ORKA-001 Advances Toward Yearly Dosing

Oruka Therapeutics’ ORKA-001 a long-acting IL-23p19 antibody in development for psoriasis, has shown a half-life of approximately 100 days and a pharmacokinetic profile that could allow once-yearly dosing.¹ Early clinical results indicate the drug may match the efficacy of current IL-23 inhibitors while providing longer-lasting effects.

ORKA-001, a humanized IgG1 monoclonal antibody engineered for half-life extension, was designed to bind selectively to IL-23p19 with sub-20 pM affinity, similar to risankizumab-rzaa and guselkumab, but incorporating structural modifications to prolong systemic persistence.¹ The goal is to maintain therapeutic exposure for 6 to 12 months on a single subcutaneous dose, potentially delivering complete skin clearance with the fewest injections in class.

“We all know IL-23 inhibitors—risankizumab, tildrakizumab, guselkumab—and we know they are great drugs,” said Andrew Blauvelt, MD, MBA, a dermatologist and clinical researcher, in an interview with Dermatology Times. “They have great efficacy, they’re safe...This is another step forward in that story.”

Preclinical Benchmarks

In comparative in vitro and ex vivo analyses, ORKA-001 was tested against risankizumab and guselkumab. The antibody demonstratedbinding affinity to IL-23 below 20 pM.² In functional assays, it achieved potent inhibition of STAT3 phosphorylation in IL-23–responsive cell lines and effectively suppressed IL-17 secretion in IL-23–stimulated human peripheral blood mononuclear cells. These results confirmed that ORKA-001’s target engagement and downstream blockade were at least comparable to, and in some measures exceeded, benchmark agents.²

In pharmacokinetic studies in cynomolgus monkeys, ORKA-001 displayed a significantly extended half-life relative to risankizumab and guselkumab.² Allometric scaling predicted that in humans, high antibody exposures could be sustained for 6 to 12 months with subcutaneous administration. Together, these findings formed the basis for the compound’s progression into first-in-human testing.

Phase 1 Prolonged Exposure

The phase 1 ORKA-001-111study (NCT06698939) was a randomized, double-blind, placebo-controlled, single-ascending-dose trial in healthy adults. Participants received subcutaneous ORKA-001 at 300 mg, 600 mg, or 1200 mg. The interim analysis showed a mean terminal half-life of approximately 100 days, more than triple that of risankizumab.¹

Single doses of ORKA-001 resulted in complete and sustained inhibition of STAT3 signaling, a downstream biomarker of IL-23 activity, through at least 24 weeks of follow-up, the longest period evaluated to date. Safety outcomes were favorable and consistent with the IL-23p19 class, with no severe or serious adverse events. The most common treatment-emergent adverse events were mild headaches, upper respiratory tract infections, and transient injection-site erythema.¹

Phase 2 The EVERLAST-A Trial

The phase 2a EVERLAST-A trial (NCT07090330), an 80-patient, randomized, double-blind, placebo-controlled study, is enrolling in the US and Canada. Patients with moderate to severe plaque psoriasis will receive 600 mg of ORKA-001 at weeks 0 and 4, with a PASI score of 100 (ie, complete clearance; PASI 100) at week 16 as the primary end point.¹

At week 28, participants achieving PASI 100 will be randomly assigned to no further dosing until disease recurrence or continue 300 mg every 6 months. This no-dose strategy directly tests ifORKA-001 can maintain off-treatment remission for a year or longer, a concept rarely formalized in psoriasis trials. Patients who have not achieved PASI 100 by week 28 will transition to 300 mg every 6 months. Placebo recipients will cross over to 600 mg of ORKA-001 at week 16 and week 20 and then follow a once-yearly schedule.¹

“We’re looking at dose ranging, we’re looking at safety, and we’re trying to find the right balance between efficacy and how long the effect can last,” Blauvelt told Dermatology Times. “The idea is that maybe we don’t need to treat as often as we do now if we can find a formulation or an approach that gives longer control.”

Initial efficacy and durability data from EVERLAST-A are expected in the second half of 2026. In the first half of 2026, Oruka Therapeutics plans to initiate EVERLAST-B, a dose-ranging phase 2b trial evaluating 37.5-mg, 300-mg, and 600-mg ORKA-001 regimens against placebo.¹

If phase 2 data are positive, it could change what constitutes optimal control in chronic psoriasis as well as potentially improve adherence and reduce cumulative drug exposure, health care visits, and overall treatment costs.

Future Questions, Directions

Long dosing intervals raise theoretical concerns about immunogenicity, antibody persistence, and the detection of delayed adverse events. Subgroup performance, particularly in patients with obesity or those with high baseline body surface area, will also influence clinical viability. Reimbursement and pricing strategy will also determine real-world adoption.

References

1. Oruka Therapeutics announces positive interim phase 1 results for ORKA-001. News release. Oruka Therapeutics Inc. September 17, 2025. Accessed October 10, 2025. https://orukatx.gcs-web.com/news-releases/news-release-details/oruka-therapeutics-announces-positive-interim-phase-1-results
2. P130 ORKA-001: a novel extended half-life monoclonal antibody targeting IL-23 with the potential to improve upon currently available therapies for psoriasis. Br J Dermatol. 2024;191(suppl 3):ljae360.160. doi:10.1093/bjd/ljae360.160