American Chiropractors Directory and News

Introduction

Nerve growth factor (NGF), discovered by Rita Levi-Montalcini in 1952, belongs to the neurotrophin family, along with as neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and brain-derived growth factor (BDNF). It plays an important role in neuronal survival during the course of embryogenesis.1,2 During development, NGF and other neurotrophins bind to a member of the tropomyosin-related kinase (Trk) receptor family and the low-affinity p75 neurotrophin receptor (NTR) on the neuronal cell surface, then activate different signaling pathways involved in neuronal growth and survival and thus modulate pain pathogenesis.3–5 Moreover, in adults, NGF influences the nociceptive neuronal activity.6

Preclinical and clinical studies have clearly highlighted the important role of NGF in acute and chronic pain modulation. In particular, chronic pain is an extremely heterogeneous source of suffering and derives from different pathological conditions, such as osteoarthritis (OA), chronic low back pain (CLBP), cancer, and other forms of disease.7 Current therapies for the treatment of chronic pain are essentially based on pharmacological approaches (ie opiates, non-steroidal anti-inflammatory drugs [NSAIDs], and other drugs), which often lead to long-term side effects.8,9 Since NGF has been identified as an important mediator of chronic pain syndromes, new strategies of treatment based on NGF blockade or anti-NGF antibodies have been demonstrated in both preclinical and clinical trials.10 Many humanized anti-NGF monoclonal antibodies (mAbs) have been tested in clinical trials as potential pain therapies (ie tanezumab, fulranumab, and fasinumab); in particular, tanezumab was used in phase III trials in OA, although the safety of these patients was not uniformly reached.11 With regard to preclinical investigations, anti-NGF mAbs have been engineered and tested for the management of OA animal models, with encouraging results.10–13 Moreover, several studies have highlighted the effect of anti-NGF antibodies in different animal models of neuropathic pain.14–16 Thus, new therapies based on the use of different mAbs targeting the NGF pathway have been tested for chronic pain treatment in preclinical and clinical studies.

Here, we review the preclinical and clinical studies on anti-NGF mAb therapy in chronic syndromes, the role of NGF in pain transduction, and the need for anti-NGF mAbs in humans. Studies cited in this narrative review were discovered through PubMed searches. PubMed was searched for both preclinical and clinical articles related to “NGF and chronic pain” and “NGF and cancer pain”.

NGF and Pain-Related Mechanisms

NGF plays an important role in the generation and maintenance of both nociceptive and neuropathic pain by regulating a complex signaling pathway. In briefly (see Kumar and Mahal17 for more details), NGF interacts with the high-affinity TrkA and lowers the neurotrophic receptor p75 (NTR) receptors. Cell survival and neurite outgrowth are reached through the activation of TrkA-mediated Ras (Rat sarcoma) and PI3 kinase (PI3K) pathways. The TrkA-activated PI3K pathway blocks the signaling through p75NTR, which leads to apoptosis. Moreover, the activation of PI3K signaling promotes the phosphorylation of the non-selective cation channel transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in the enhancement of nociceptive function.

NGF can modulate nociception by releasing inflammatory mediators, by regulating the activity of the nociceptive ion channel/receptor and the expression of the nociceptive gene, and by the sprouting of local neurons in complex machinery involved in its downstream signaling pathways.17,18

In Vivo Preclinical Studies on the Effects of Anti-NGF mAbs in Animal Models of Chronic Pain: An Update

Since NGF can modulate pain in chronic conditions, new therapeutic approaches, based on the use of different neutralizing or antibodies targeting its pathway, have been developed and tested in animal models of chronic pain (Table 1).19–30 In particular, anti-NGF mAbs have been engineered and tested for the management of osteoarthritis (OA), a progressive degenerative joint disease. Importantly, the earlier published studies, only detected the effects of NGF blockade on pain behavior, whereas more recent studies also assessed the effects on pathological joints. These studies also highlighted some adverse effects linked to anti-NGF treatment, including cartilage damage, tibial osteophytes, and subchondral bone sclerosis.10

The first report on the effects of NGF blockade (using a neutralizing antibody against NGF) in an animal model of OA was published by McNamee et al.19 In this study, the authors used a mouse model of destabilization of the medial meniscus (DMM) of OA to test the effects of NGF and its soluble receptor, TrkAD5, in pain assessment. Their data demonstrated that TrkAD5 suppressed the pain in OA mice. Similar findings were presented by Flannery et al in a rat mono-iodoacetate (MIA) model.20 Bryden et al demonstrated that a subcutaneous injection of anti-NGF mAb, in a rat MIA model, reversed deficits in burrowing compared to non-treated mice.21 To date, few preclinical studies conducted on animal models of chronic pain have assessed both pain and joint changes after anti-NGF mAb treatment. Ishikawa et al demonstrated that a single dose of an anti-NGF antibody had a long-lasting analgesic effect on pain during motion, lesion, and joint edema in a rat model of OA.22 In the same year (2015), a research group proved, for the first time, the efficacy of a canine-specific anti-NGF mAb in a dog with degenerative joint disease.23

Another study based on pain assessment was performed by Kc et al, which assessed the effect of multiple intra-articular administrations of an anti-NGF mAb into the knee of protein kinase Cδ (PKCδ) null mice subjected to DMM surgery.24 Informative data on the evaluation of the effects of NGF blockade in pain and joint assessment were obtained by performing experiments on rat meniscal surgery models. Specifically, Nwosu et al reported that NGF blockade, obtained by inhibiting TrkA (AR786), reduced pain behavior in two rat models of OA.25 LaBranche et al26 showed that tanezumab influenced weight-bearing and subsequent cartilage damage in the rat medial meniscal tear (MMT) model. Specifically, the authors demonstrated that treatment with tanezumab (at any dose) reduced gait imbalances induced by meniscal injury in the treated rat, but increased cartilage damage and subchondral bone sclerosis compared to controls. Xu et al27 demonstrated that anti-NGF mAb treatment (mainly in the early stages of the disorder) attenuated OA but increased cartilage damage in a rat model resembling the key clinical features of OA compared to controls. Nevertheless, these studies confirmed the analgesic role of anti-NGF mAb in the treatment of OA. Majuta et al demonstrated that anti-NGF improved limb use in a rodent model, by controlling pain after joint/orthopedic surgery.28 Miyagi et al demonstrated that an injection of anti-NGF antibody into the knee joint provoked an impairment of gait and dysregulation of calcitonin gene-related peptide (CGRP) in dorsal root ganglion (DRG) neurons in a knee OA pain mouse model.29

Promising results were obtained by von Loga et al, who demonstrated the therapeutic efficacy of a novel NGF vaccine (CuMVttNGF) in the alleviation of spontaneous pain behavior in surgically induced murine OA.30

Altogether, these studies support the idea that the blockade of NGF signaling is effective in treating chronic pain, especially in OA.

