Recently, SynAct Pharma announced that they have submitted a Clinical Trial Application to initiate EXPAND, a phase IIb study with AP1189 in newly diagnosed patients with rheumatoid arthritis. The aim is to confirm the encouraging phase IIa results and to identify AP1189’s full efficacy potential. The company was recently also approved for listing on Nasdaq Stockholm Main Market with an expected first day of trading on July 12. BioStock got in touch with SynAct Pharma’s CEO Jeppe Øvlesen and CSO Thomas Jonassen.

SynAct Pharma’s drug candidate AP1189 selectively targets the melanocortin system for the treatment of inflammatory diseases. The aim is to induce resolution of the inflammation by balancing the immune system, without causing immunosuppression. Strengthened by encouraging phase IIa results in rheumatoid arthritis (RA) from the BEGIN study, the company has decided to continue the development in two clinical phase II studies – EXPAND in newly diagnosed RA patients and RESOLVE in DMARD-IR patients.

Submitted CTA for EXPAND

SynAct Pharma is soon ready to initiate EXPAND after having submitted a Clinical Trial Application (CTA). The study will include 120 treatment naïve RA patients, i.e. patients that have not been treated for their disease yet. 100 mg of AP1189 will be given in combination with methotrexate (MTX), a common first-line treatment.

The purpose of the EXPAND study is to confirm the safety and efficacy results from BEGIN and identify the full treatment potential of AP1189, as well as enable late-stage development. The aim is to enrol the first patient in Q3 2022 and report key data before the end of 2023.

Confirm previous results and explore full potential

In BEGIN, AP1189 was found to be safe and well-tolerated and, most importantly, it demonstrated a clinically meaningful effect in RA patients already after 4 weeks. A significantly greater reduction in Clinical Disease Activity Index (CDAI) was seen with the 100 mg dose of AP1189 in combination with MTX. In the EXPAND study, the dosing period will be prolonged from 4 to 12 weeks and the newly developed AP1189 tablets will be used, which is expected to improve the response rates according to the company.

First of all, how does it feel to soon be able to initiate SynAct Pharma’s first phase IIb study?

– It is a major step for us to be able to initiate a phase IIb study. We are in a very exciting position where we have successfully completed a phase IIa study in newly diagnosed RA patients and are now taking a step up to a larger study with longer treatment period. A CTA has been submitted for the EXPAND study and our RA development activities are conducted according to plan.

– I would also like to mention that we have now been approved for listing on Nasdaq Stockholm, which is another milestone for us and our shareholders.

Where will the patients be recruited and how long time do you expect it to take?

– The study will be conducted in Moldova and Bulgaria, as the BEGIN study, and potentially in other European countries as well. We expect to get the CTA approval during the summer and then initiate patient recruitment after the summer break.

– In the BEGIN study, we were able to recruit almost half the patients at 6 sites in the selected countries within 6 months. Now we have doubled the number of sites, so we believe that it is absolutely possible to recruit the 120 patients for the EXPAND study during the planned recruitment phase.

»Now we have doubled the number of sites, so we believe that it is absolutely possible to recruit the 120 patients for the EXPAND study during the planned recruitment phase.«

– We will dose AP1189 on top of the MTX treatment for 12 weeks, in line with recommendation from the current guidelines for development of new compounds in RA. The ambition is to present data during the second half of 2023.

Is there a risk that the EXPAND study could be affected by the situation in Ukraine?

– We have a plan and additional sites ready if our study in any way would be affected by Russia’s invasion of Ukraine. But so far, the activities at the hospitals are completely normal and we have seen a lot of interest from investigators who would like to participate in the EXPAND study.

You and CBO James Knight recently participated in BIO International Convention 2022 in San Diego – how was the event?

– We were very busy and had more than 35 interesting meetings with potential partners. As I mentioned earlier, it is clear that we are now in a very exciting position. If we can present a positive outcome from the EXPAND study, we would have a very attractive asset and additional phase II results strengthening our case in RA.

»We had more than 35 interesting meetings with potential partners. As I mentioned earlier, it is clear that we are now in a very exciting position.«

Could you tell us a bit more about the patient group in the EXPAND study?

– The patient group in the EXPAND study will be very similar to the one in the BEGIN study. The patients are recently diagnosed with RA and have a score over 22 on Clinical Disease Activity Index (CDAI), a scoring system that is easy to handle in the daily clinic and used more and more in the clinic to evaluate progress in treatment effects. If you have a CDAI higher than 22, then you are considered to have high disease activity.

