Safety and Efficacy of Fulranumab in Osteoarthritis of the Hip and Knee: Results From Four Randomized, Double-blind, Placebo-controlled Phase III Studies
Abstract
Purpose: To evaluate the safety and efficacy of fulranumab as adjunct or monotherapy in patients with knee or hip pain related to moderate-to-severe osteoarthritis.
Methods: Osteoarthritic patients (aged ≥18 years) from 4 phase 3 randomized, double-blind (DB), placebo-controlled studies were randomized to receive placebo, fulranumab 1 mg every 4 weeks (Q4wk), or 3 mg Q4wk in 16-week DB phase, followed by a 52-week post-treatment follow-up phase. Safety assessments included treatment-emergent adverse events (TEAEs), and neurological, sympathetic and joint-related events of interest. Efficacy assessments included pain and physical function subscales of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores.
Findings: Of 245 patients from the ITT set (median age, 64 years; women, 62%), 84 (34%) completed DB phase; the majority of discontinuations (57%) were due to early study termination. In DB phase, incidence of TEAEs in fulranumab 3 mg (57.8%) and 1 mg (56.8%) was similar to placebo (56.8%). Two events adjudicated as joint-related events of interest include rapidly progressive osteoarthritis and fracture of unknown etiology. There were no new neurological TEAEs. Fulranumab showed evidence of efficacy in improving pain and physical function based on WOMAC subscales scores. Due to premature study termination, the number of patients enrolled were too small to make any definitive efficacy claims.
Implications: Treatment with fulranumab was generally tolerated with no new safety signals. Within the limited sample analyzed, fulranumab showed evidence of improvement of pain and function in patients with moderate-to-severe osteoarthritis who had failed prior therapy and were candidates for joint replacement surgery.
Clinical trial registration numbers: NCT02336685, NCT02336698, NCT02289716, NCT02301234
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References
[1]. Vos T, Allen C, Arora M, et al. Global, regional, and national incidence prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388:1545-1602, 2016. https://doi.org/10.1016/S0140-6736(16)31678-6.
[2]. Thysen S, Luyten FP, Lories RJU. Targets, models and challenges in osteoarthritis research. Dis Model Mech 8:17-30, 2015. https://doi.org/10.1242/dmm.016881.
[3]. Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage 21:1145-1153, 2013. https://doi.org/10.1016/j.joca.2013.03.018.
[4]. McAlindon TE, Bannuru R, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 22:363-388, 2014. https://doi.org/10.1016/j.joca.2014.01.003.
[5]. American Academy of Orthopaedic Surgeons. Treatment of osteoarthritis of the knee. Evidence-based guideline Edition 2. 2013. Adopted by the American Academy of Orthopaedic Surgeons. URL: https://www.aaos.org/research/guidelines/treatmentofosteoarthritisofthekneeguideline.pdf.
[6]. Fernandes L, Hagen KB, Bijlsma JW, et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis 72:1125-1135, 2013. http://dx.doi.org/10.1136/annrheumdis-2012-202745.
[7]. Pivec R, Issa K, Naziri Q, Kapadia BH, Bonutti PM, Mont MA. Opioid use prior to total hip arthroplasty leads to worse clinical outcomes. Int Orthop 38:1159-1165, 2014. http://dx.doi.org/10.1007/s00264-014-2298-x.
[8]. Al-Saeed A. Gastrointestinal and Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs. Oman Med J 26:385-391, 2011. http://dx.org/10.5001/omj.2011.101.
[9]. McNamee KE, Burleigh A, Gompels LL, et al. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain 149:386-392, 2010. https://doi.org/10.1016/j.pain.2010.03.002.
[10]. Shelton DL, Zeller J, Ho WH, Pons J, Rosenthal A. Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. Pain 116:8-16, 2005. https://doi.org/10.1016/j.pain.2005.03.039.
[11]. Matthews GL, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs 16:479-491, 2011.
[12]. Sanga P, Katz N, Polverejan E, et al. 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. Arthritis Rheumatol 69:763-73, 2017. https://doi.org/10.1002/art.39943.
[13]. Mayorga AJ, Wang S, Kelly KM, Thipphawong J. Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomized, placebo- and active-controlled trial. Int J Clin Pract 70:493-505, 2016. https://doi.org/10.1111/ijcp.12807.
[14]. 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 154:1910-1919, 2013. https://doi.org/10.1016/j.pain.2013.05.051.
[15]. Schnitzer TJ, Marks JA. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 23 Suppl 1:S8-S17, 2015. https://doi.org/10.1016/j.joca.2014.10.003.