Effects of Anti-NGF mAbs on Neuropathic and Cancer Pain: An Update on Preclinical Studies

NGF plays important roles in nociception and in the maintenance, development, and injury of the sensory nervous system, which are directly involved in cancer pain manifestations.31 Based on these features, numerous preclinical studies have been conducted using anti-NGF mAbs therapy to manage cancer and neuropathic pain.17,32–42 Dai et al demonstrated that NGF inhibition mitigated chronic constriction injury (CCI)-induced neuropathic pain through the inhibition of downstream p65 and mitogen-activated protein kinase (MAPK).32 da Silva et al demonstrated that anti-NGF treatment reduced chronic neuropathic pain by changing peripheral mediators and brain activity in rats with CCI.14 Similarly, Dos Reis, in a rat model of trigeminal neuropathic pain, demonstrated that local treatment with anti-NGF attenuated heat hyperalgesia.33 With regard to cancer-related pain, a few preclinical studies have been conducted using anti-NGF mAb as a potential therapeutic choice. The first report was published by Sevcik et al.34 The authors demonstrated that an innovative NGF sequestering antibody was able to relieve cancer pain-related behaviors in a mouse model of bone cancer compared to conventional treatment with morphine. Similarly, Halvorson et al, in a prostate mouse model of bone cancer pain, demonstrated that anti-NGF treatment effectively suppressed alterations in functional connectivity after cancer-induced bone pain in mice.35 Later, Mantyh et al, using a mouse model of bone cancer pain, demonstrated that the analgesia obtained with administration of anti-NGF mAb stopped the development of severe cancer pain.36 A report by Ye et al highlighted the associations between pain, proliferation, and cachexia in oral cancer.37 Similarly, Jimenez-Andrade et al demonstrated that treatment with anti-NGF therapy in the early and later stages of the disease reduced cancer pain.38 Subsequently, Kumar et al published a review on the role of NGF/TrkA signaling in the treatment of chronic pain.17 Sainoh et al demonstrated that treatment with anti-NGF antibodies could be considered a valuable tool for the treatment of neuropathic cancer pain by lowering mechanical allodynia and upregulating the expression of pain markers.39

Guedon et al conducted a study on the effects of anti-NGF mAb or anti- purinergic receptor (P2X3) on skeletal pain-related behaviors in a murine model of cancer-induced bone pain (CIBP). Their data showed that, differently from anti-P2X3, which only attenuated the hypersensitivity of the skin, anti-NGF mAbs also mitigated skeletal pain-associated behaviors.40 In 2019, Buehlmann et al demonstrated that anti-NGF mAb treatment can prevent pain-induced adaptations in brain functional networks after persistent nociceptive input from cancer-induced bone pain.41 These findings suggest that anti-NGF therapy could be used successfully to treat neuropathic cancer pain.

Clinical Trials: Safety and Efficacy of Anti-NGF mAbs in Chronic Pain Treatment

Several mAbs that bind to NGF (ie tanezumab, fulranumab, and fasinumab) have been used in clinical studies for different chronic pain conditions, especially OA. (For a comprehensive review on this topic, see Wise et al.43) Specifically, phase I and phase II clinical trials have been conducted to test the efficacy of mAbs targeting NGF in pain attenuation in both knee and hip OA.43–71 As described by Wise et al,43 two primary endpoints have been used to study NGF inhibition in knee and hip OA in different studies: the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, which allows the meta-analyses of data; and function subscales, which are associated with the physician’s global assessment (PGA). Overall, all of these studies demonstrated the efficacy of anti-NGF antibodies in pain alleviation and an improvement of the main patient outcomes compared to placebo (used as a control) for hip and knee OA. Despite these enthusiastic results, the meta-analyses conducted on data that emerged from these clinical trials found that treatment with mAbs targeting NGF increased the risk of neurological adverse effects (ie paresthesia, hypoesthesia, and peripheral neuropathy). However, no differences in serious adverse effects were detected after treatment with anti-NGF antibody compared to NSAID or placebo treatments, thus indicating the safety of the treatments used in these studies. To date, the clinical trials conducted on this topic have reported that NGF inhibitors attenuated joint pain and improved function compared with NSAIDs for a duration of up to 8 weeks. Specifically, the clinical efficacy of tanezumab started from week 4 after initiation of treatment and persisted for another 8 weeks thereafter. As discussed by Wise et al,43 whereas anti-NGF mAbs produced significant pain relief and functional improvement in patients with knee and/or hip OA, clinical trials and meta-analyses conducted with tanezumab on non-specific low back pain (LBP) gave mixed and confusing findings, but showed that LBP was less responsive to anti-NGF agents than OA, even when tanezumab was used at higher doses. In particular, the meta-analysis conducted by Sanga et al, on the efficacy of anti-NGF mAbs (tanezumab, fulranumab, and fasinumab) in the treatment of CLBP, showed a slight improvement of pain and functions and an increase in neurological adverse effects compared to placebo.54 Finally, no conclusive evidence on the effectiveness of anti-NGF mAbs in chronic visceral or neuropathic pain has been presented.54

