SynAct Pharma fokuserar på att vända situationen efter de nedslående studieresultaten med läkemedelskandidaten resomelagon. Det svenska bioteknikbolaget genomför en riktad nyemission om 49,2 Mkr för att utveckla kandidaten vidare inom ledgångsreumatism. BioStock kontaktade SynActs CSO Thomas Jonassen för att få veta mer. 

En av de vanligaste kroniska inflammatoriska autoimmuna sjukdomarna är reumatoid artrit (RA) – en sjukdom som har få behandlingsalternativ. Metotrexat (MTX), som är ett sjukdomsmodifierande antireumatiskt läkemedel (DMARD), är den vanligaste första linjens behandling för RA. Dock upplever en betydande andel av patienterna otillräckligt svar (IR) på sin initiala behandling med MTX. Denna patientpopulation, kallad primära MTX-IR-patienter eller DMARD-IR-patienter, har inte bara ett stort medicinskt behov utan attraherar även betydande intresse för partnerskap. 

Förändringar för SynAct

SynAct Pharma är ett bioteknikbolag i klinisk fas som utnyttjar melanokortinsystemet – ett nätverk av peptider och receptorer i kroppen som styr ett antal fysiologiska funktioner, bland annat inflammation. Bolaget använder systemet för att tackla kroniska inflammatoriska tillstånd så som RA, utan att hämma immunförsvaret. 

I slutet av förra året identifierade Synact oegentligheter och oväntade i den kliniska studie som utvärderade bolagets ledande kandidat resomelagon i patienter med måttlig till svår aktiv reumatoid artrit som fått ofullständigt svar på MTX. Detta utlöste diskussioner om bästa vägen framåt, samt ett behov av omstrukturering av styrelse och ledning där man bland annat utsåg Jeppe Øvlesen till vd igen. Detta beslutades vid bolagets extra bolagsstämma förra månaden. Läs det senaste om förändringarna här. 

Nu fokuserar Synact på att vända situationen genom en ny strategisk plan och en riktad nyemission om 49,2 Mkr. Likviden kommer att gå till fortsatt utveckling av resomelagon i en fas IIb-studie i RA. 

Bolagets CSO kommenterar 

BioStock kontaktade SynActs CSO Thomas Jonassen för att få veta mer om vad väntar härnäst inom RA-projektet. 

How will SynAct continue the development of resomelagon in RA?

– Following the completion of the BEGIN, EXPAND and part A of the RESOLVE study we now know much more about the possibilities to develop resomelagon in Rheumatoid Arthritis (RA). A straightforward and clinically very interesting way would be to continue development of the compound as a Glucocorticoid (GC) and TNF-blocker sparing agent.

– A very clear recommendation from the current treatment guidelines is to reduce the use of GC to an absolute minimum. Even the so-called bridge treatment consisting of up to three months dosing to suppress symptoms while the slower onset of acting drugs such as Methotrexate (MTX) induces its clinical effects is questioned in the latest version of the treatment guidelines (ACR 21 and EULAR 22). The issue is that without adding GC to MTX treatment fewer patients reach the treatment goal of significant reduction in disease activity within three months and disease control within six months. Consequently, adding GC to the MTX treatment is widely used. The major problems with the GCs are the unwanted side effect profile, especially following continued treatment, and once GCs are introduced it’s too often difficult to postpone the treatment again. For both patients and the rheumatologist, this is what they really want to avoid, but, as highlighted in the latest version of the European treatment guideline, that chronic GC therapy is used in about half of all RA patients.

– We see this as an opportunity to develop resomelagon as first-line treatment in combination with Methotrexate (MTX) in newly diagnosed RA patients with high disease activity including signs of systemic inflammation. In these patients, the current treatment recommendations are associated with disease control in approximately half the patient population pending co-administration with GCs and in many patients, second-line treatment with TNF-blockers will be initiated early.