[16]. Ruit KG, Osborne PA, Schmidt RE, Johnson EM, Jr., Snider WD. Nerve growth factor regulates sympathetic ganglion cell morphology and survival in the adult mouse. J Neurosci 10:2412-2419, 1990. https://doi.org/10.1523/JNEUROSCI..
[17]. Bannwarth B, Kostine M. Nerve growth factor antagonists: is the future if monoclonal antibodies becoming clearer? Drugs 77:1377-1387, 2017. https://doi.org/10.1007/s40265-017-0781-6.
[18]. Miller R E, Malfait A M, Block J A. Current status of nerve growth factor antibodies for the treatment of osteoarthritis pain. Clin Exp Rheumatol 35 Suppl 107:85-87, 2017.
[19]. Mullard A. Drug developers reboot anti-NGFs pain programmes. Nat Rev 14:279-298, 2015. https://doi.org/10.1038/nrd4612.
[20]. Dolgin E. Panel backs pain drug studies with new safety checks. Nat Med 18(4):472, 2012. https://doi.org/10.1038/nm0412-472.
[21]. Janssen Research & Development, LLC. Janssen Announces Discontinuation of Fulranumab Phase 3 Development Program in Osteoarthritis Pain. Titusville, NJ. March 31, 2016. https://www.jnj.com/media-center/press-releases/janssen-announces-discontinuation-of-fulranumab-phase-3-development-program-in-osteoarthritis-pain
[22]. Cornblath DR1, Chaudhry V, Carter K, et al. Total neuropathy score: validation and reliability study. Neurology 53:1660-1664, 1999. https://doi.org/10.1212/WNL.53.8.1660.
[23]. Bellamy N. The WOMAC Knee and Hip Osteoarthritis Indices: development, validation, globalization and influence on the development of the AUSCAN Hand Osteoarthritis Indices. Clin Exp Rheumatol 23 Suppl 39:S148–53, 2005.
[24]. McConnell S, Kolopack P, Davis AM. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC): a review of its utility and measurement properties. Arthritis Rheum 45:453-461, 2001.
[25]. Ornetti P, Dougados M, Paternotte S, Logeart I, Gossec L. Validation of a numerical rating scale to assess functional impairment in hip and knee osteoarthritis: comparison with the WOMAC function scale. Annals of the rheumatic diseases 70:740-746, 2011. http://dx.doi.org/10.1136/ard.2010.135483.
[26]. Ehrich EW, Davies GM, Watson DJ, Bolognese JA, Seidenberg BC, Bellamy N. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol 27:2635-2641, 2000.
[27]. Gentelle‐Bonnassies S, le Claire P, Mezieres M, Ayral X, Dougados M. Comparison of the responsiveness of symptomatic outcome measures in knee osteoarthritis. Arthritis Care Res 13:280-285, 2000.
[28]. Martin DP, Engelberg RU, Agel J, Swiontkowski MF. Comparison of the musculoskeletal function assessment questionnaire with the short form-36, the Western Ontario and McMaster Universities Osteoarthritis Index, and the Sickness Impact Profile health-status measures. J Bone Joint Surg Am 79:1323-1335, 1997.
[29]. Conner-Spady BL, Marshall DA, Bohm E, et al. Reliability and validity of the EQ-5D-5L compared to the EQ-5D-3L in patients with osteoarthritis referred for hip and knee replacement. Qual Life Res 24:1775-1784, 2015. https://doi.org/10.1007/s11136-014-0910-6.
[30]. Bellamy N, Campbell J, Haraoui B, et al. Clinimetric properties of the AUSCAN Osteoarthritis Hand Index: an evaluation of reliability, validity and responsiveness. Osteoarthritis and Cartilage 10:863-869, 2002.
[31]. Chang DS, Hsu E, Hottinger DG, Cohen SP. Anti-nerve growth factor in pain management: current evidence. J Pain Res 9:373-383, 2016. http://doi.org/10.2147/JPR.S89061.
[32]. Wang H, Romano G, Frustaci ME, et al. Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial. Neurology 83:628-637, 2014. https://doi.org/10.1212/WNL.0000000000000686.
[33]. Sanga P, Polverejan E, Wang S, Kelly KM, Thipphawong J. Efficacy, safety, and tolerability of fulranumab as an adjunctive therapy in patients with inadequately controlled, moderate-to-severe chronic low back pain: a randomized, double-blind, placebo-controlled, dose-ranging, dose-loading phase II study. Clin Ther 38:1435-50, 2016. https://doi.org/10.1016/j.clinthera.2016.03.030.