Adverse Effects of Anti-NGF mAb Therapy for OA: An Update on the Clinical Trials

Clinical trials and meta-analyses conducted on the use of anti-NGF mAbs in the treatment of OA (mainly tanezumab) reported some unforeseen side effects, particularly rapidly progressive osteoarthritis (RPOA) of both the knee and hip joints. Brown et al,44 in a randomized, double-blind, placebo-controlled phase III trial, showed that tanezumab (2.5, 5, or 10 mg, i.v.) alleviated osteoarthritic knee pain. However, an increase in neurological adverse effects was detected in the tanezumab compared to the placebo group, while no RPOA was detected. In a phase III placebo- and oxycodone-controlled study of tanezumab in adults with OA pain of the hip or knee, Spierings et al45 demonstrated the major efficacy of tanezumab in pain alleviation and the highest number of adverse effects in the oxycodone group. Similarly, Balanescu et al,46 in a phase III randomized clinical trial of tanezumab with diclofenac versus placebo in patients with OA pain of the hip or knee, showed a major efficacy of tanezumab on all primary outcomes. Total joint replacement (TJR) was frequently observed in the tanezumab group. Similar adverse events were observed in all groups, and one case of RPOA was confirmed by adjudication. Ekman et al47 tested the efficacy and safety of tanezumab (5 or 10 mg) for the treatment of OA of the knee or hip versus placebo or naproxen. They reported that tanezumab ameliorated the pain and PGA (at the dose of 5 mg) and function (at both doses) more than naproxen. No differences in side effects were detected in any treatment group, and one TJR was reported in the tanezumab group. Later, Schnitzer et al48 demonstrated that tanezumab improved pain and function in patients with OA more than NSAIDs and placebo. Regarding side effects, paresthesia and hypoesthesia were greater in patients with tanezumab than in patients treated with placebo and NSAIDs. Moreover, RPOA was observed mainly in patients treated with tanezumab alone. A clinical trial conducted by Birbara et al49 demonstrated the efficacy and safety of tanezumab in patients with knee or hip OA. A few cases of RPOA and TJRs were observed. Similarly, in two different clinical trials, Schnitzer et al50,51 showed that tanezumab improved all outcomes of patients with knee or hip OA. With regard to adverse effects, TJRs and RPOA were more evident in the tanezumab than in the placebo group, in a dose-dependent manner. Neurological adverse effects were also detected. Berenbaum et al,52 in a randomized phase III study, demonstrated the efficacy and safety of tanezumab (2.5 or 5 mg) for OA of the hip or knee. RPOA occurred more frequently with a higher dose of tanezumab (5 mg). TJRs were similarly distributed across all three groups. Hypoesthesia and paresthesia were also detected in both tanezumab groups.

A few trials have been conducted with other mABs. Mayorga et al53 conducted a randomized clinical controlled trial to test the efficacy and safety of fulranumab as monotherapy in patients with chronic knee pain of primary OA versus placebo and oxycodone treatment. Their data showed that the fulranumab group had better outcomes compared to the oxycodone group, but not to the placebo group. Neurological adverse events were higher in the fulranumab group than in the placebo group, but similar to the oxycodone group. More cases of TJRs were detected in the fulranumab group. Subsequently, Sanga et al54 demonstrated that long-term treatment with fulranumab was generally well tolerated and efficacious in patients with knee or hip OA.

Neurological adverse events and RPOA were more common in the fulranumab than in the placebo group. Dakin et al55 demonstrated that fasinumab provided improvements in OA pain and function, compared to placebo groups. Arthropathies, TRJs, and RPOA were more often observed in the fasinumab group. From these studies, it emerged that RPOA was associated with higher doses of anti-NGF antibodies used alone or with NSAIDs, although the underlying molecular mechanism is currently unknown. As reported by Wise et al,43 an adjudication was performed by independent committees of experts to understand the risks associated with the use of anti-NGF mAbs.56,57 The clinical trial development programs subsequently resumed using lower doses of anti-NGF mAbs (2.5 and 5 mg for tanezumab) in patients with painful knee or hip OA.12,58–71 Altogether, these studies indicate that anti-NGF mAbs represent a valuable biological therapy for OA pain, but some patients treated with the antibodies develop RPOA and neurological disorders. Unfortunately, the underlying molecular mechanisms have not been completely elucidated. It is possible that the inhibition of NGF signaling, via TrkA and p75 receptors on nociceptors, could compromise the loading signals of the joints, thus enhancing their degeneration.

Conclusions and Future Perspectives

Accumulating pieces of evidence have demonstrated that anti-NGF mAb therapy (ie fasinumab and tanezumab) ameliorates different chronic pain conditions, especially OA, CLBP, and neuropathic pain. Moreover, the analgesic efficacy of these anti-NGF antibodies is potentiated by the reduction of adverse effects associated with conventional pharmacological pain therapies (NSAIDs and opioids).72,73 Thus, anti-NGF mAb therapy could represent an alternative non-opioid therapeutic choice for pain management. Further studies are needed to understand the levels of analgesic effect, duration, immunogenicity, and potential adverse events of anti-NGF mAbs. Wtih regard to adverse events, in patients with large joint OA and treated with anti-NGF antibodies, RPOA and joint fractures have been reported. Thus, to ensure the safety of anti-NGF mAb treatment in these patients and others with chronic pain syndromes, it is necessary to set up new clinical studies focused on the identification of risk factors of patients with OA who manifest RPOA.

Disclosure

Sabrina Bimonte and Marco Cascella are co-first authors for this study. The authors report no conflicts of interest in this work.

References

1. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24(1):677–736. doi:10.1146/annurev.neuro.24.1.677

2. Aloe L, Montalcini Leva R. The discovery of nerve growth factor and modern neurobiology. Trends Cell Biol. 2004;14(7):395–399. doi:10.1016/j.tcb.2004.05.011

3. Lewin GR, Ritter AM, Mendell LM. Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. J Neurosci. 1993;13(5):2136–2148. doi:10.1523/JNEUROSCI.13-05-02136.1993

4. Mizumura K, Murase S. Role of nerve growth factor in pain. Handb Exp Pharmacol. 2015;227:57–77.

5. Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology. 2011;115(1):189–204. doi:10.1097/ALN.0b013e31821b1ac5

6. Lindsay RM, Harmar AJ. Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons. Nature. 1989;337(6205):362–364. doi:10.1038/337362a0

7. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413(6852):203–210. doi:10.1038/35093019

8. Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci. 2006;27(2):85–91. doi:10.1016/j.tips.2005.12.001

9. Watson JJ, Allen SJ, Dawbarn D. Targeting nerve growth factor in pain: what is the therapeutic potential? Bio Drugs. 2008;22(6):349–359.

