TNF-α inhibitor tanfanercept (HBM9036) improves signs and symptoms of dry eye in a phase 2 trial in the controlled adverse environment in China
Yanling Dong, Shuang Wang, Lin Cong, Ting Zhang, Jun Cheng, Nannan Yang, Xiaohong Qu, Dongfang Li, Xueying Zhou, Holly Wang, Michael Lee, Meng Wang, Stephen Chen, George W Ousler, Xiaoxiang Chen, Lixin Xie, Yanling Dong, Shuang Wang, Lin Cong, Ting Zhang, Jun Cheng, Nannan Yang, Xiaohong Qu, Dongfang Li, Xueying Zhou, Holly Wang, Michael Lee, Meng Wang, Stephen Chen, George W Ousler, Xiaoxiang Chen, Lixin Xie
Abstract
Purpose: This study evaluated the clinical safety and efficacy of tanfanercept (HBM9036) ophthalmic solution as a novel treatment for dry eye disease (DED) in a controlled adverse environment (CAE) study conducted in China.
Methods: In a single-center, double-masked, randomized, placebo-controlled study, 100 patients received 0.25% tanfanercept, or placebo, twice daily for eight weeks. A mobile international CAE® DE Model was used for patient selection with a standardized challenge endpoint. Primary efficacy endpoint was fluorescein inferior corneal staining score (ICSS) pre- to post-CAE challenge from baseline. Secondary endpoints included Schirmer's Tear Test, Tear-Film Break-Up Time, Ocular Discomfort Score, Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire, total corneal staining score (TCSS), and drop comfort. Signs and symptoms were assessed both pre- and post-CAE to evaluate the efficacy of tanfanercept on both environmental and CAE endpoints.
Results: The tanfanercept treatment group showed improvement in ICSS pre- to post-CAE change from baseline scores when compared to placebo (- 0.61 ± 0.11 and - 0.54 ± 0.11, respectively; mean difference = 0.07, p = 0.65). TCSS pre-post-CAE change from baseline scores was also in favor of active when compared to placebo (- 1.03 ± 0.21 and - 0.67 ± 0.21, respectively; mean difference = 0.37, p = 0.23). Schirmer's score improvement was demonstrated in favor of active (1.87 ± 0.62 mm) as compared to placebo (1.28 ± 0.62 mm; mean difference = 0.59 mm, p = 0.50). Change from baseline in mean Tear-Film Break-up Time favored active treatment over placebo (mean difference = 1.21 s, p = 0.45). Notably, the tanfanercept showed more obvious benefits for each DED sign in a subgroup of subjects ≥ 35 years of age. Tanfanercept was well tolerated with no serious adverse events occurring during the study.
Conclusion: Tanfanercept demonstrated improvements in favor of active as compared to placebo in the signs of DED, being safe and well tolerated. These data support further evaluation of tanfanercept for the treatment of DED in China.
Trial registration: This study was retrospectively registered at ClinicalTrials.gov (NCT04092907) on September 17, 2019.
Keywords: Controlled adverse environment; Dry eye disease; TNF-TNFR1 inhibitor; Tanfanercept.
Conflict of interest statement
All authors declare that they have no conflict of interest.
© 2022. The Author(s).
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References
- Song P, Xia W, Wang M, Chang X, Wang J, Jin S, Wang J, Wei W, Rudan I. Variations of dry eye disease prevalence by age, sex and geographic characteristics in China: a systematic review and meta-analysis. J Glob Health. 2018;8(2):020503. doi: 10.7189/jogh.08.020503.
- Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the physicians' health studies. Arch Ophthalmol. 2009;127(6):763–768. doi: 10.1001/archophthalmol.2009.103.
- Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136(2):318–326. doi: 10.1016/s0002-9394(03)00218-6.
- Schaumberg DA, Sullivan DA, Dana MR. Epidemiology of dry eye syndrome. Adv Exp Med Biol. 2002;506(Pt B):989–998. doi: 10.1007/978-1-4615-0717-8_140.
- Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol. 2001;45(Suppl 2):S199–202. doi: 10.1016/s0039-6257(00)00202-2.
- Mah F, Milner M, Yiu S, Donnenfeld E, Conway TM, Hollander DA. PERSIST: physician's evaluation of restasis [(R)] satisfaction in second trial of topical cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review. Clin Ophthalmol. 2012;6:1971–1976. doi: 10.2147/OPTH.S30261.