[34]. Flemming DJ, Gustas-French CN. Rapidly Progressive Osteoarthritis: A Review of the Clinical and Radiologic Presentation. Curr Rheumatol Rep 19:42, 2017. https://doi.org/10.1007/s11926-017-0665-5.
[35]. Dworkin RH, Turk DC, Peirce-Sandner S, et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain 153:1148-1158, 2012. https://doi.org/10.1016/j.pain.2012.03.003.
[36]. Farrar JT, Troxel AB, Haynes K, et al. Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: An ACTTION study. Pain 155:1622-1631, 2014. https://doi.org/10.1016/j.pain.2014.05.009.
[2]. Thysen S, Luyten FP, Lories RJU. Targets, models and challenges in osteoarthritis research. Dis Model Mech 8:17-30, 2015. https://doi.org/10.1242/dmm.016881.
[3]. Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage 21:1145-1153, 2013. https://doi.org/10.1016/j.joca.2013.03.018.
[4]. McAlindon TE, Bannuru R, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 22:363-388, 2014. https://doi.org/10.1016/j.joca.2014.01.003.
[5]. American Academy of Orthopaedic Surgeons. Treatment of osteoarthritis of the knee. Evidence-based guideline Edition 2. 2013. Adopted by the American Academy of Orthopaedic Surgeons. URL: https://www.aaos.org/research/guidelines/treatmentofosteoarthritisofthekneeguideline.pdf.
[6]. Fernandes L, Hagen KB, Bijlsma JW, et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis 72:1125-1135, 2013. http://dx.doi.org/10.1136/annrheumdis-2012-202745.
[7]. Pivec R, Issa K, Naziri Q, Kapadia BH, Bonutti PM, Mont MA. Opioid use prior to total hip arthroplasty leads to worse clinical outcomes. Int Orthop 38:1159-1165, 2014. http://dx.doi.org/10.1007/s00264-014-2298-x.
[8]. Al-Saeed A. Gastrointestinal and Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs. Oman Med J 26:385-391, 2011. http://dx.org/10.5001/omj.2011.101.
[9]. McNamee KE, Burleigh A, Gompels LL, et al. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain 149:386-392, 2010. https://doi.org/10.1016/j.pain.2010.03.002.
[10]. Shelton DL, Zeller J, Ho WH, Pons J, Rosenthal A. Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. Pain 116:8-16, 2005. https://doi.org/10.1016/j.pain.2005.03.039.
[11]. Matthews GL, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs 16:479-491, 2011.
[12]. Sanga P, Katz N, Polverejan E, et al. 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. Arthritis Rheumatol 69:763-73, 2017. https://doi.org/10.1002/art.39943.
[13]. Mayorga AJ, Wang S, Kelly KM, Thipphawong J. Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomized, placebo- and active-controlled trial. Int J Clin Pract 70:493-505, 2016. https://doi.org/10.1111/ijcp.12807.
[14]. 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 154:1910-1919, 2013. https://doi.org/10.1016/j.pain.2013.05.051.
[15]. Schnitzer TJ, Marks JA. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 23 Suppl 1:S8-S17, 2015. https://doi.org/10.1016/j.joca.2014.10.003.
[16]. Ruit KG, Osborne PA, Schmidt RE, Johnson EM, Jr., Snider WD. Nerve growth factor regulates sympathetic ganglion cell morphology and survival in the adult mouse. J Neurosci 10:2412-2419, 1990. https://doi.org/10.1523/JNEUROSCI..
[17]. Bannwarth B, Kostine M. Nerve growth factor antagonists: is the future if monoclonal antibodies becoming clearer? Drugs 77:1377-1387, 2017. https://doi.org/10.1007/s40265-017-0781-6.
[18]. Miller R E, Malfait A M, Block J A. Current status of nerve growth factor antibodies for the treatment of osteoarthritis pain. Clin Exp Rheumatol 35 Suppl 107:85-87, 2017.
[19]. Mullard A. Drug developers reboot anti-NGFs pain programmes. Nat Rev 14:279-298, 2015. https://doi.org/10.1038/nrd4612.
[20]. Dolgin E. Panel backs pain drug studies with new safety checks. Nat Med 18(4):472, 2012. https://doi.org/10.1038/nm0412-472.
