Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma

Abstract

Background: Conjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo.

Objective: The objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma.

Methods: We evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo.

Results: In ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation.

Conclusions: Dupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug-disease interaction. CLINICALTRIALS.

Gov identifiers: NCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb).

Conflict of interest statement

Ashish Bansal, Zhen Chen, Mohamed A. Kamal, Brad Shumel, Paola Mina-Osorio, Neil M. H. Graham, Faisal A. Khokhar, and Marius Ardeleanu are employees and shareholders of Regeneron Pharmaceuticals, Inc. Eric L. Simpson reports grants from AbbVie, Celgene, Eli Lilly, Galderma, Kyowa Hakko Kirin, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Tioga; and personal fees from AbbVie, Boehringer-Ingelheim, Dermavant, Dermira, Eli Lilly, Forte Bio, Incyte, LEO Pharma, MedImmune, Menlo Therapeutics, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron Pharmaceuticals, Inc., Sanofi, and Valeant. Amy S. Paller has served as a scientific adviser and/or clinical study investigator for Almirall, Amgen, Asana, Boehringer-Ingelheim, Castle Creek, Celgene, Dermavant, Dermira, Eli Lilly, Forte, Galderma, Incyte, Janssen, Lenus, LEO Pharma, Life Max, MEDACorp, Meiji Sieka, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, Sol Gel, and Verrica. Elaine C. Siegfried has served as a scientific adviser and/or clinical study investigator for Eli Lilly, Janssen, Novartis, Novan, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, UCB Pharma, and Verrica; as a paid speaker for Regeneron Pharmaceuticals, Inc.; and as a DSMB member for GSK, LEO Pharma, Novan, Pfizer, and UCB. Andrew Blauvelt has served as a scientific adviser and/or clinical study investigator for AbbVie, Aclaris, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly and Company, Forte, Galderma, Janssen, LEO Pharma, Novartis, Ortho, Pfizer, Rapt, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi Genzyme, Sun Pharma, and UCB Pharma; and as a paid speaker for AbbVie. Marjolein de Bruin-Weller has served as a principal investigator, consultant, and advisory board member for AbbVie; principal investigator, advisory board member, and consultant for Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme; an advisory board member and consultant for Eli Lilly; a principal investigator, consultant, and advisory board member for LEO Pharma; a principal investigator, consultant, and advisory board member for Pfizer; and an advisory board member for UCB. Jonathan Corren has served as a speaker for AstraZeneca, Genentech, Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi; has received consulting fees from AstraZeneca, Genentech, Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi; has received research funds from AstraZeneca, Genentech, Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi; and has served as an advisory board member for AstraZeneca, Genentech, Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi. Lawrence Sher has served as an advisory board member for Aimmune, Optinose, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; as a speaker for Aimmune, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; and as a principal investigator for Aimmune, Amgen, AstraZeneca, Circassia, DBV Technologies, Galderma, GSK, Merck, Mylan, Novartis, Optinose, Pearl, Pfizer, Sanofi, and Teva; and has received grants from Glenmark, Genzyme, and Sanofi Genzyme. Emma Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, AstraZeneca, Boehringer-Ingelheim, Celgene, Dermavant, DS Biopharma, Eli Lilly, Galderma, Glenmark/Ichnos Sciences, Innovaderm, Janssen, Kiniska, Kyowa Kirin, LEO Pharma, Novan, Novartis, Pfizer, Ralexar, Regeneron Pharmaceuticals, Inc., Sienna Biopharma, UCB, and Union Therapeutics/Antibiotx; and is a consultant for AbbVie, Aditum Bio, Almirall, Alpine, Amgen, Arena, Asana Biosciences, AstraZeneca, Bluefin Biomedicine, Boehringer-Ingelheim, Boston Pharmaceuticals, Botanix, Bristol-Myers Squibb, Cara Therapeutics, Celgene, Clinical Outcome Solutions, DBV, Dermavent, Dermira, Douglas Pharmaceutical, DS Biopharma, Eli Lilly, EMD Serono, Evelo Bioscience, Evidera, FIDE, Galderma, GSK, Haus Bioceuticals, Ichnos Sciences, Incyte, Kyowa Kirin, Larrk Bio, LEO Pharma, Medicxi, Medscape, Neuralstem, Noble Insights, Novan, Novartix, Okava Pharmaceuticals, Pandion Therapeutics, Pfizer, Principia Biopharma, RAPT Therapeutics, Realm, Regeneron Pharmaceuticals, Inc., Sanofi, SATO Pharmaceutical, Sienna Biopharma, Seanegy Dermatology, Seelos Therapeutics, Serpin Pharma, Siolta Therapeutics, Sonoma Biotherapeutics, Sun Pharma, Target PharmaSolutions and Union Therapeutics/AntibioTx, Vanda Pharmaceuticals, Ventyx Biosciences, and Vimalan. Nadia Daizadeh, Leda Mannent, and Naimish Patel are employees of and may hold stock and/or stock options in Sanofi.

Figures

Fig. 1

Time to first conjunctivitis event, and exposure–response relationship. a Time to first conjunctivitis event in ADOL. b Relationship between exposure and risk of developing conjunctivitis in ADOL: logistic regression relating probability of developing conjunctivitis with dupilumab trough concentration at week 16. The mean regression line is blue, and the confidence interval around the regression line is represented by the gray area. Patients without any conjunctivitis events are shown at the bottom of the figure and those with one or more conjunctivitis event are shown at the top of the figure; the open green circles (300 mg q4w) and open red squares (200/300 mg q2w) are offset so that each circle/square can be seen. The y-axis represents the probability of a patient reporting one or more conjunctivitis event. Means of response variables (open black circles) and confidence intervals (green vertical lines) around the means are presented in the figures by quartile of exposure. c Time to first conjunctivitis event in PED-OLE. Time to onset of first conjunctivitis event was based on the compiled overall conjunctivitis definition that included all component MedDRA PTs [conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial, conjunctivitis viral, conjunctivitis adenoviral, and atopic keratoconjunctivitis]. “Censored” (i.e., vertical crossbars) refers to patients in the overall population who discontinued from the study. MedDRA Medical Dictionary for Regulatory Activities, PT MedDRA Preferred Term, qw once weekly, q2w every 2 weeks, q4w every 4 weeks