PowerPoint Presentation Poster #12797Safety of long-term proactive management with fixed-dose combination calcipotriene 0.005% and betamethasone dipropionate 0.064% foam in patients with psoriasis vulgaris: results of a Phase III, multicentre, randomized, 52-week, vehicle-controlled trial Mark Lebwohl1, Jean-Philippe Lacour2, Monika Liljedahl3, Charles Lynde4,5, Marie Holst Mørch3, Diamant Thaçi6 and Richard B Warren7 1Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Department of Dermatology, University Hospital of Nice, Nice, France; 3LEO Pharma A/S, Ballerup, Denmark; 4Lynde Dermatology, Probity Medical Research, Markham, ON, Canada; 5Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany; 7Dermatology Centre, Salford Royal NHS Foundation Trust and NIHR Biomedical Research Centre, University of Manchester, Manchester, UK Materials and Methods Introduction  Topical therapies are considered first-line treatment for psoriasis,1 however maintaining long-term disease control is a challenge, with many patients untreated or undertreated.2 Current topical psoriasis treatment relies on a reactive approach to disease flares, as opposed to a more long-term proactive approach.3  Data supporting the efficacy and safety of calcipotriene 0.005% and betamethasone dipropionate 0.064% (Cal/BD) foam approved as a reactive treatment are available from trials of 4- and 12-weeks duration in patients with psoriasis vulgaris (plaque psoriasis).4,5,6,7  Here, we report the safety of Cal/BD foam for the long-term proactive management of psoriasis over 52 weeks (NCT02899962). Data from the open-label lead-in phase of this trial are presented in poster #16830. Presented at AAD Annual Meeting 2020, Denver, Colorado, USA, March 20–24, 2020 References 1. Feldman, et al. Am Health Drugs Benefits. 2016:9;504‒513; 2. Armstrong, et al. JAMA Dermatol. 2013:149;1180‒1185; 3. Bonnekoh, et al. EMJ Dermatol. 2017:5;36‒43; 4. EMC. Enstilar Summary of Product Characteristics 2018; 5. FDA. Enstilar - Prescribing Information 2019; 6. Paul, et al. J Eur Acad Dermatol Venereol. 2017:31;119‒126; 7. Koo, et al. J Dermatolog Treat. 2016:27;120‒127 Acknowledgements The authors thank the investigators and patients who participated in this trial. The authors would like to thank Lauren Whyte, PhD, a freelance Medical Writer contracted by Ashfield Healthcare Communications, part of UDG Healthcare plc, for medical writing support, funded by LEO Pharma in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Disclosures All authors met the ICMJE authorship criteria and had full access to the relevant data. Neither honoraria nor payments were made for authorship. ML, J-PL, DT, RBW, CL have consulted for, conducted studies funded by, or received honoraria for services provided to LEO Pharma; ML, MHM are employees of LEO Pharma. Fixed-dose combination calcipotriene (Cal) 0.005%/betamethasone dipropionate (BD) 0.064% aerosol foam is approved for the treatment of psoriasis vulgaris (plaque psoriasis) for up to 4 weeks in adults (under the trade name Enstilar® in the US and Enstilar® or Enstilum® in the EU). Cal/BD foam is also approved in the US for adolescents 12–18 years. Funding This study was funded by LEO Pharma. Safety objectives and endpoints  To evaluate the long-term safety of proactive management with Cal/BD foam (up to 52 weeks) in patients with psoriasis. Safety endpoints included: ─ Adverse events (AEs) associated with long-term corticosteroid use. ─ Incidence of rebound (see table 3 for definition). ─ Effect on calcium metabolism based on serum/urinary calcium. ─ Effect on HPA-axis based on serum cortisol.  This Phase III, multicenter trial included a 4-week open-label lead-in phase in adult patients with: ─ Trunk and/or limb psoriasis, involving 2–30% of body surface area (BSA); physician’s global assessment (PGA) of disease severity ≥’mild’; modified psoriasis area and severity index (m- PASI) ≥2.  Following the open-label lead-in phase, patients with treatment success (PGA score of ‘clear’ or ‘almost clear’ [PGA<2] with at least a 2-grade improvement from baseline) were randomized to the 52-week double-blind, vehicle-controlled maintenance phase.  The trial included a subgroup of patients at assigned sites who underwent hypothalamic pituitary adrenal (HPA) testing. The HPA-axis group was required to have more severe disease: ─ At least ‘moderate’ psoriasis, affecting 10–30% BSA and normal adrenal function at baseline. Results Patient population  545 patients were randomized (safety analysis set [SAS]; proactive n=272; reactive n=273). 251 (46.1%) patients completed the trial. Mean age was 52.2 years; 91% patients were white and 68% were male. AEs during maintenance phase Table 1. Overview of AEs AEs adjudicated as associated with long-term corticosteroid use in maintenance phase  Chorioretinopathy in one patient: severe intensity, onset on Day 310, considered possibly related to treatment by investigator, led to withdrawal of treatment [proactive].  Pain of skin in one patient: moderate intensity, onset on Day 73, not considered related to treatment by investigator, no action taken with treatment [proactive].  