- Tauber J, Karpecki P, Latkany R, Luchs J, Martel J, Sall K, Raychaudhuri A, Smith V, Semba CP, OPUS-2 Investigators Lifitegrast ophthalmic solution 50% versus placebo for treatment of dry eye disease: results of the randomized phase III OPUS-2 study. Ophthalmology. 2015;122(12):2423–2431. doi: 10.1016/j.ophtha.2015.08.001.
- Mandal A, Gote V, Pal D, Ogundele A, Mitra AK. Ocular pharmacokinetics of a topical ophthalmic nanomicellar solution of cyclosporine [Cequa(R)] for dry eye disease. Pharm Res. 2019;36(2):36. doi: 10.1007/s11095-018-2556-5.
- Albertsmeyer AC, Kakkassery V, Spurr-Michaud S, Beeks O, Gipson IK. Effect of pro-inflammatory mediators on membrane-associated mucins expressed by human ocular surface epithelial cells. Exp Eye Res. 2010;90(3):444–451. doi: 10.1016/j.exer.2009.12.009.
- Massingale ML, Li X, Vallabhajosyula M, Chen D, Wei Y, Asbell PA. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea. 2009;28(9):1023–1027. doi: 10.1097/ICO.0b013e3181a16578.
- Zoukhri D, Hodges RR, Byon D, Kublin CL. Role of proinflammatory cytokines in the impaired lacrimation associated with autoimmune xerophthalmia. Invest Ophthalmol Vis Sci. 2002;43(5):1429–1436.
- Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296(5573):1634–1635. doi: 10.1126/science.1071924.
- Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants-past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453–472. doi: 10.1016/j.cytogfr.2014.07.016.
- Allansmith M, de Ramus A, Maurice D. The dynamics of IgG in the cornea. Investig Ophthalmol Vis Sci. 1979;18(9):947–955.
- Lee HB, Choi HJ, Cho SM, Kang S, Ahn HK, Song YJ, Kim YJ, Son WC. Efficacy of HL036 versus cyclosporine a in the treatment of naturally occurring canine keratoconjunctivitis sicca. Curr Eye Res. 2018;43(7):889–895. doi: 10.1080/02713683.2018.1461909.
- Ousler GW, Gomes PJ, Welch D, Abelson MB. Methodologies for the study of ocular surface disease. Ocul Surf. 2005;3(3):143–154. doi: 10.1016/s1542-0124(12)70196-9.
- Ousler GW, 3rd, Rimmer D, Smith LM, Abelson MB. Use of the controlled adverse environment (CAE) in clinical research: a review. Ophthalmol Ther. 2017;6(2):263–276. doi: 10.1007/s40123-017-0110-x.
- Bond MR, Pilowsky I. Subjective assessment of pain and its relationship to the administration of analgesics in patients with advanced cancer. J Psychosom Res. 1966;10:203–208. doi: 10.1016/0022-3999(66)90064-X.
- Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the ocular surface disease index. Arch Ophthalmol. 2000;118(5):615–621. doi: 10.1001/archopht.118.5.615.
- Gong L, Sun X, Ma Z, Wang Q, Xu X, Chen X, Shao Y, Yao K, Tang L, Gu Y, Yuan H, Chua WH, Chuan JC, Tong L. A randomised, parallel-group comparison study of diquafosol ophthalmic solution in patients with dry eye in China and Singapore. Br J Ophthalmol. 2015;99(7):903–908. doi: 10.1136/bjophthalmol-2014-306084.
- Sall K, Stevenson OD, Mundorf TK, Reis BL, CsA Phase 3 Study Group Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology. 2000;107(4):631–639. doi: 10.1016/s0161-6420(99)00176-1.
- Tsubota K, Ashell P, Dogru M, Fonn D, Foulks G, Schaumberg D, Schein O, Watanabe H. Design and conduct of clinical trials: report of the clinical trials subcommittee of the international dry eye workshop. Ocul Surf. 2007;5(2):153–162. doi: 10.1016/s1542-0124(12)70084-8.
- Pepose JS, Qazi MA, Devries DK. Longitudinal changes in dry eye symptoms and signs following lifitegrast therapy and relationship to tear osmolarity. Clin Ophthalmol. 2019;13:571–579. doi: 10.2147/OPTH.S196593.
Source: PubMed