– A reduction in the use of GCs and a postponed introduction of TNF-blockers would be a very attractive treatment goal as both the GCs and the TNF-blockers, despite being effective, are associated with unwanted side effects. Having the results from the BEGIN study and from the patients presented as newly diagnosed with systemic inflammation in the EXPAND study in mind, a relevant next step would be a dose range phase IIb study to be set up under the existing US-IND covering the treatment of RA with resomelagon.

– Another possibility highlighted by our clinical advisors would be to explore the option of using the compound as a G- sparing compound in more advanced disease in patients where combination treatment with MTX and a biologic DMARD (bDMARD) such as the TNF-blockers cannot control the disease activity. Here low dose GC treatment, applied after several attempts to apply another bDMARD or a JAK inhibitor, often is the way to address the disease. An oral compound such as resomelagon with what seems to be an attractive side effect profile could be a novel treatment opportunity for these patients. This should evidently be explored as one of the treatment opportunities beyond the early patients that currently have our focus. However, we have to realise that we need to be very focused simply because we work on a very limited budget.

What about DMARD-IR patients, e.g. positioning resomelagon as second-line treatment?

– The RESOLVE study was set up to test resomelagon’s potential as a novel treatment option in patients with a lack of disease control despite a minimum of three months of treatment with a stable dose of MTX. The primary aim of part A, where we only dosed for four weeks, was to identify feasible doses for further development, i.e. to set the doses to be applied in part B of the study, a 12 week’s phase IIb study.

– Unfortunately, the data did not give us an indication that the compound was active in the patients, and we need to explore further in these patients before we can go to phase IIb. The major reason for the unexpected outcome can most likely be explained by large heterogeneity in the recruited patient population with many chronic patients, of which many had been treated for years in non-optimal ways. Only a minority of these patients is characterised by a lack of treatment effects following first-line treatment with MTX.

– Before any potential development of the compound in part B of the RESOLVE study additional exploratory studies with dosing to the “right” patient population should be done. The most logical way to define such patients would be to look at current treatment guidelines, where a DMARD-IR patient is defined as a RA patient experiencing an incomplete response (IR) to first-line treatment, e.g. as mentioned above, this patient will have a lack effect after three months treatment with MTX often in combination with GC or lack of disease control after six months first-line treatment. In addition to not responding to first-line treatment, we would most likely also have to select the patients based on signs of systemic inflammation (defined as CRP outside normal range). Moreover, the patients should also present with what is called poor prognosis factors (high disease activity, signs of morphological changes in the joint structures or treatment with MTX in combination with another conventional DMARD) and we should ensure that the patients were newly diagnosed when the MTX treatment was initiated.

– In a clinical development context, unfortunately, the narrow window of opportunity mentioned above means that it would be difficult to recruit such patients for our trials, and to focus on such patients as the primary development path for resomelagon would be something I would not recommend.

– DMARD-IR patients are typically the first patient population for drug candidates in RA. The potential commercial partners can benchmark an effect of a given drug candidate to what they already know, but very few DMARD-IR compounds have been developed in a patient population as defined above. Rather most studies include patients comparable to what we included in the RESOLVE part A, and typically a compound has a good chance to show effect only if it can suppress the immune system. However, resomelagon promotes inflammatory resolution rather than immune suppression, meaning that you need to be much more selective in your patient selection to fully describe the effect.

– From a commercial point of view, development within DMARD-IR patients for most is considered more attractive than for first-line treatment as the traditional approach for willingness to pay for first-line treatment is limited. You often hear stated that MTX is cheap, and GC are cheap and consequently all other potential first-line treatments will be set at a low price. However, if you can show that you can reduce the use of GC, postpone the use of TNF-blockers and other more expensive compounds, and at the same time potentially reduce the need for clinical visits due to a patient friendly profile of an oral, well tolerated compound without immunosuppressive potential, I would be very surprised if a fair price could not be reached.