10. Miller RE, Block JA, Malfait AM. Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models? Curr Opin Rheumatol. 2017;29(1):110–118. doi:10.1097/BOR.0000000000000354

11. Yeh JF, Akinci A, Al Shaker M, et al. Monoclonal antibodies for chronic pain: a practical review of mechanisms and clinical applications. Mol Pain. 2017;13:1744806917740233. doi:10.1177/1744806917740233

12. 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(16):1521–1531. doi:10.1056/NEJMoa0901510

13. Enomoto M, Mantyh PW, Murrell J, Innes JF, Lascelles BDX. Anti-nerve growth factor monoclonal antibodies for the control of pain in dogs and cats. Vet Rec. 2019;184(1):23. doi:10.1136/vr.104590

14. da Silva JT, Evangelista BG, Venega RAG, Seminowicz DA, Chacur M. Anti-NGF treatment can reduce chronic neuropathic pain by changing peripheral mediators and brain activity in rats. Behav Pharmacol. 2019;30(1):79–88. doi:10.1097/FBP.0000000000000422

15. Sabsovich I, Wei T, Guo TZ, et al. Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I. Pain. 2008;138(1):47–60. doi:10.1016/j.pain.2007.11.004

16. Khan N, Smith MT. Neurotrophins and neuropathic pain: role in pathobiology. Molecules. 2015;20(6):10657–10688. doi:10.3390/molecules200610657

17. Kumar V, Mahal BA. NGF – the TrkA to successful pain treatment. J Pain Res. 2012;5:279–287. doi:10.2147/JPR.S33408

18. Barker PA, Mantyh P, Arendt-Nielsen L, Viktrup L, Tive L. Nerve growth factor signaling and its contribution to pain. J Pain Res. 2020;26(13):1223–1241. doi:10.2147/JPR.S247472

19. 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. 2010;149(2):386–392. doi:10.1016/j.pain.2010.03.002

20. Flannery CR, Moran N, Blasioli D, et al. Efficacy of a novel, locally delivered TrkA inhibitor in preclinical models of OA and joint pain. Osteoarthritis Cartilage. 2015;23(Supplement 2):A26–81. doi:10.1016/j.joca.2015.02.100

21. Bryden LA, Nicholson JR, Doods H, Pekcec A. Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy. Osteoarthritis Cartilage. 2015;23(9):1605–1612. doi:10.1016/j.joca.2015.05.001

22. Ishikawa G, Koya Y, Tanaka H, Nagakura Y. Long-term analgesic effect of a single dose of anti-NGF antibody on pain during motion without notable suppression of joint edema and lesion in a rat model of osteoarthritis. Osteoarthritis Cartilage. 2015;23(6):925–932. doi:10.1016/j.joca.2015.02.002

23. Lascelles BD, Knazovicky D, Case B, et al. A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. BMC Vet Res. 2015;30(11):101. doi:10.1186/s12917-015-0413-x

24. Kc R, Li X, Kroin JS, et al. PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. Ann Rheum Dis. 2016;75(12):2133–2141. doi:10.1136/annrheumdis-2015-208444

25. Nwosu LN, Mapp PI, Chapman V, Walsh DA. Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis. Ann Rheum Dis. 2016;75(6):1246–1254. doi:10.1136/annrheumdis-2014-207203

26. LaBranche TP, Bendele AM, Omura BC, et al. Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model. Ann Rheum Dis. 2017;76(1):295–302. doi:10.1136/annrheumdis-2015-208913

27. Xu L, Nwosu LN, Burston JJ, et al. The anti-NGF antibody muMab 911 both prevents and reverses pain behaviour and subchondral osteoclast numbers in a rat model of osteoarthritis pain. Osteoarthritis Cartilage. 2016;24(9):1587–1595. doi:10.1016/j.joca.2016.05.015

28. Majuta LA, Guedon JG, Mitchell SAT, Ossipov MH, Mantyh PW. Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery-induced pain. Pain. 2017;158(4):605–617. doi:10.1097/j.pain.0000000000000799

29. Miyagi M, Ishikawa T, Kamoda H, et al. Efficacy of nerve growth factor antibody in a knee osteoarthritis pain model in mice. BMC Musculoskelet Disord. 2017;18(1):428. doi:10.1186/s12891-017-1792-x

30. von Loga IS, El-Turabi A, Jostins L, et al. Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis. Ann Rheum Dis. 2019;78(5):672–675. doi:10.1136/annrheumdis-2018-214489

31. Johnson EM Jr, Rich KM, Yip HK. The role of NGF in sensory neurons in vivo. Trends Neurosci. 1986;9:33–37. doi:10.1016/0166-2236(86)90012-3

32. Dai WL, Yan B, Bao YN, Fan JF, Liu JH. Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK/NF-κB signaling pathways. Cell Commun Signal. 2020;18(1):66. doi:10.1186/s12964-020-00556-3

33. Dos Reis RC, Kopruszinski CM, Nones CF, Chichorro JG. Nerve growth factor induces facial heat hyperalgesia and plays a role in trigeminal neuropathic pain in rats. Behav Pharmacol. 2016;27(6):528–535. doi:10.1097/FBP.0000000000000246

34. Sevcik MA, Ghilardi JR, Peters CM, et al. Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization. Pain. 2005;115(1–2):128–141. doi:10.1016/j.pain.2005.02.022

35. Halvorson KG, Kubota K, Sevcik MA, et al. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone. Cancer Res. 2005;65(20):9426–9435. doi:10.1158/0008-5472.CAN-05-0826

36. Mantyh WG, Jimenez-Andrade JM, Stake JI, et al. Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain. Neuroscience. 2010;171(2):588–598. doi:10.1016/j.neuroscience.2010.08.056

