Rheumatoid Arthritis

Disease Background

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that typically affects more than just the joints. RA is an autoimmune disorder, a disease where the immune system mistakenly attacks your body’s own tissues. RA affects the lining of the joints, causing a painful swelling that can result in cartilage and bone erosion and joint deformity. RA is often associated with symptoms involving other parts of the body including the skin, eyes, lungs, heart, and blood vessels. While new types of medications have improved treatment options, significant unmet needs still exist. For most patients, RA still progresses, and damage accumulates. Patients cycle through therapies and classes of therapies and must deal with periods of acute disease activity called flares, which can occur several times per year and drive the need to adjust the dose of current drugs or to change to a new therapy to maintain control of the disease.

Clinical development of AP1189 in RA

In November 2021, SynAct announced results from the Phase 2a study of AP1189 in newly diagnosed and previously untreated RA patients presenting with severe disease activity. The study, called BEGIN, was a randomized, double-blind, placebo controlled multicenter study in previous treatment naïve RA patients where either 50 mg or 100 mg of AP1189 or placebo was administered in addition to methotrexate (MTX). MTX is a disease modifying anti-rheumatic drug (DMARD) that is typically used as a first line of therapy. MTX tends to work well in most patients, but it can take up to 6-8 weeks for the drug to take full effect, and up to 40% of patients will not achieve a full response to MTX therapy and will require dose escalation or the addition of additional drugs like biological therapies which can induce a higher degree of immunosuppression.

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AP1189 given once daily for four weeks was safe and well tolerated in the applied patient population. 100 mg of AP1189 demonstrated a statistically significant mean reduction in the clinical disease activity index (CDAI), the primary study endpoint, from baseline to four weeks that was more than 65% higher than the effect seen in the placebo-treated control group (mean reduction in CDAI: AP1189 100 mg (n=33): 15.5 points compared with placebo (n=30): 9.3%, p = 0.0394). The 100 mg AP1189 group also demonstrated a significantly higher fraction of patients achieving ACR20 than placebo treated patients (ACR20: AP1189 (n=33) 100 mg: 60,6%; Placebo (n=30): 33.3%, P=0.0437) within the 4 weeks.

Based upon this initial promising data, SynAct announced a trial expansion in May 2021, increasing the overall trial size by up to 20 patients in order to increase the probability of demonstrating statistical significance in this POC trial. Trial recruitment is completed and SynAct expects to conclude the trial in Q4 of this year with top-line presented by the end of November, 2021.

Potential Utility of AP1189 in RA

The emerging clinical profile of AP1189 could potentially support multiple uses in the treatment of RA:

Emerging AP1189 Clinical profile
Oral Dosing oral solid formulation to be used in the next clinical trial
Quick Onset of Action as early as 2-weeks
High Response Rate within 4 weeks
Safe and Well Tolerated
No Immunosuppression
no treatment limiting Aes seen to date
Steroid-Free MoA potential to be steroid sparing
Compatible with MTX no known theoretical DMARD drug interactions

Continued Development

Based upon the results of the BEGIN RA study, the company intends to initiate two additional Phase 2 clinical studies in RA with AP1189 in 2022.

EXPAND – A 12-week Phase 2b study of daily AP1189 in MTX-naïve patients with severe disease activity

The EXPAND study is designed to test the treatment effect of 12-weeks of AP1189 on disease activity as measured by the ACR20 response rate as well as other RA disease measures and to confirm the safety profile of the molecule. This study utilizes the newly developed solid tablet formulation of AP1189 and will dose for 12-weeks as opposed to the 4-weeks of dosing in the BEGIN trial. The Company conducts the study at clinics in Europe in a cost-efficient approach with the aim to report key data in the second half of 2023. Following approval of the CTA, recruitment to study started in September 2022. The figure below provides an overview of the design of EXPAND.

RESOLVE – 12-week Phase 2a/b study of daily AP1189 in patients with an incomplete response to first-line disease modifying anti-rheumatic drugs (DMARD-IR) who are experiencing moderate to severe disease activity
A large percentage of patients treated with DMARDs never achieve the full desired effect, have a diminishing treatment effect, or suffer from side effects that can prevent further treatment. These patients who experience an inadequate response to DMARDs are referred to as DMARD-IR (inadequate responder).

The Company believes that AP1189 could be very well suited for DMARD-IR patients given the emerging profile of an efficacious, safe, and well tolerated once-daily oral therapy. The DMARD-IR patient population has high commercial attractiveness and SynAct considers further clinical development in DMARD-IR to be both relevant and necessary.

The intention is to develop AP1189 in DMARD-IR patients under an IND (Investigational New Drug) which is being prepared and expected to be submitted in Q3 2022. Therefore, the final design of the study is pending.