SynAct Pharma continues to make progress in the development of the anti-inflammatory drug candidate AP1189. The company recently announced that AP1189 can be dosed for three months in future clinical studies, supported by preclinical toxicology results. Also, SynAct has now formulated AP1189 as a tablet – which is another big step for future clinical development. By the end of November, SynAct Pharma expects to present key results from BEGIN, a clinical phase IIa study in the primary indication rheumatoid arthritis. BioStock reached out to the company’s CSO Thomas Jonassen and CMO Anders Dyhr Toft for a comment.

SynAct Pharma conducts research and development in inflammatory and autoimmune diseases. The company research platform is based on the endogenous hormone melanocortin, which is activated in inflammatory conditions and contributes with anti-inflammatory effects that are crucial for the healing process and recovery to normal tissue function.

The lead drug candidate AP1189 is a First-in-Class melanocortin agonist that promotes resolution of inflammation by selectively activating melanocortin type 1 (MCr1) and type 3 (MCr3) receptors on immune cells. When these receptors are activated, two anti-inflammatory processes begin – reduced release of pro-inflammatory mediators and efferocytosis, i.e., “clean-up” of dead cells.

RA data readout around the corner

 The primary indication for AP1189 is active rheumatoid arthritis (RA) and AP1189 is also being tested in Nephrotic Syndrome (NS). In 2020, SynAct Pharma added AP1189 as an adjunctive therapy in hospitalised patients with Covid-19 in order to prevent acute respiratory distress syndrome (ARDS) to its pipeline, given the common denominator in all three indications; an uncontrollable state of hyper-inflammation.

The candidate is currently being evaluated in two clinical phase IIa studies, one in RA and one in NS. In the RA study, called BEGIN, the last patient has completed dosing and key results will be presented by the end of November 2021.

Positive effect on Covid-19 patients with ARDS

Earlier this year, SynAct Pharma announced positive data from a third phase IIa study with AP1189 – this time in Covid-19 patients with ARDS, a serious lung condition where ventilatory treatment is often needed. The results showed that AP1189 helped patients recover respiratory function, leading to earlier discharge from the hospital.

Toxicology studies support three months dosing

SynAct Pharma recently completed preclinical toxicology studies aimed to support three-month dosing in humans with AP1189. No unexpected observations were identified, and the no-observed-adverse-effect levels (NOAEL) were at the same, or higher, levels as in previous preclinical toxicology studies with the candidate.

Based on these results, SynAct Pharma is now able to apply for clinical trials testing AP1189 in patients for a treatment duration of up to three months.

Interview with CSO Thomas Jonassen

BioStock reached out to co-founder and current CSO Thomas Jonassen to learn more about AP1189, the new data and the recently communicated tablet formulation, along with the implications of these news items.

To get a grasp of the competitive landscape, what makes AP1189 stand out compared to other drugs for inflammatory diseases? 

– A major difference between most current treatment opportunities and AP1189 for treatment of autoimmune and inflammatory diseases is that AP1189 promotes resolution, i.e. it not only reduces inflammation by inhibiting pro-inflammatory pathways, recruitment and activation of white cells and other immune active cells, but also stimulates pathways that help clearing up inflamed tissue.

»A major difference between most current treatment opportunities and AP1189 for treatment of autoimmune and inflammatory diseases is that AP1189 promotes resolution«

– This means that the effect is twofold: Firstly, the compound inhibits but does not block anti-inflammatory pathways. Secondly, it stimulates resolution. This is unique. And importantly, this most likely means that immunosuppression, one of the most treatment-limiting effects of most anti-inflammatory compounds, is potentially avoided. In addition, the compound, in contrast to the class of drugs called biologics, is given orally as a once-daily tablet.

Given the abovementioned results from the preclinical toxicology studies, you will be able to dose AP1189 for three months in upcoming clinical trials. Could you elaborate on why a longer dosing period is important? 

– Most inflammatory and autoimmune diseases are chronic diseases and even the most effective treatment approach can hardly be expected to induce full activity within a four week period – which is the time span we have been limited to in prior and ongoing studies.