37. Ye Y, Dang D, Zhang J, et al. Nerve growth factor links oral cancer progression, pain, and cachexia. Mol Cancer Ther. 2011;10(9):1667–1676. doi:10.1158/1535-7163.MCT-11-0123

38. Jimenez-Andrade JM, Ghilardi JR, Castañeda-Corral G, Kuskowski MA, Mantyh PW. Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain. Pain. 2011;152(11):2564–2574. doi:10.1016/j.pain.2011.07.020

39. Sainoh T, Sakuma Y, Miyagi M, et al. Efficacy of anti-nerve growth factor therapy for discogenic neck pain in rats. Spine (Phila Pa 1976). 2014;39(13):E757–62. doi:10.1097/BRS.0000000000000340

40. Guedon JG, Longo G, Majuta LA, Thomspon ML, Fealk MN, Mantyh PW. Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain. Pain. 2016;157(6):1239–1247. doi:10.1097/j.pain.0000000000000514

41. Buehlmann D, Ielacqua GD, Xandry J, Rudin M. Prospective administration of anti-nerve growth factor treatment effectively suppresses functional connectivity alterations after cancer-induced bone pain in mice. Pain. 2019;160(1):151–159. doi:10.1097/j.pain.0000000000001388

42. Miyagi M, Ishikawa T, Kamoda H, et al. The efficacy of nerve growth factor antibody in a mouse model of neuropathic cancer pain. Exp Anim. 2016;65(4):337–343. doi:10.1538/expanim.16-0014

43. Wise BL, Seidel MF, Lane NE. The evolution of nerve growth factor inhibition in clinical medicine. Nat Rev Rheumatol. 2021;17(1):34–46. doi:10.1038/s41584-020-00528-4

44. Brown MT, Murphy FT, Radin DM, Davignon I, Smith MD, West CR. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J Pain. 2012;13(8):790–798. doi:10.1016/j.jpain.2012.05.006

45. Spierings ELH, Fidelholtz J, Wolfram G, Smith MD, Brown MT, West CR. A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee. Pain. 2013;154(9):1603–1612. doi:10.1016/j.pain.2013.04.035

46. Balanescu AR, Feist E, Wolfram G, et al. Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial. Ann Rheum Dis. 2014;73(9):1665–1672. doi:10.1136/annrheumdis-2012-203164

47. Ekman EF, Gimbel JS, Bello AE, et al. Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen. J Rheumatol. 2014;41(11):2249–2259. doi:10.3899/jrheum.131294

48. Schnitzer TJ, Ekman EF, Spierings ELH, et al. Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain. Ann Rheum Dis. 2015;74(6):1202–1211. doi:10.1136/annrheumdis-2013-204905

49. Birbara C, Dabezies EJ Jr, Burr AM, et al. Safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis. J Pain Res. 2018;8(11):151–164. doi:10.2147/JPR.S135257

50. Schnitzer TJ, Easton R, Pang S, et al. Effect of tanezumab on joint pain, physical function, and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee: a randomized clinical trial. JAMA. 2019;322(1):37–48. doi:10.1001/jama.2019.8044

51. Schnitzer TJ, Khan A, Bessette L, et al. Onset and maintenance of efficacy of subcutaneous tanezumab in patients with moderate to severe osteoarthritis of the knee or hip: a 16-Week Dose-Titration Study. Semin Arthritis Rheum. 2020;50(3):387–393. doi:10.1016/j.semarthrit.2020.03.004

52. Berenbaum F, Blanco FJ, Guermazi A, et al. Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period. Ann Rheum Dis. 2020;79(6):800–810. doi:10.1136/annrheumdis-2019-216296

53. 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 randomised, placebo- and active-controlled trial. Int J Clin Pract. 2016;70(6):493–505. doi:10.1111/ijcp.12807

54. 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. 2017;69(4):763–773. doi:10.1002/art.39943

55. Dakin P, DiMartino SJ, Gao H, et al. The efficacy, tolerability, and joint safety of fasinumab in osteoarthritis pain: a phase IIB/III double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheumatol. 2019;71(11):1824–1834. doi:10.1002/art.41012

56. Bannwarth B, Kostine M. Targeting nerve growth factor (NGF) for pain management: what does the future hold for NGF antagonists? Drugs. 2014;74(6):619–626. doi:10.1007/s40265-014-0208-6

57. Hochberg MC, Tive LA, Abramson SB, et al. When is osteonecrosis not osteonecrosis?: adjudication of reported serious adverse joint events in the tanezumab clinical development program. Arthritis Rheumatol. 2016;68(2):382–391. doi:10.1002/art.39492

58. Hochberg MC, Carrino J, Schnitzer T, et al. Subcutaneous tanezumab versus NSAID for the treatment of osteoarthritis: joint safety events in a randomized, double- blind, active- controlled, 80-week, phase-3 study. Arthritis Rheumatol. 2019;71:2756.

59. US National Library of Medicine. ClinicalTrials.gov; 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT02709486. Accessed June 11, 2021.

60. US National Library of Medicine. ClinicalTrials.gov; 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT02528188. Accessed June 11, 2021.

61. Rashad S, Hemingway A, Rainsford K, et al. Effect of non- steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet. 1989;2(8662):519–522. doi:10.1016/S0140-6736(89)90651-X

62. Chen MR, Dragoo JL. The effect of nonsteroidal anti- inflammatory drugs on tissue healing. Knee Surg Sports Traumatol Arthrosc. 2013;21(3):540–549. doi:10.1007/s00167-012-2095-2

63. 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(7):1009–1021. doi:10.1016/j.pain.2013.03.006

64. Gimbel JS, Kivitz AJ, Bramson C, et al. Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain. Pain. 2014;155(9):1793–1801.

65. Hochberg MC, Carrino J, Schnitzer T, et al. Verburg KM Subcutaneous tanezumab versus NSAID for the treatment of osteoarthritis: joint safety events in a randomized, double-blind, active-controlled, 80-week, phase-3 study [abstract]. Arthritis Rheumatol. 2019;71:2756.