Application site pain in one patient: 3 events of mild intensity, onset on Days 1, 12 and 20, considered probably related to treatment by investigator, no action taken with treatment [reactive]. Rebound Other safety results  No consistent changes or differences in serum or urinary calcium between the two treatment groups. ─ No difference in the number of patients moving from low or normal to high calcium or from normal or high to low calcium in either serum or urine. Most patients had levels that remained stable over time. ─ No clinically significant abnormalities in calcium metabolism were observed.  In the HPA-axis group, no patient had serum cortisol ≤18 µg/dL at both 30 and 60 min after ACTH challenge. 1Considered possibly or probably related to trial product by the investigator Conclusions  Proactive management with Cal/BD foam was well tolerated, with a favorable safety profile over the extended treatment period that was similar to the vehicle-controlled reactive treatment group.  Proactive management with Cal/BD foam had no clinically significant effects on the HPA-axis or calcium metabolism. Table 3. Summary of rebounds* Trial design and treatments Table 2. Rate of AEs per 100 patient-years Double-blind treatment  ‘Proactive’ management was treatment with Cal/BD foam twice-weekly for 52 weeks when in remission.  ‘Reactive’ management was treatment with vehicle foam twice-weekly for 52 weeks when in remission.  Relapse: PGA≥2 [either previously treated and/or new skin area]). Flare medication (as separate flare bottles) was Cal/BD foam once-daily for 4 weeks for both the proactive and reactive management groups (Figure 1). Primary objective  Efficacy objectives, endpoints and data are presented in poster #18223. *Rebound defined as i) m-PASI ≥12 AND increase from baseline in m-PASI ≥125% or ii) development of more inflammatory disease within 2 months after discontinuation of open-label, maintenance or flare medication. Most frequently reported AEs  AEs reported in >5% of patients: nasopharyngitis (8.1% proactive vs 7.0% reactive) and upper respiratory tract infection (5.9% vs 5.5%); all were considered not related to trial product by the investigator. AE category Proactive (N=272) Reactive (N=273) Number of AEs Number (%) of patients Number of AEs Number (%) of patients All AEs 303 133 (48.9) 279 130 (47.6) Serious AEs 15 14 (5.1) 14 11 (4.0) Treatment- related AEs1 5 5 (1.8) 8 7 (2.6) AEs leading to withdrawal 2 2 (0.7) 1 1 (0.4) Severe AEs 8 8 (2.9) 15 14 (5.1) Number of rebounds within 2 months Proactive (N=272) Reactive (N=273) After discontinuation of open-label treatment 6 7 After discontinuation of relapse treatment 4 17 After discontinuation of proactive management 0 1 Proactive (N=272) Reactive (N=273) AEs per 100 patient-years 168.6 158.4 Serious AEs per 100 patient-years 8.3 7.9 Treatment-related AEs per 100 patient-years 2.8 4.5 Figure 1. Trial design Screening & washout (up to 4 weeks) Maintenance phase Follow- up for 8 weeks 1 0 2 4 3 8 4 12 5 16 6 20 7 24 8 28 9 32 10 36 11 40 12 44 13 48 14 52 15 56 FU1 58 FU2 60 FU3 64 Visit Week Cal/BD foam once daily for 4 weeks* Relapse (PGA ≥2) 1:1 RandomizationBaseline End of maintenance phase Follow-up for rebound Adults with plaque psoriasis * Success following 4 weeks of once daily flare medication was defined as PGA<2 (‘clear [0]’ or ‘almost clear’ [1]) ** Patients re-started the twice-weekly maintenance according to the original randomization scheme. PGA<2** PGA ≥2 Withdrawn Open-label lead-in phase Cal/BD foam daily for 4 weeks Proactive management: Cal/BD foam twice weekly for 52 weeks Reactive management: vehicle foam twice weekly for 52 weeks  One patient in each group had an AE of pigmentation disorder considered possibly related to trial product by the investigator. No AEs of skin atrophy were reported. Figure 2. Patient disposition Entered open-label lead-in phase (n=650) Discontinued (n=105) • Adverse event (n=2); Lost to follow-up (n=9); W ithdrawal by patient (n=11); Lack of efficacy (n=4); Patient did not achieve treatment success at end of open-label lead-in phase (n=68); Failed screening (n=1); Other (n=10) Proactive management (n=272 SAS [n=256 FAS]) Reactive management (n=273 SAS [n=265 FAS]) Completed the trial (n=251 SAS [n=246 FAS]) Discontinued (n=141 SAS) • Adverse event (n=2); Lost to follow-up (n=12); W ithdrawal by patient (n=30); Lack of efficacy (n=20); Patient did not achieve treatment success after open-label lead-in phase (n=3); Other (n=9); Patient not clear or almost clear (PGA<2) after treatment of relapse (n=65). Discontinued (n=153 SAS) • Adverse event (n=1); Death (n=1); Lost to follow-up (n=14); W ithdrawal by patient (n=36); Lack of efficacy (n=16); Patient did not achieve treatment success after open-label lead-in phase (n=2); Other (n=13); Patient not clear or almost clear (PGA<2) after treatment of relapse (n=70). Experienced at least one relapse (n=210 FAS) Experienced at least one relapse (n=237 FAS) Randomized into maintenance phase (n=545 SAS [n=521 FAS]) Randomized in error* (n=24 [16 proactive and 8 reactive]) Completed (n=5) Discontinued (n=19) *excluded from full analysis set (FAS) The safety analysis set (SAS) included all patients exposed to Cal/BD foam or vehicle foam following randomization. The FAS included all randomized patients who had treatment success at randomization. Slide Number 1