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SynAct Pharma moves forward with filing process

SynAct

SynAct Pharma moves forward with filing process

4 July, 2024

Following previous studies in rheumatoid arthritis, SynAct Pharma knows much more about the possibilies and requirements for assessing resomelagon’s effect. The company is now acting on its strategy by initiating the filing process for a new clinical phase IIb study with resomelagon in patients with severe, newly diagnosed RA with signs of systemic inflammation. BioStock reached out to CEO Jeppe Øvlesen to learn more about the clinical trial, named ADVANCE.

SynAct Pharma is a biotech company focused on developing treatments to resolve inflammation in inflammatory and autoimmune diseases. Its lead candidate, resomelagon (AP1189), is a once-daily oral melanocortin agonist that selectively activates melanocortin receptors 1 and 3, which play key roles in inflammation and its resolution.

Learnings from recent studies

Resomelagon has been evaluated for the treatment of rheumatoid arthritis (RA) in three clinical trials. In the first phase IIa study (BEGIN), resomelagon achieved a significant reduction in disease activity, successfully reaching the primary endpoint.

The company’s second RA study, the EXPAND phase IIb trial, did not meet the primary endpoint. However, subset results showed significant treatment effect compared to placebo in newly diagnosed patients with high disease activity and signs of systemic inflammation. Hence, SynAct Pharma decided on setting up a new phase IIb trial (ADVANCE) focusing on newly diagnosed patients with high disease activity including signs of systemic inflammation – a patient group where it is often needed to cotreat with potent compounds with unwanted side effect profiles as glucocorticoids and TNF-blockers to get control of the disease.

The primary aim of the ADVANCE study is to confirm the treatment potential of the compound and to identify optimal doses for phase III development in patients with severe newly diagnosed RA.

Filing initiated and recruitment to begin

ADVANCE is set up as a double-blind placebo-controlled multi-center study and will be conducted at clinical sites in the US and Europe. SynAct Pharma and its assigned CRO have worked diligently to meet the deadline of initiating the filing process of the clinical trial applications in the second quarter. On July 1, SynAct Pharma announced that the filing process has been initiated, with the submission for the ADVANCE study already underway in the US.

– The submission is a part of the ambitious schedule that has been laid out in collaboration with our CRO and advisors to continue the development of resomelagon (AP1189) in RA. Our team and CRO have done a tremendous effort in getting the project back on track, says Jeppe Øvlesen, CEO of SynAct Pharma.

The submission in the US will be followed by submission of clinical trials applications in Europe in the coming weeks. The company aims to initiate active patient recruitment in Q3 2024, with the goal of completing enrolment by Q4 2025.

Aim of ADVANCE study

The study will include 240 patients showing signs of severe RA (DAS28-CPR >5.1; CDAI >22) including signs of systemic inflammation defined as high-sensitivity CPR above normal range (>3 mg/L).

Three different doses of resomelagon will be tested vs placebo treatment, given once daily for 12 weeks in combination with methotrexate (MTX). The primary efficacy readout is induced reduction in disease activity score (DAS28-CRP), which is a widely used scoring system that asses the severity of RA by considering the number of tender and swollen joints, general health, and CRP levels.

Early intervention for RA

The ADVANCE study is going to answer the question of whether resomelagon is suitable and clinically relevant as a first-line treatment in combination with MTX for RA patients. According to Thomas Jonassen, CSO at SynAct Pharma, resomelagon has the potential to be a novel, early alternative for severe RA patients, thereby reducing the need for glucocorticoids (GCs) and postponing the use of the biologics:

– We are confident resomelagon has tremendous potential for early intervention in patients with severe RA. These patients are often cotreated with GCs and second line treatment with biologics, as the TNF-blockers, will often be introduced very early to increase the likelihood of obtaining disease control. However, these treatment options are associated with unwanted side effects.

CEO comments

Jeppe Øvlesen
Jeppe Øvlesen, CEO of SynAct Pharma

BioStock talked to SynAct Pharma’s CEO Jeppe Øvlesen to learn more about resomelagon’s potential and the upcoming ADVANCE study in US and Europe.

What are the main differences in the patient inclusion criteria between the ADVANCE study and your previous RA studies with resomelagon?