66. US National Library of Medicine. ClinicalTrials.gov; 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT02709486. Accessed June 11, 2021.

67. Garber K, Aloe L. Fate of novel painkiller mAbs hangs in balance. Nat Biotechnol. 2011;29(3):173–174. doi:10.1038/nbt0311-173

68. US National Library of Medicine. ClinicalTrials.gov; 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT02528188. Accessed June 11, 2021.

69. 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(7):1009–1021.

70. Leite VF, Buehler AM, El Abd O, et al. Anti-nerve growth factor in the treatment of low back pain and radiculopathy: a systematic review and a meta-analysis. Pain Physician. 2014;17(1):E45–E60.

71. Karsdal MA, Verburg KM, West CR, et al. Serological biomarker profiles of rapidly progressive osteoarthritis in tanezumab- treated patients. Osteoarthritis Cartilage. 2019;27(3):484–492. doi:10.1016/j.joca.2018.12.001

72. Bimonte S, Cascella M, Schiavone V, Mehrabi-Kermani F, Cuomo A. The roles of epigallocatechin-3-gallate in the treatment of neuropathic pain: an update on preclinical in vivo studies and future perspectives. Drug Des Devel Ther. 2017;11:2737–2742. doi:10.2147/DDDT.S142475

73. Cuomo A, Bimonte S, Forte CA, Botti G, Cascella M. Multimodal approaches and tailored therapies for pain management: the trolley analgesic model. J Pain Res. 2019;19(12):711–714. doi:10.2147/JPR.S178910

TARRYTOWN, N.Y. and PARIS, June 25, 2021 /PRNewswire/ — 

Approval based on a Phase 3 trial demonstrating Libtayo significantly improved overall survival compared to chemotherapy in advanced NSCLC that included challenging-to-treat patient populations

Libtayo now approved by the European Commission for three advanced cancers

Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi today announced that the European Commission (EC) has approved the PD-1 inhibitor Libtayo® (cemiplimab) for the first-line treatment of adults with non-small cell lung cancer (NSCLC) whose tumor cells have ≥50% PD-L1 expression and no EGFR, ALK or ROS1 aberrations. Patients must have metastatic NSCLC or locally advanced NSCLC and not be a candidate for definitive chemoradiation.

Libtayo is now approved for three advanced cancers in the European Union. The EC also approved Libtayo in advanced basal cell carcinoma (BCC), the first treatment to be indicated for those patients who have progressed on or are intolerant to a hedgehog pathway inhibitor (HHI). In 2019, Libtayo was approved by the EC as the first treatment for adults with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation. Across all of its approved indications, Libtayo had a generally consistent safety profile. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue during or after treatment with Libtayo.

“Libtayo has demonstrated a highly significant improvement in overall survival compared to chemotherapy for patients with advanced non-small cell lung cancer with high PD-L1 expression and a variety of challenging-to-treat disease characteristics,” said Israel Lowy, M.D., Ph.D., Senior Vice President, Translational and Clinical Sciences, Oncology at Regeneron. “Beyond the primary analysis, we continue to conduct post-hoc analyses of our Phase 3 trial with the goal of informing treatment in this patient population.”

The EC approval in advanced NSCLC is based on data from a global Phase 3 trial that enrolled 710 patients from 24 countries. The trial, which was one of the largest for a PD-1 inhibitor in advanced NSCLC, was designed to be more reflective of clinical practice by including challenging-to-treat and often underrepresented disease characteristics. Among those enrolled, 12% had pre-treated and clinically stable brain metastases, 44% had squamous cell histology and 16% had locally advanced NSCLC that was not a candidate for definitive chemoradiation. Furthermore, patients whose disease progressed in the trial were able to change their therapy: those assigned to chemotherapy could crossover to Libtayo treatment, while those assigned to Libtayo monotherapy could continue Libtayo treatment and add four cycles of chemotherapy.

In the overall study population, Libtayo significantly reduced the risk of death by 32% and extended median overall survival (OS) by 8 months compared to chemotherapy, even with 74% of patients crossing over to Libtayo following disease progression on chemotherapy (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.53-0.87; p=0.0022). The median OS was 22 months for Libtayo (range: 18 months to not evaluable) and 14 months for chemotherapy (range: 12 to 19 months). A prespecified analysis of data from patients whose cancers had PD-L1 expression ≥50% (n=563) based on a validated assay was also conducted. As published in The Lancet, Libtayo reduced the risk of death by 43% for patients in this population; median OS was not reached for Libtayo (95% CI: 18 months to not evaluable) and was 14 months for chemotherapy (95% CI: 11 to 18 months).

In the Phase 3 trial, safety was assessed in 697 patients, with a duration of exposure of 27 weeks (range: 9 days to 115 weeks) for the Libtayo group and 18 weeks (range: 18 days to 87 weeks) for the chemotherapy group. Serious adverse reactions (AEs) in at least 2% of patients were pneumonia (5% Libtayo, 6% chemotherapy) and pneumonitis (2% Libtayo, 0% chemotherapy). Treatment was permanently discontinued due to AEs in 6% of Libtayo patients; AEs resulting in permanent discontinuation in at least 2 patients were pneumonitis, pneumonia, ischemic stroke and increased aspartate aminotransferase. No new Libtayo safety signals were observed.

“We are confident that Libtayo has the potential to become an important treatment option for patients in the European Union and thank all the investigators, patients and their families who helped us reach this milestone,” said Peter C. Adamson, M.D., Global Development Head, Oncology at Sanofi. “We are anticipating results from our ongoing Phase 3 trial of Libtayo plus chemotherapy in patients with advanced non-small cell lung cancer and remain committed to studying Libtayo in additional cancer settings where there is the potential to improve the outcome for patients.”

About the Phase 3 Trial in Advanced NSCLC
EMPOWER-Lung 1 was an open-label, randomized, multi-center Phase 3 trial designed to investigate Libtayo monotherapy compared to platinum-doublet chemotherapy as first-line treatment in patients with advanced NSCLC who tested positive for PD-L1 in ≥50% of tumor cells and had no EGFR, ALK or ROS1 aberrations. PD-L1 expression was confirmed using the Agilent Dako PD-L1 IHC 22C3 pharmDx kit.

