Phase 2b Study Identifies Dose-Response Signals for APPA in Knee Osteoarthritis, with Statistically Significant Benefits on Several Outcomes at the Higher Dose in Patients with Higher Baseline Pain

NBCD A/S and AKL Therapeutics today reported findings from a Phase 2b clinical study evaluating APPA, an investigational fixed-dose oral combination of apocynin and paeonol, in patients with knee osteoarthritis (OA), moderate-to-severe pain and features of nociplastic pain. The findings, reported in an abstract at ACR Convergence 2026 (abstract 0636, Poster Session A, 8 November 2026)[1], showed a consistent dose-response pattern across secondary pain measures and identified statistically significant benefits on several outcomes in a prespecified subgroup of patients with higher baseline pain. Although the study did not meet its primary endpoint in the overall population, the findings provide a rationale for further evaluation of APPA, particularly at the higher dose and in patients with a greater pain burden.

The randomized, double-blind, placebo-controlled study enrolled 225 participants, randomized 1:1:1 to receive APPA at doses of 800 mg or 1,200 mg twice daily, or placebo, over 12 weeks. A total of 205 participants completed the study.

While the primary endpoint of change from baseline to Day 84 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain in the intention-to-treat (ITT) population was not met, a consistent, dose-dependent signal of benefit was observed across secondary pain measures, including Weekly Average of Daily Pain (WADP) and the Intermittent and Constant Osteoarthritis Pain (ICOAP).

Further, a prespecified subgroup analysis of participants with higher baseline WOMAC pain scores (>30 out of 50) showed a particularly encouraging efficacy signal with a clinically meaningful effect size. In this subgroup, the 1,200 mg twice-daily dose demonstrated statistically significant benefits on several outcomes, with a pattern of improvement across most endpoints. These hypothesis-generating findings support further investigation of APPA in patients with a greater pain burden, a population in which effective treatment remains an important clinical need.

APPA was generally well tolerated during the study. The most frequently reported adverse event was transient, mild gastrointestinal discomfort.

A multi-pathway approach to the complexity of osteoarthritis pain

Osteoarthritis is a leading cause of chronic pain and disability worldwide. Despite the availability of non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids and other symptomatic treatments, many patients continue to experience inadequate pain relief. Treatment choices can also be constrained by tolerability concerns, contraindications and the practical limitations of injectable therapies.

APPA: an investigational oral approach

APPA combines apocynin and paeonol in a fixed 2:7 ratio and is being developed as an oral, multi-pathway investigational treatment. Its scientific rationale is based on modulating multiple biological pathways implicated in inflammation, with the aim of addressing the complexity of osteoarthritis pain. This approach may be relevant to patients whose pain involves more than one underlying mechanism.

Asger Bihlet, Chief Scientific Officer of NBCD A/S, said: “The Phase 2b findings are encouraging, with a consistent dose-response pattern across several pain measures and particularly promising results in patients with higher baseline pain. Demonstration of pain and symptom benefit in OA clinical trials is very challenging, and the statistically significant findings, across several outcomes in this prespecified subgroup, provide an important direction for the program and support further development of APPA. Combined with the opportunity to optimize APPA’s formulation and drug exposure, these results give us a clear rationale for the next stage of clinical development.”

David Miles, Chief Executive Officer of AKL Therapeutics, said: “The Phase 2b findings provide a meaningful basis for the next stage of APPA’s development. The dose-response signals and the results in patients with higher baseline pain give us important questions to pursue as we refine the formulation, dose and target patient population. We believe this is a promising opportunity to advance a differentiated oral approach to osteoarthritis pain, and we look forward to evaluating its potential in further clinical studies.”

Next steps: optimizing APPA’s formulation and clinical development

The next stage of APPA’s development will include evaluation of patented liquid formulations intended to address the substantial variability and further increase the bioavailability observed in the pharmacokinetic substudy.

Together with the dose-response signals and findings in patients with higher baseline pain, this work provides a direction for refining APPA’s formulation, dose and target patient population. Further clinical studies will be required to confirm the efficacy findings and establish the candidate’s potential role in the treatment of osteoarthritis.

About APPA

• APPA is an oral, patented, fixed-dose combination of apocynin and paeonol in a 2:7 ratio. Both compounds are synthetically produced for pharmaceutical development and are secondary metabolites of plant origin.
• APPA is being investigated for its potential to modulate inflammatory pathways involving NF-κB and Nrf2 and to influence the formation of neutrophil extracellular traps (NETs).
• Its multi-pathway mechanism is being investigated as a potential means of addressing biological processes implicated in osteoarthritis pain.

About NBCD A/S

NBCD A/S is a full-service expert contract research organization (CRO) specializing in musculoskeletal clinical research. NBCD’s clinical research supports the development of new treatment approaches for patients with musculoskeletal and related conditions.

NBCD A/S is based in Copenhagen, Denmark. For more information, visit https://www.nbcd.com/.

About AKL Research & Development (AKLRD), trading as AKL Therapeutics

AKL Therapeutics focuses on the development of treatments for inflammatory diseases, including osteoarthritis. Its approach involves identifying biologically active secondary metabolites of plant origin, synthesizing them for pharmaceutical development and evaluating them through standard clinical development programs.

AKLRD is based at the Stevenage Bioscience Catalyst in Hertfordshire, UK. For more information, visit https://www.aklrd.com/.

Important information: APPA is investigational and has not been approved for commercial use. Its safety and efficacy have not been established by regulatory authorities.

[1] ACR Convergence 2026 Bihlet A, Petersen N, Kaaber A, Petersen E, Rovsing H, Alexandersen P, Larsen S, Lau E, Miles D, Reynolds A, Conaghan P. “Evidence of a Dose-Response Relationship in a Phase 2b Study of a Fixed-Dose Combination of Apocynin and Paeonol in Knee OA Patients With Moderate to Severe Pain and Nociplastic Pain Features [abstract]”. Arthritis Rheumatol. 2026; 78 (suppl 9). Abstract 636.