– Further, and importantly, even if we could show an attractive treatment effect and a good safety profile of resomelagon as a second-line compound, e.g. as a potential alternative to TNF-blockers in DMARD-IR patients, it’s not the same as to say you have “a winner.” As one of our clinical advisors phrased it: “Even in a best-case scenario where the FDA have approved the compound as a first-line agent after a cDMARD such as MTX, and that it showed a favourable safety profile and in head-to-head trials with current therapies showed rapid onset of action and good clinical efficacy, it would be unlikely that it would be widely used.” This simply because physicians would prioritise the use of TNF-blockers and JAK-inhibitors, despite their less attractive side effect profile, as they are so well integrated into daily clinical practice. Evidently, this is not necessarily the mainstream perspective for all rheumatologists, but it highlights that it is not straightforward to expect that good data in DMARD-IR patients is the same that you have a good business case.

– Consequently, for us as a small company it would be more attractive to show that we could postpone or even reduce the need for TNF-blockers with a safe and well tolerated compound like resomelagon implemented very early in the treatment of RA, then it would be to aim at competing with the TNF- blockers in the group of patients who did not respond to first-line treatment. Perhaps it also should be mentioned that the reason why the TNF-blockers are not considered first-line treatment is not as much related to efficacy, as they are very effective, but rather that the safety profile can’t justify it being positioned as first-line treatment.

– For the reason above, we will not have our primary focus on developing resomelagon as a novel option for second-line treatment, meaning that we will not set the next study up in (early) DMARD-IR patients, but would rather, when we have our next study in newly diagnosed patients up and running, explore the possibilities to generate a clinical proof of concept in a smaller exploratory study. If it shows effective, we could consider continuing with development in phase IIb, but it would probably need some kind of commitment from a commercial partner, as it more than anything else should be seen like a benchmark study to show the full potential of the compound.

– Instead, the primary focus is to start with an adequately powered, well-designed phase IIb dose-ranging study, establishing the proof-of-concept that resomelagon may postpone or even reduce the need for TNF-blockers with a safe and well tolerated compound implemented very early in the treatment, in patients with systemic inflammation, who would otherwise be considered candidates for GC bridging therapy with MTX.

How important is Eastern Europe for this project?

– Eastern Europe represents a large portion of the population in Europe and many clinical trials are conducted in full or part at sites here. In fact, about half of the phase II studies registered on clinicaltrials.gov as an industry sponsored phase II study with intervention in RA include sites in Eastern Europe. This is true both for the studies started before 2015 and after, and also for studies with big pharma as sponsors.

– As for all other territories, there are good sites not only with regard to the possibility to recruit patients, but also, importantly, sites that are very experienced in conducting clinical trials, with very good and dedicated staff and with very good quality in the data they deliver, i.e. that documentation and accuracy are to the point. You can also find sites that have difficulties finding patients and/or delivering a less satisfying quality, as we do here in Western Europe and in the US as well.

– However, as the healthcare systems in Eastern European societies keep developing, their possibilities to get the right treatment and to get it on time, are different from what we know here in the Nordic Countries. We saw that in the EXPAND study, where a large fraction of patients had a long gap from RA diagnosis until initiation of treatment. Such patients were evidently not what we had in mind when we set up the study, and we were therefore not specific enough in our inclusion criteria. Knowing that we should be more selective in our inclusion criteria, it is a quite simple task to avoid getting the” wrong patients“ to be part of future studies. Likewise for the patient population in the RESOLVE part A. We got many chronic patients in that study. However, it was not only sites from Eastern Europe, that recruited such patients. Also, the majority of patients recruited at the sites in the US should be considered chronic and, in many cases, not patients treated up to date. This is not only a question of where to find your patients, but also about being specific in your inclusion criteria.

– In other words, you can find the right patients at sites in Eastern Europe, and you can trust the quality of the data you get if you work with the right sites and set up your protocol in the right way. Or, phrased differently, to continue to recruit patients from selected sites in Eastern Europe, together with sites in other parts of Europe and the US would be a wise decision, because we have the data from the previous studies that will guide us in the right direction, as opposed to embarking on a complete new path with sites and countries where we do not have any experience.