The trial randomized 710 patients 1:1 who had either previously untreated metastatic NSCLC (stage IV) or locally advanced NSCLC (stage IIIB/C) who were not candidates for surgical resection or definitive chemoradiation or who had progressed after treatment with definitive chemoradiation. Those receiving Libtayo were intravenously administered a 350 mg dose every three weeks for up to 108 weeks, while those receiving chemotherapy received an investigator-selected, platinum-doublet chemotherapy regimen for four to six cycles (with or without maintenance pemetrexed chemotherapy).

The primary endpoints were OS and progression-free survival, and secondary endpoints included objective response rate, duration of response and quality of life. In 2020, the trial was stopped early due to a significant improvement in OS.

About Libtayo
Libtayo is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T-cells. By binding to PD-1, Libtayo has been shown to block cancer cells from using the PD-1 pathway to suppress T-cell activation.

The extensive clinical program for Libtayo is focused on difficult-to-treat cancers. Current clinical development programs include Libtayo in combination with chemotherapy for advanced NSCLC irrespective of PD-L1 expression and Libtayo monotherapy for advanced cervical cancer. Libtayo is also being investigated in combination with either conventional or novel therapeutic approaches for other solid tumors and blood cancers. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority.

The generic name for Libtayo in its approved U.S. indications is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA). Libtayo is being jointly developed by Regeneron and Sanofi under a global collaboration agreement.

About Regeneron’s VelocImmune® Technology
Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create approximately a quarter of all original, FDA-approved fully human monoclonal antibodies currently available. This includes REGEN–COV™ (casirivimab and imdevimab), Dupixent® (dupilumab), Libtayo® (cemiplimab-rwlc), Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab-dgnb) and Inmazeb™ (atoltivimab, maftivimab and odesivimab-ebgn).

IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. PATIENTS

What is Libtayo?
Libtayo is a prescription medicine used to treat people with a type of skin cancer called cutaneous squamous cell carcinoma (CSCC) that has spread or cannot be cured by surgery or radiation.

Libtayo is a prescription medicine used to treat people with a type of skin cancer called basal cell carcinoma that cannot be removed by surgery (locally advanced BCC) and have received treatment with an HHI, or cannot receive treatment with an HHI.

Libtayo is a prescription medicine used to treat people with a type of skin cancer called basal cell carcinoma that has spread (metastatic BCC) and have received treatment with a hedgehog pathway inhibitor (HHI), or cannot receive treatment with an HHI. This use is approved based on how many patients responded to treatment and how long they responded. Studies are ongoing to provide additional information about clinical benefit.

Libtayo is a prescription medicine used to treat people with a type of lung cancer called non-small cell lung cancer (NSCLC). Libtayo may be used as your first treatment when your lung cancer has not spread outside your chest (locally advanced lung cancer) and you cannot have surgery or chemotherapy with radiation, or your lung cancer has spread to other areas of your body (metastatic lung cancer), and your tumor tests positive for high “PD-L1” and your tumor does not have an abnormal “EGFR”, “ALK “or “ROS1” gene.

It is not known if Libtayo is safe and effective in children.

What is the most important information I should know about Libtayo?
Libtayo is a medicine that may treat certain cancers by working with your immune system. Libtayo can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:

• Lung problems: cough, shortness of breath, or chest pain
• Intestinal problems: diarrhea (loose stools) or more frequent bowel movements than usual, stools that are black, tarry, sticky or have blood or mucus, or severe stomach-area (abdomen) pain or tenderness
• Liver problems: yellowing of your skin or the whites of your eyes, severe nausea or vomiting, pain on the right side of your stomach area (abdomen), dark urine (tea colored), or bleeding or bruising more easily than normal
• Hormone gland problems: headache that will not go away or unusual headaches, eye sensitivity to light, eye problems, rapid heartbeat, increased sweating, extreme tiredness, weight gain or weight loss, feeling more hungry or thirsty than usual, urinating more often than usual, hair loss, feeling cold, constipation, your voice gets deeper, dizziness or fainting, or changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
• Kidney problems: decrease in your amount of urine, blood in your urine, swelling of your ankles, or loss of appetite
• Skin problems: rash, itching, skin blistering or peeling, painful sores or ulcers in mouth or nose, throat, or genital area, fever or flu-like symptoms, or swollen lymph nodes
• Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with Libtayo. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: chest pain, irregular heartbeat, shortness of breath or swelling of ankles, confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs, double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight, persistent or severe muscle pain or weakness, muscle cramps, low red blood cells, or bruising
• Infusion reactions that can sometimes be severe. Signs and symptoms of infusion reactions may include: nausea, chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness, feel like passing out, fever, back or neck pain, or facial swelling
• Rejection of a transplanted organ. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.
• Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with Libtayo. Your healthcare provider will monitor you for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with Libtayo. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with Libtayo if you have severe side effects.

Before you receive Libtayo, tell your healthcare provider about all your medical conditions, including if you:

• have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
• have received an organ transplant
• have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
• have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
• are pregnant or plan to become pregnant. Libtayo can harm your unborn baby

Females who are able to become pregnant:
– Your healthcare provider will give you a pregnancy test before you start treatment.
– You should use an effective method of birth control during your treatment and for at least 4 months after your last dose of Libtayo. Talk with your healthcare provider about birth control methods that you can use during this time.
– Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Libtayo.

• are breastfeeding or plan to breastfeed. It is not known if Libtayo passes into your breast milk. Do not breastfeed during treatment and for at least 4 months after the last dose of Libtayo.

Tell your healthcare provider about all the medicines you take, including prescription and over- the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Libtayo include muscle or bone pain, tiredness, rash, and diarrhea. These are not all the possible side effects of Libtayo. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Regeneron Pharmaceuticals and Sanofi at 1-877-542-8296.

Please see full Prescribing Information, including Medication Guide.

