tucson, AZ, Schwartzman RJ, MD; Drexel University College of Medicine, Philadelphia PA, Shamim T, MD; Heartland Clinical Research, Inc., Omaha, NE, Steinberg JM, MD; Sunrise Clinical Research, Inc., Hollywood, FL, Tuchman M, MD; Palm Beach Neurological Center Advanced Research Consultants, Inc., Palm Beach Gardens, FL, Upender R, MD; HCCA Clinical Research Solutions, Tullahoma, TN, Weintraub JR, DO; Ann Arbor, MI, White A, MD; Port Orange, Fl, Wymer JP, MD, PhD; Upstate Clinical Research, LLC, Albany, NY, Beesley BA, MD, Upstate Clinical Research, LLC, Albany, NY, Young DG; MD Northern California Research, Sacramento, CA, Belgium: Hans G, MD, PhD;UZ Antwerpen, Edegem, Belgium, Morlion B, MD; UZ Leuven, Pellenberg, Belgium, Vanelderen P, MD; Ziekenhuis Oost-Limburg, Genk, Belgium, Spain: Guerrero A, MD; Hospital Clinico San Carlos, Madrid, Spain, Gomar C, MD, PhD; Hospital Clinic de Barcelona, Barcelona, Spain, de Andres JA, MD, PhD; Hospital General de Valencia, Valencia, Spain, Pêrez C, MD; Hospital de La Princesa, Madrid, Spain, Vincente-Fatela L MD, PhD; Hospital Doce de Octubre, Madrid, Spain (Note: some sites had coprimary investigators or the primary investigator changed during the course of the study).
1. Bouhassira D, Lantéri-Minet M, Attal N, et al.. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136:380–387.
2. Torrance N, Smith BH, Bennett MI, et al.. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006;7:281–289.
3. Ossipov MH, Porreca F. Challenges in the development of novel treatment strategies for neuropathic pain. NeuroRx. 2005;2:650–661.
4. Gilron I, Watson CP, Cahill CM, et al.. Neuropathic pain: a practical guide for the clinician. CMAJ. 2006;175:265–275.
5. Zis P, Apsokardos A, Isaia C, et al.. Posttraumatic and postsurgical neuropathic pain responsive to treatment with capsaicin 8% topical patch. Pain Physician. 2014;17:E213–E218.
6. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain. 1996;67:241–251.
7. Attal N, Bouhassira D. Pharmacotherapy of neuropathic pain: which drugs, which treatment algorithms? Pain. 2015;156(suppl 1):S104–S114.
8. Finnerup NB, Attal N, Haroutounian S, et al.. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162–173.
9. Parsons B, Schaefer C, Mann R, et al.. Economic and humanistic burden of post-trauma and post-surgical neuropathic pain among adults in the United States. J Pain Res. 2013;6:459–469.
10. Song H, Lee J, Lee M, et al.. Burden of illness, quality of life, and healthcare utilization among patients with herpes zoster in South Korea: a prospective clinical-epidemiological study. Int J Infect Dis. 2014;20:23–30.
11. Akkaya T, Ozkan D. Chronic post-surgical pain. Agri. 2009;21:1–9.
12. Sacks GM. Unmet need in the treatment of postherpetic neuralgia. Am J Manag Care. 2013;19:S207–S213.
13. Katz N, Borenstein DG, Birbara C, et al.. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain. 2011;152:2248–2258.
14. Kivitz AJ, Gimbel JS, Bramson C, et al.. Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain. Pain. 2013;154:1009–1021.
15. Lane NE, Schnitzer TJ, Birbara CA, et al.. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363:1521–1531.
16. Schnitzer TJ, Lane NE, Birbara C, et al.. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage. 2011;19:639–646.
17. Wild KD, Bian D, Zhu D, et al.. Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance. J Pharmacol Exp Ther. 2007;322:282–287.
18. Sanga P, Katz N, Polverejan E, et al.. Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain. Pain. 2013;154:1910–1919.
19. Wang H, Romano G, Frustaci ME, et al.. Fulranumab for treatment of diabetic peripheral neuropathic pain: a randomized controlled trial. Neurology. 2014;83:628–637.
20. Bouhassira D, Attal N, Fermanian J, et al.. Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 2004;108:248–257.
21. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994;23:129–138.
22. Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. J Manipulative Physiol Ther. 2004;27:26–35.
23. Hefti FF, Rosenthal A, Walicke PA, et al.. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci. 2006;27:85–91.
24. Nicol GD, Vasko MR. Unraveling the story of NGF-mediated sensitization of nociceptive sensory neurons: ON or OFF the Trks? Mol Interv. 2007;7:26–41.
25. Singla N, Hunsinger M, Chang PD, et al.. Assay sensitivity of pain intensity versus pain relief in acute pain clinical trials: ACTTION systematic review and meta-analysis. J Pain. 2015;16:683–691.
26. Bramson C, Herrmann DN, Carey W, et al.. Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain. Pain Med. 2015;16:1163–1176.
27. Bannwarth B, Kostine M. Targeting nerve growth factor (NGF) for pain management: what does the future hold for NGF antagonists? Drugs. 2014;74:619–626.
antinerve growth factor; fulranumab; neuropathic pain; postherpetic neuralgia; posttraumatic neuropathy
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