– These patients, and even those with moderate disease activity, will typically be allocated to treatment with disease modulating anti-inflammatory agents, so-called DMARDs. The first-line treatment is Methotrexate (MTX), which originally was developed as a cancer therapy, but in lower doses is used widely in RA.

– In the Nordics, we have relatively new guidelines with quite an aggressive dose regimen, where you start on 10-15 mg MTX and then as fast as possible increase to 25 mg. Glucocorticoid (GCs) treatment is usually also added, not at least given as injection into the joints. In the EXPAND study, we will mimic the treatment approach in the US, which is more conservative with regard to increasing the dose of MTX and the use of GCs. The more conservative approach is explained with the unwanted side effects profiles of MTX and GCs.

What results do you want to obtain in the EXPAND study?

– The ultimate ambition of a treatment regiment is to induce remission, i.e. bring the disease activity down to low disease activity, as well as reduce fatigue, disability etc. However, the primary goal in EXPAND is not to reach disease remission within 12 weeks. Actually, in many patients this can only be achieved by use of GC treatment associated with often quite severe side effects.

– Consequently, the primary efficacy read-out is the proportion of patients achieving a 20 per cent improvement on the American College of Rheumatology scoring system, ACR, at 12 weeks relative to placebo. What we saw in the BEGIN study was that 60 per cent qualified for the ACR20 after four weeks of treatment, which is comparable to what is seen following treatment with JAK inhibitor, a class of drugs that are very effective. However, they are labelled with black box warnings due to severe side effects, and recently FDA changed the label for some of them so the use should be restricted to patients who do not respond to second-line treatment.

Do you believe that the prolonged dosing in EXPAND can provide even better efficacy results than shown in BEGIN?

We believe that the response rates will increase with the prolonged dosing. The ambition is to show treatment effect (ACR20) in 75-80 per cent of the patients after three months of dosing with AP1189, which is in the range of three months data for JAK inhibitors.

»We believe that the response rates will increase with the prolonged dosing. The ambition is to show treatment effect (ACR20) in 75-80 per cent of the patients «

– The results from the BEGIN study looked very good and we are also very optimistic about the EXPAND study. We hope that we can continue to show a good safety profile.

– Since AP1189 is a resolution therapy, and not an immunosuppressive treatment, the risk of suppression of the immune system and thereby the risk to get infections is reduced. Infections are otherwise a side effect that is typically associated with RA drugs and other inflammatory diseases. Our approach, which we can confirm in the EXPAND study, could be a game-changer as we modulate the immune system, rather than blocking it. Actually, that is probably what makes us stand out.

Could you tell us a bit more about the potential clinical benefits of first-line treatment with AP1189 in combination with MTX?

– If we will be able to show that the combination is well tolerated and has an additive effect, it could potentially reduce the need for increased doses of MTX and the need to treat with glucocorticoids.

Why have you decided to focus the clinical development on both DMARD-IR patients with insufficient response to MTX and newly diagnosed, previously untreated RA patients?

– I think the reason is quite clear – there is a huge market and request for new treatments from DMARD-IR patients. These patients have been treated with first-line treatment for at least three months and still have significant symptoms. New treatment alternatives for these patients are what patients, rheumatologists and pharma companies, i.e. potential partners,  are looking for.

– However, we also want to take advantage of the opportunities in treatment-naïve patients, especially since we already have seen great results with AP1189 in these patients. But from a commercial perspective the biggest market is in DMARD-IR.

Could you also give us an update on the interactions with FDA regarding the RESOLVE study in DMARD-IR patients?

– We have presented the intended setup of the RESOLVE study to the FDA and got the written response from them earlier this week. The next step is therefore to continue the Investigation new drug (IND) application and start part A of RESOLVE, which is a dose range study for four weeks to identify relevant doses to part B – a phase IIb study with a larger patient population and 12 weeks of dosing. We intend to file the IND following by initiation of the study during the autumn.

»We are working on new compounds and hope to be able to communicate more on this during the second half of the year.«

What other development activities are you focusing on right now?

–  We also see a large potential of the compound in the nephrology space and look very much forward to get the amended study in nephrotic syndrome (NS) up and running.

– Beside the clinical programmes, we are working on new compounds and hope to be able to communicate more on this during the second half of the year.

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