About Regeneron
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for over 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to nine FDA-approved treatments and numerous product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, hematologic conditions, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite technologies, such as VelocImmune, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.

For additional information about the company, please visit www.regeneron.com or follow @Regeneron on Twitter.

About Sanofi
Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.

With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.

Sanofi, Empowering Life

Regeneron Forward-Looking Statements and Use of Digital Media
This press release includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. (“Regeneron” or the “Company”), and actual events or results may differ materially from these forward-looking statements. Words such as “anticipate,” “expect,” “intend,” “plan,” “believe,” “seek,” “estimate,” variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the impact of SARS-CoV-2 (the virus that has caused the COVID-19 pandemic) on Regeneron’s business and its employees, collaborators, and suppliers and other third parties on which Regeneron relies, Regeneron’s and its collaborators’ ability to continue to conduct research and clinical programs, Regeneron’s ability to manage its supply chain, net product sales of products marketed or otherwise commercialized by Regeneron and/or its collaborators (collectively, “Regeneron’s Products”), and the global economy; the nature, timing, and possible success and therapeutic applications of Regeneron’s Products and product candidates being developed by Regeneron and/or its collaborators (collectively, “Regeneron’s Product Candidates”) and research and clinical programs now underway or planned, including without limitation Libtayo® (cemiplimab) for the treatment of non-small cell lung cancer (“NSCLC”); uncertainty of the utilization, market acceptance, and commercial success of Regeneron’s Products (such as Libtayo) and Regeneron’s Product Candidates and the impact of studies (whether conducted by Regeneron or others and whether mandated or voluntary), including the study discussed in this press release, on any of the foregoing; the likelihood, timing, and scope of possible regulatory approval and commercial launch of Regeneron’s Product Candidates and new indications for Regeneron’s Products, such as possible regulatory approval of Libtayo in combination with chemotherapy for advanced NSCLC irrespective of PD-L1 expression and as monotherapy for advanced cervical cancer (as well as in combination with either conventional or novel therapeutic approaches for both solid tumors and blood cancers); the ability of Regeneron’s collaborators, suppliers, or other third parties (as applicable) to perform manufacturing, filling, finishing, packaging, labeling, distribution, and other steps related to Regeneron’s Products and Regeneron’s Product Candidates; the ability of Regeneron to manufacture and manage supply chains for multiple products and product candidates; safety issues resulting from the administration of Regeneron’s Products (such as Libtayo) and Regeneron’s Product Candidates in patients, including serious complications or side effects in connection with the use of Regeneron’s Products and Regeneron’s Product Candidates in clinical trials; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron’s ability to continue to develop or commercialize Regeneron’s Products and Regeneron’s Product Candidates, including without limitation Libtayo; ongoing regulatory obligations and oversight impacting Regeneron’s Products, research and clinical programs, and business, including those relating to patient privacy; the availability and extent of reimbursement of Regeneron’s Products from third-party payers, including private payer healthcare and insurance programs, health maintenance organizations, pharmacy benefit management companies, and government programs such as Medicare and Medicaid; coverage and reimbursement determinations by such payers and new policies and procedures adopted by such payers; competing drugs and product candidates that may be superior to, or more cost effective than, Regeneron’s Products and Regeneron’s Product Candidates; the extent to which the results from the research and development programs conducted by Regeneron and/or its collaborators may be replicated in other studies and/or lead to advancement of product candidates to clinical trials, therapeutic applications, or regulatory approval; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its financial projections or guidance and changes to the assumptions underlying those projections or guidance; the potential for any license, collaboration, or supply agreement, including Regeneron’s agreements with Sanofi, Bayer, and Teva Pharmaceutical Industries Ltd. (or their respective affiliated companies, as applicable), to be cancelled or terminated; and risks associated with intellectual property of other parties and pending or future litigation relating thereto (including without limitation the patent litigation and other related proceedings relating to EYLEA® (aflibercept) Injection, Dupixent® (dupilumab), Praluent® (alirocumab), and REGEN-COV™ (casirivimab and imdevimab)), other litigation and other proceedings and government investigations relating to the Company and/or its operations, the ultimate outcome of any such proceedings and investigations, and the impact any of the foregoing may have on Regeneron’s business, prospects, operating results, and financial condition. A more complete description of these and other material risks can be found in Regeneron’s filings with the U.S. Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2020 and its Form 10-Q for the quarterly period ended March 31, 2021. Any forward-looking statements are made based on management’s current beliefs and judgment, and the reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update (publicly or otherwise) any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise.

Regeneron uses its media and investor relations website and social media outlets to publish important information about the Company, including information that may be deemed material to investors. Financial and other information about Regeneron is routinely posted and is accessible on Regeneron’s media and investor relations website (http://newsroom.regeneron.com) and its Twitter feed (http://twitter.com/regeneron).

Sanofi Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include projections and estimates regarding the marketing and other potential of the product, or regarding potential future revenues from the product. Forward-looking statements are generally identified by the words “expects”, “anticipates”, “believes”, “intends”, “estimates”, “plans” and similar expressions. Although Sanofi’s management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, unexpected regulatory actions or delays, or government regulation generally, that could affect the availability or commercial potential of the product, the fact that product may not be commercially successful, the uncertainties inherent in research and development, including future clinical data and analysis of existing clinical data relating to the product, including post marketing, unexpected safety, quality or manufacturing issues, competition in general, risks associated with intellectual property and any related future litigation and the ultimate outcome of such litigation, and volatile economic and market conditions, and the impact that COVID-19 will have on us, our customers, suppliers, vendors, and other business partners, and the financial condition of any one of them, as well as on our employees and on the global economy as a whole.  Any material effect of COVID-19 on any of the foregoing could also adversely impact us. This situation is changing rapidly and additional impacts may arise of which we are not currently aware and may exacerbate other previously identified risks. The risks and uncertainties also include the uncertainties discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in Sanofi’s annual report on Form 20-F for the year ended December 31, 2020. Other than as required by applicable law, Sanofi does not undertake any obligation to update or revise any forward-looking information or statements.

SOURCE Regeneron Pharmaceuticals, Inc.

Related Links

www.regeneron.com