 –  Moreover, even though that you would be able to reduce symptoms, it is usually so that with injection of glucocorticoid into a joint, the symptoms will re-emerge as soon at the effect of the injection disappears. In other words, anti-inflammatory treatment is not curative, but aiming at controlling symptoms. Consequently, not only should a compound like AP1189 most likely be given for more than 4 weeks to induce its full effect, but to bring a disease like rheumatoid arthritis to full remission and keep it under control, then longer treatment time would be needed. Three months of treatment is therefore a logical next step as it would give sufficient time to induce disease recovery, which from a drug development perspective naturally is the aim. Finally, 3 months of dosing in phase IIb is what regulatory authorities request before entering into phase III development.

SynAct Pharma has developed a new tablet formulation for AP1189. Given your vast experience in drug development, how would you quantify the importance of this milestone?

  – This is a major milestone. Tablet formulation sounds trivial, but it is far from that. We have up to now been able to use a suspension, i.e. that the patients every morning had to take a bottle with the compound presented as a powder, add water, shake intensively and then drink the suspension. The new tablet, developed by our COO Thomas Boesen together with skilled tablet developers, makes the whole difference. Our studies in animals showed superior absorption and we look very much forward to get the data later this month from the ongoing bioequivalence study in man.

 – The drug exposure profile from the new tablet is so attractive that we filed a patent application earlier this year, aiming to cover the unique and honestly surprisingly good properties. To sum it up, to have the possibility to dose with a tablet with unique properties covered by new IP brings the entire AP1189 project to a whole new level.

»The drug exposure profile from the new tablet is so attractive that we filed a patent application earlier this year, aiming to cover the unique and honestly surprisingly good properties«

In the long run, SynAct Pharma’s goal is to become a top player in resolution therapy. Could you define resolution therapy, why it is an interesting segment and give us further insight on how you plan to reach this goal?

  – It think that the description given above that resolution therapy in addition to inducing anti-inflammation, but not immunosuppression; and then in parallel stimulate endogenous pathways including what we call efferocytosis, i.e. stimulating immune active cells as neutrophils and macrophages to clear up the ongoing inflammation and thereby reduce the likelihood to go into chronic inflammation with tissue disruption and irreversible loss of function, is a unique novel way of addressing autoimmune and inflammatory diseases.

 – The data we have generated in COVID-19 infected patients show the potential in acute virus-induced hyperinflammation, and if we in a few weeks can confirm the findings from phase IIa Part 1 in patients with rheumatoid arthritis, then we have strong evidence that resolution therapy is a novel and very promising treatment approach.

Interview with CMO Anders Dyhr Toft

In August, Anders Dyhr Toft entered the position as CMO at SynAct Pharma, and was given the task to lead the clinical development and medical affairs in close collaboration with CSO Thomas Jonassen. BioStock reached out to Dyhr Toft for further information on the next development steps for AP1189.

What hopes do you have for the results from the phase IIa study with AP1189 in RA (BEGIN) that will be presented later this month?

 – I very much hope that we can demonstrate a clinically relevant level of efficacy, despite only 4 weeks of treatment in this study. On the safety side, I hope that we can demonstrate an attractive profile. There are many marketed treatments for rheumatoid arthritis and almost for all of these there are safety aspects that need attention in the clinic today.

Earlier this year, SynAct Pharma announced positive data from a phase IIa clinical study of AP1189 in Covid-19 infected patients with ARDS. Can you tell us a bit more about the results from this study and what the next step will be within this indication?

 – Due to the known mode-of-action of AP1189 on immune cells, then it was speculated that AP1189 would also be effective in the hyper-inflammatory state that causes respiratory insufficiency – the most common cause of hospitalization and death – in people infected with COVID-19. SynAct was fast to conduct a randomized placebo-controlled trial in Brazil where it was demonstrated that AP1189 reduced time to respiratory recovery (i.e. no need for supplementary oxygen treatment) by 4 days and reduced time to hospital discharge by more than 3 days. These results are very significant – given the fact that both oxygen and hospital beds become scarce resources in many countries when COVID waves hit. With these results, we are currently exploring what the next necessary steps are towards obtaining Emergency Use Approval in select countries.

»SynAct was fast to conduct a randomized placebo-controlled trial in Brazil where it was demonstrated that AP1189 reduced time to respiratory recovery (i.e. no need for supplementary oxygen treatment) by 4 days and reduced time to hospital discharge by more than 3 days.«

What milestones can we look forward to in the coming year? 

 – Well, the read-out on the BEGIN study this month is what takes all my band-width at current. But I certainly look forward to progress the further development of AP1189, both in current and future indications.

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