– In the ADVANCE study, we will focus on newly diagnosed RA patients with high disease activity including signs of systemic inflammation. These patients could be considered difficult-to-treat patients, many of which have what is called poor prognosis factors, i.e. indication that the aim of disease control is difficult and there is a high risk to develop irreversible loss of function in the joints. In the BEGIN study, the vast majority of the patients are comparable to what we want to include in the ADVANCE study. In the EXPAND study, half of the patients included did not show signs of systemic inflammation or were not really newly diagnosed.

What speaks for this study to be more successful than the previous studies?

– We focus on the patient population that, according to mode of action of the compound and previous clinical studies, responds very well to the compound. We therefore strongly believe that our novel treatment approach of pharmacological resolution can make a difference in these rather severe affected patients. Remember, the current treatment options, i.e. GCs and early intervention with TNF-blockers, are, even though often effective, not really patient-friendly treatment options and should be reduced and/or postponed as much as possible.

Why have you chosen DAS28-CRP as primary efficacy readout in the ADVANCE study?

– The ADVANCE study is a so called phase IIb dose-range study and we have designed the study to optimize the likelihood not only to show treatment effects relative to placebo, but also to evaluate dose range responses between the different doses of resomelagon. This is needed to identify which dose(s) to bring forward into phase III, and DAS28-CPR is superior to ACR20 for such purposes. Actually, the FDA very specifically in its RA development recommendation guideline states that “clinical endpoint such as the ACR20 response criteria may not be optimal for this purpose, because it is a dichotomous endpoint (only two possible outcomes), and using the proportion of responders in a small group of patients could be unreliable. Endpoints such as DAS28, hybrid ACR response, and other continuous variables may be more sensitive to change and provide a more suitable alternative to ACR responder index.

– In other words, we use changes in DAS28-CRP to optimize the likelihood of success defined as showing treatment effect of the compound superior to placebo and to optimize the likelihood to be able to show dose response on the applied doses.

You mention that resomelagon has the potential to reduce the need for glucocorticoids and delay the use of biologics such as TNF blockers. Why is this important?

– It is well know that Glucocorticoids (GC) have a whole range of unwanted side effects – these can be accepted in the setting where the compounds are used for short term treatment as bridge treatment to get symptom control, but treatment should be reduced to as little as possible and never exceed 3 months treatment. However, it is reported that up to 50 per cent of all RA patients end in more chronic GC treatment – evidently if the use of the GCs can be reduced /controlled to a minimum it would be a big milestone.

– For the TNF-blockers and other biologics, the situation is that compounds are effective, but the side effect profile is not attractive. Immune suppression is the most important as it increases the rate of infections, but even more severe side effects can/will develop. Consequently, the compounds should be used if and when needed, but should not be used for first line. However, TNF-blockers are introduced relatively early in more severe cases as the alternative would be to use “too much” GCs.

– The likelihood that our compound induces immunosuppression is very low as it does not suppress the immune system, but rather stimulates resolution, i.e. modulate an activated immune system to reach a new setpoint thereby reducing the disease activity. This all equals a much more patient-friendly treatment approach and when introduced as early as possible in the patient it has the potential to reduce the use of GCs and reduce/postpone the use of the TNF-blockers.

What challenges do you anticipate in conducting this multi-center study ADVANCE, and how is SynAct Pharma preparing to address these challenges?

– The major challenge is, as for all other clinical trials, to get the right clinical site to participate and prioritize the study. The sites should be able to recruit patients and do it in a diligent and continuous approach until we have all patients in. Together with our CRO, we work continiously to secure a positive interaction with sites, ensuring a succesful execution of the study.

In parallell with the ADVANCE study, you are continuing discussions with potential partners and Key Opinion Leaders. What feedback have you received regarding the strategy you are currently pursuing?

– First and foremost is that if the ADVANCE study confirms resomelagon as an effective non-immunosuppressive treatment option in the patients, it could help to reduce the use of GCs and delay the use of the TNF-blockers. For both a patients and doctors it would be a big improvement in the current treatment of more severe newly diagnosed RA patients. Further, do not forget that if we succeed, potential partners and KOLs see a number of other patients groups and indications where resomelagon could make a difference.

– We are very pleased that all potential partners remain interested in following our success. One of our priorities is keeping them updated during the coming months and maintaning regular interactions. This will put us in a strong position for any possible deals once we receive positive data.

– In addition we are currently exploring other partnerships for the TXP compounds. SynAct has a clear plan now and is pushing forward.

The content of BioStock’s news and analyses is independent but the work of BioStock is to a certain degree financed by life science companies. The above article concerns a company from which BioStock has received financing.

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