[21]. Janssen Research & Development, LLC. Janssen Announces Discontinuation of Fulranumab Phase 3 Development Program in Osteoarthritis Pain. Titusville, NJ. March 31, 2016. https://www.jnj.com/media-center/press-releases/janssen-announces-discontinuation-of-fulranumab-phase-3-development-program-in-osteoarthritis-pain
[22]. Cornblath DR1, Chaudhry V, Carter K, et al. Total neuropathy score: validation and reliability study. Neurology 53:1660-1664, 1999. https://doi.org/10.1212/WNL.53.8.1660.
[23]. Bellamy N. The WOMAC Knee and Hip Osteoarthritis Indices: development, validation, globalization and influence on the development of the AUSCAN Hand Osteoarthritis Indices. Clin Exp Rheumatol 23 Suppl 39:S148–53, 2005.
[24]. McConnell S, Kolopack P, Davis AM. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC): a review of its utility and measurement properties. Arthritis Rheum 45:453-461, 2001.
[25]. Ornetti P, Dougados M, Paternotte S, Logeart I, Gossec L. Validation of a numerical rating scale to assess functional impairment in hip and knee osteoarthritis: comparison with the WOMAC function scale. Annals of the rheumatic diseases 70:740-746, 2011. http://dx.doi.org/10.1136/ard.2010.135483.
[26]. Ehrich EW, Davies GM, Watson DJ, Bolognese JA, Seidenberg BC, Bellamy N. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol 27:2635-2641, 2000.
[27]. Gentelle‐Bonnassies S, le Claire P, Mezieres M, Ayral X, Dougados M. Comparison of the responsiveness of symptomatic outcome measures in knee osteoarthritis. Arthritis Care Res 13:280-285, 2000.
[28]. Martin DP, Engelberg RU, Agel J, Swiontkowski MF. Comparison of the musculoskeletal function assessment questionnaire with the short form-36, the Western Ontario and McMaster Universities Osteoarthritis Index, and the Sickness Impact Profile health-status measures. J Bone Joint Surg Am 79:1323-1335, 1997.
[29]. Conner-Spady BL, Marshall DA, Bohm E, et al. Reliability and validity of the EQ-5D-5L compared to the EQ-5D-3L in patients with osteoarthritis referred for hip and knee replacement. Qual Life Res 24:1775-1784, 2015. https://doi.org/10.1007/s11136-014-0910-6.
[30]. Bellamy N, Campbell J, Haraoui B, et al. Clinimetric properties of the AUSCAN Osteoarthritis Hand Index: an evaluation of reliability, validity and responsiveness. Osteoarthritis and Cartilage 10:863-869, 2002.
[31]. Chang DS, Hsu E, Hottinger DG, Cohen SP. Anti-nerve growth factor in pain management: current evidence. J Pain Res 9:373-383, 2016. http://doi.org/10.2147/JPR.S89061.
[32]. Wang H, Romano G, Frustaci ME, et al. Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial. Neurology 83:628-637, 2014. https://doi.org/10.1212/WNL.0000000000000686.
[33]. Sanga P, Polverejan E, Wang S, Kelly KM, Thipphawong J. Efficacy, safety, and tolerability of fulranumab as an adjunctive therapy in patients with inadequately controlled, moderate-to-severe chronic low back pain: a randomized, double-blind, placebo-controlled, dose-ranging, dose-loading phase II study. Clin Ther 38:1435-50, 2016. https://doi.org/10.1016/j.clinthera.2016.03.030.
[34]. Flemming DJ, Gustas-French CN. Rapidly Progressive Osteoarthritis: A Review of the Clinical and Radiologic Presentation. Curr Rheumatol Rep 19:42, 2017. https://doi.org/10.1007/s11926-017-0665-5.
[35]. Dworkin RH, Turk DC, Peirce-Sandner S, et al. Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain 153:1148-1158, 2012. https://doi.org/10.1016/j.pain.2012.03.003.
[36]. Farrar JT, Troxel AB, Haynes K, et al. Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: An ACTTION study. Pain 155:1622-1631, 2014. https://doi.org/10.1016/j.pain.2014.05.009.
Authors
Kelly, K. M., Sanga, P., Zaki, N., Wang, S., Haeussler, J., Louie, J., & Thipphawong, J. (2019). Safety and Efficacy of Fulranumab in Osteoarthritis of the Hip and Knee: Results From Four Randomized, Double-blind, Placebo-controlled Phase III Studies. Journal of Current Medical Research and Opinion, 2(04), 133–143. https://doi.org/10.15520/jcmro.v2i04.144
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