SynAct Pharma fortsätter att göra framsteg i utvecklingen av den antiinflammatoriska läkemedelskandidaten AP1189. Med stöd av prekliniska toxikologiska resultat meddelade bolaget nyligen att AP1189 kan doseras i tre månader i framtida kliniska studier. Dessutom har SynAct utvecklat en tablettformulering för AP1189 – vilket utgör ytterligare ett stort steg inför den kliniska utvecklingen. I slutet av november räknar SynAct Pharma med att kunna presentera nyckelresultat från BEGIN, en klinisk fas IIa-studie inom reumatoid artrit. BioStock kontaktade bolagets CSO Thomas Jonassen och CMO Anders Dyhr Toft för en kommentar.

SynAct Pharma bedriver forskning och utveckling inom inflammatoriska och autoimmuna sjukdomar. Bolagets forskningsplattform baseras på det kroppsegna hormonet melanokortin, som aktiveras vid inflammatoriska tillstånd och bidrar med anti-inflammatoriska effekter som är avgörande för läkningsprocessen och återhämtning till normal vävnadsfunktion.

Den ledande läkemedelskandidaten AP1189 är en ”First-in-Class” melanokortin-agonist som främjar upplösning av inflammation genom att selektivt aktivera melanokortin-receptorer typ 1 (MCr1) och typ 3 (MCr3) på immunceller. När dessa receptorer aktiveras startar två antiinflammatoriska processer – minskad frisättning av pro-inflammatoriska mediatorer och efferocytos, d.v.s. att döda celler ”städas bort”.

Dataavläsning från klinisk studie inom RA runt hörnet

Den primära indikationen för AP1189 är aktiv reumatoid artrit (RA), men läkemedelskandidaten testas även för behandling av nefrotiskt syndrom (NS). Under 2020 adderade SynAct Pharma ytterligare en indikation till sin pipeline, nämligen behandling av covid-19-patienter i syfte att förhindra Acute Respiratory Distress Syndrome (ARDS). Den gemensamma nämnaren för samtliga indikationer är ett okontrollerbart tillstånd av hyperinflammation.

Kandidaten utvärderas för tillfället i två kliniska fas IIa-studier, en i RA och en i NS. I RA-studien, som går under namnet BEGIN, har den sista patienten erhållit sin sista dos och nyckelresultat kommer att presenteras i slutet av november 2021. 

Positiv effekt på covid-19 patienter med ARDS

Tidigare i år tillkännagav SynAct Pharma positiva data från en tredje fas IIa-studie med AP1189 – denna gång i covid-19-patienter med ARDS, ett allvarligt lungtillstånd där syrgasbehandling ofta behövs. Resultaten visade att AP1189 kan hjälpa patienter att uppnå förbättrad lungfunktion, vilket skulle kunna leda till tidigare utskrivning från sjukhuset.

Toxikologiska studier möjliggör dosering i tre månader

SynAct Pharma slutförde nyligen prekliniska toxikologiska studier med syfte att möjliggöra tre månaders dosering med AP1189 i människor. Inga oväntade observationer identifierades, och de så kallade no-observed-adverse-effect levels (NOAEL) låg på samma, eller högre, nivåer som hade identifierats i tidigare prekliniska toxikologiska studier med kandidaten.

Baserat på dessa resultat kan SynAct Pharma nu ansöka om kliniska prövningar med AP1189 på patienter under en behandlingstid på upp till tre månader.

Intervju med CSO Thomas Jonassen

BioStock kontaktade Thomas Jonassen, medgrundare och nuvarande CSO, för att få veta mer om AP1189, bolagets studiedata och den nyutvecklade tablettformuleringen, samt vad dessa nyheter innebär för bolaget.

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.

Intervju med CMO Anders Dyhr Toft

I augusti tillträdde Anders Dyhr Toft tjänsten som CMO på SynAct Pharma och fick i uppdrag att leda den kliniska utvecklingen i nära samarbete med CSO Thomas Jonassen. BioStock kontaktade Dyhr Toft för att få information om nästa utvecklingssteg för 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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