What can you tell us about your experience with the CRO for this study?

– The way the company communicated during the autumn gave many the impression that the CRO, meaning the company that we engaged to run the studies, was to blame for the data we got. However, the issues related to the data were not a question of the CRO recruiting the wrong patients, accepting questionable data or other, that could explain why we did not get the data, we had expected/hoped for.

– First and foremost, we have learned, that treatment with resomelagon most likely should be restricted to relatively newly diagnosed patients with signs of systemic inflammation, i.e. more severe disease in the early stage of the disease, and you can’t blame the CRO for not solely recruiting those patients when the protocol didn’t describe that.

– When it comes to recruiting patients to a given study, it’s the inclusion and exclusion criteria that define the patients that eventually will participate in the study. The company make a study synopsis, where the inclusion and exclusion criteria are described, and based on that, the CRO writes the protocol that in the end will be approved by the company and the health authorities in the countries where the study is performed. In the current case, we as a company discussed it internally, got input from rheumatologists and even discussed it at the R&D committee on the Board. We also had a constructive discussion with the CRO, not at least their CSO, who is quite skilled in the field. We all agreed that we had recruited more broadly, both with regard to disease development and inflammatory status, than we would have if we had to rerun the studies. This is how it works in science, you set up a hypothesis, test it and learn from there and evidently you can’t blame the CRO if you as a company set up the wrong hypothesis.

– Further, an external audit concluded that the quality of the data reported from our RESOLVE study was to the point, that we as company did our overview of the study as we should, and that the data was suitable for analysis and for further decisions. The report also states that the interviewed SynAct staff appeared very knowledgeable and experienced. So, any statement like the studies suffered for lack of company overview and in the hands of a less experienced CRO is nonsense.

– There was an issue with one site in the RESOLVE study. The issue was identified as part of the routine central monitoring process by our CRO in late spring 2023. A full investigation was conducted including a site audit by the CRO. When we got the unblinded data in late October 2023, we saw further issues that needed unblinding to be identified. Based on that we have decided to exclude all efficacy and exposure data from that site, but the impact on the overall data for the trial was found to be negligible. This can happen also in Western Europe and the US, as it was related to a single associate person’s misinterpretation of the way source data should be handled.

– We have also learned from the process how to optimise communication between us and the CRO. Where we, following the implementation of a recommendation from the FDA to version 2 of the RESOLVE protocol, could have avoided some unclarities. However, this would not have changed anything on the outcome of the study, which more than else suffered from a too broad inclusion criteria.

– Finally, it would be appropriate to mention, that one of our newly announced high profiled clinical advisors (key opinion leader) has worked with the CRO for years and has very specifically recommended that we continue to use them. Not least due to their ability to handle and interpret data.

What can you tell us about the outcome of the recent EGM and the directed share issue?

– It has been a very challenging period in SynAct, and we now have to build from a very low point when it comes to market cap. Since we reported high level data from the EXPAND study early in September, a communication that was far from optimal, I have repeatedly been contacted by long term shareholders and supporters of SynAct Pharma. I am very grateful for the continued support.

– Following the call for the EGM, Jeppe and I experienced fantastic support. So even as it has to be considered a last option decision, it seems like the right choice. At the EMG, more than 10 million out of the around 35 million votes in the company were present. A large portion of these votes through power of attorney sent to Jeppe. A formal count of votes was not done at the EGM, but we know that we controlled around 75 per cent of the votes, which clearly shows that we made the right decision.

– Now we must move on. At the start it will be very focused to bring resomelagon further forward in RA. With the directed issue we have just announced we get enough money in to initiate further development in RA. This evidently makes a difference, and to do that on a premium secure the current owners, and hopefully it with be interpreted by the market as a signal that we can get the company back on track.

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