Oral orismilast: Efficacy and safety in moderate‐to‐severe psoriasis and development of modified release tablets

Abstract

Background Orismilast is a high‐potency phosphodiesterase 4 (PDE4) inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes. Objectives The objective of this phase 2a trial was to examine the efficacy and safety of orismilast for psoriasis using a first‐generation immediate‐release (IR) formulation. The objective of the subsequent phase 1 trial was to test new formulations designed to minimize the gastrointestinal (GI)‐related adverse events (AEs) observed with the first‐generation IR formulation. We examined the following: (1) pharmacokinetic (PK) properties of orismilast modified release (MR) and IR, (2) food effects on PK properties of orismilast MR or IR, (3) safety of orismilast MR compared to placebo. Methods In a phase 2a prospective, randomized, double‐blind, placebo‐controlled trial, patients with moderate‐to‐severe psoriasis were randomized to receive 30 mg oral orismilast IR or placebo over 16 weeks. The single‐site phase 1 trial consisted of three parts: (1) participants received a single 30 mg dose of orismilast MR and IR (open‐label), (2) participants received 30 mg orismilast MR or IR under either fasting condition, following a high‐fat meal or low‐fat meal (open‐label) and (3) participants received up to 60 mg orismilast MR twice‐daily or a placebo for 17 days (double‐blind). Results In the phase 2a trial, treatment with orismilast IR significantly improved the mean Psoriasis Area Severity Index score at week 16 compared to placebo. The phase 1 trial revealed comparable PK properties of the orismilast MR and IR formulations, with participants in the orismilast MR group experiencing fewer GI‐related AEs than those receiving orismilast IR (16.7% vs. 33.3%). Conclusion Orismilast IR displayed higher efficacy compared to placebo in patients with moderate‐to‐severe psoriasis at week 16. Orismilast MR had similar PK properties and fewer GI disorders compared to the IR formulation in healthy participants. Future development of orismilast will be based on the MR formulation.

New and Emerging Oral/Topical Small-Molecule Treatments for Psoriasis

“…Apremilast was the first PDE4 inhibitor approved for the treatment of psoriasis in 2014 [ 56 ]. Roflumilast, another PDE4 inhibitor initially approved for chronic obstructive pulmonary disease with available generics, has also demonstrated its efficacy in the treatment of psoriasis in an investigator-initiated clinical trial [ 57 ], and new oral PDE4 inhibitors are being developed, such as orismilast [ 58 ], Hemay005 (mufemilast), and ME3183 [ 59 ].…”

“…Orismilast is a potent oral PDE4 inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes. A randomized, double-blind, placebo-controlled phase IIa trial involved 36 patients with moderate to severe psoriasis, randomly assigned to receive either placebo or orismilast 30 mg BID [ 58 ]. By week 16, 44.4% of patients receiving orismilast achieved PASI75, versus 5.6% in the placebo group.…”

“…By week 16, 44.4% of patients receiving orismilast achieved PASI75, versus 5.6% in the placebo group. The predominant AE reported in the orismilast group included nausea and diarrhea [ 58 ]. Subsequently, a phase IIb randomized clinical trial enrolled 202 patients to assess the efficacy and safety of orismilast in individuals with moderate-to-severe plaque psoriasis (NCT05190419).…”

Inflammation and Psoriasis: A Comprehensive Review

“…Apremilast is an oral PDE4 inhibitor that leads to an increase in intracellular cAMP level, the subsequent production of the anti-inflammatory cytokine IL-10, and the decreased production of pro-inflammatory TNF-α, IL-23, and IFN-γ [195,196]. Another oral PDE4 inhibitor, Orismilast IR (instant release), proved its efficacy and safety for moderate to severe psoriasis in a phase 2a trial with 44.4% of patients achieving PASI 75 response compared to the placebo group (5.6%) at week 16 [197]. Topical PDE4 inhibitor-Roflumilast was approved by the FDA in July 2022 for the treatment of plaque psoriasis for adults and children over the age of 12 [198].…”

Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open‐label, single‐centre, single‐arm, dose‐finding clinical trial

“…Thus, PDE4‐inhibition appears a relevant mode of action for HS 7,16 . Orismilast is an oral PDE4‐inibitor holding potential for improved efficacy compared to currently available PDE4‐inhibitors 15,17 . This trial assesses tolerability, safety and efficacy of oral orismilast in HS, and represents the first treatment experience with orismilast in patients with HS.…”