Bioteknikbolaget Cyxone förbereder läkemedelskandidaten Rabeximod för nästa kliniska steg. Nyligen tillkännagav bolaget ett samarbete med professor Costantino Pitzalis, en världsledande expert som omdefinierar klinisk prövningsdesign inom ledgångsreumatism, för att ge råd om den kommande fas IIb-studien. BioStock kontaktade professor Pitzalis för att höra hans syn på Rabeximod och vilken inverkan läkemedelskandidaten potentiellt kan göra på marknaden för ledgångsreumatism.

Malmöbaserade bioteknikbolaget Cyxone utvecklar Rabeximod för behandling av ledgångsreumatism (RA). Rabeximod är en läkemedelskandidat med en verkningsmekanism som bland annat har potential att skydda leden från de skador som uppstår vid RA. Kandidaten genomgår för närvarande även en fas II-studie på patienter med måttlig covid-19. Preliminära resultat från denna studie förväntas under tredje kvartalet.

Stort behov av nya behandlingar för RA

Rabeximod är en oralt formulerad läkemedelskandidat där målet är att utveckla en väl tolererad och effektiv behandling för de tidiga stadierna av sjukdomen, samt även i senare skeden. Läkemedelskandidaten riktar in sig på en proinflammatorisk makrofag som spelar en viktig roll i den inflammatoriska process som orsakar strukturella skador i leden och som driver kliniska RA-symtom.

Idag är en av de vanligaste första linjen-behandlingarna för RA-patienter metotrexat (MTX), som är förknippad med biverkningar som illamående, huvudvärk och ett nedsatt allmäntillstånd efter dosering. Cyxones läkemedelskandidat kan erbjuda ett nytt tillvägagångssätt och har visat sig vara väl tolererad i tidigare kliniska prövningar.

Världsledande expert

Rabeximod förbereds för närvarande för en kommande fas IIb-studie, och Cyxone tillkännagav nyligen ett samarbete med den världsledande experten inom RA, professor Costantino Pitzalis.

Professor Pitzalis är professor i reumatologi vid William Harvey Research Institute, Barts och London School of Medicine and Dentistry. Han utbildade sig i medicin i Italien 1983. År 1985 flyttade han till Storbritannien som forskare vid institutionen för reumatologi vid Guy’s Hospital där han började sin akademiska karriär med att forska om reumatism och psoriasisartrit i fyra år, vilket ledde till en doktorsexamen vid University of London. Idag är professor Pitzalis känd som en världsledande expert inom ledgångsreumatism och inom biopsidrivna kliniska studier med 290 publicerade vetenskapliga artiklar inom inflammation, immunitet och artros.

Professor Pitzalis har varit involverad i flera utvecklingsprojekt inom RA varav många idag är marknadsgodkända RA-läkemedel. Han har ett stort intresse kring innovativa patientcentrerade, molekylära patologidrivna kliniska prövningsmetoder, ett intresse som kommer av hans erfarenhet av att jobba med patienter och en förståelse för bristerna i existerande behandlingar.

»Prof. Pitzalis is the Chief Investigator of a comprehensive biopsy-driven stratified-medicine randomised clinical trials (RCTs) programme funded by MRC/VA and NIHR. Prof. Pitzalis is uniquely positioned to understand how Rabeximod with its novel mode of action can fit into the early RA treatment market.

For Cyxone, the collaboration with Prof Pitzalis validates our business case for the development of Rabeximod as an alternative first-line treatment to methotrexate and supports our hypothesis that Rabeximod by its unique mode of action and good safety profile can serve to provide a convenient drug, which patients can easily tolerate, and which makes a significant impact on slowing or preventing the progression of the disease.« – Tara Heitner, vd Cyxone

Professor Pitzalis kommenterar

BioStock kontaktade professor Pitzalis för att höra hans syn på projektet och vad Rabeximod kan tillföra RA-patienter för att förbättra deras situation.

Professor Pitzalis, how would you characterise the development within the RA field today?

– The rheumatology community needs to develop an alternative strategy with innovative trials that will facilitate the development of novel drugs to address unmet treatment needs. For example, there are patients with disease that do not respond to existing medications. And many patients who simply do not take their medication due to the debilitating side effects.

– We need to develop better therapeutics where patients do not have to compromise between disease progression and quality of life. In addition, the lack of predictors of response to individual therapeutics, which are used on a “trial and error” basis complicates the problem. Therefore, our group and others have been trying to define histological and molecular predictors of response to treatment while novel molecules are being developed in the attempt to target more patients failing other drugs.

– Although pharmaceutical companies continue to produce a rich pipeline of novel therapeutics, the complexities and extraordinary costs of conventional trials have limited their development.

– Therefore, we also need to be able to run trials more efficiently by reducing the number of participants required in each trial and reducing the costs associated with performing single trials in multiple disease indications.

– If trials become simpler, less costly and deliver more information, this will only help patients in the end. Ultimately, we want to deliver precision medicine, that is treatments tailored to the cellular and molecular signature of the patient.

You have been involved in developing several recently approved RA therapies. Why do you believe that there is a need for a drug like Rabeximod?

– Indeed, I have seen a very positive evolution in the treatment of RA since I started my career. There are today many drugs on the market for RA such as biologics targeting IL6 and TNF alpha and now JAK inhibitors. These are making a difference for patients who respond, however unfortunately there are many patients who do not respond or who respond poorly. Furthermore, these drugs are taken as injections which many patients do not like. But these are drugs intended as second- or third-line treatments after failure of first line treatment.

– First line treatment for patients with RA is mainly MTX. And this is a problem in the RA field today. This is a very inexpensive drug that does slow down the progression of RA, however at a high cost to patient quality of life. Too many patients, experience days of nausea and sluggishness after taking the drug – the so called MTX hangover. And many experience unacceptable side effects like severe stomach problems. In reality, many patients choose not to take their medication, and this is why RA progresses.

– Rabeximod promises something different. It is a drug candidate which can be taken as a pill, and it has a good safety and tolerability profile compared to MTX. Rabeximod has demonstrated improvement over MTX in the phase IIa trial. If we can show even the same efficacy as MTX with Rabeximod, without the side effects in the upcoming phase IIb trial, then this can make a big difference for patients.

The collaboration involves performing mechanistic ex vivo studies of Rabeximod action, what is the value and expected outcome of these investigations?

– We expect to advance and expand on our mechanistic understanding of the unique therapeutic candidate Rabeximod, on track to enter phase IIb clinical trials. The mode of action of Rabeximod is differentiated from current therapies and offers a route to functional modulation of macrophages, key cells in synovial pathology and RA pathogenesis by inhibiting the production of proinflammatory cytokines critical to drive disease and structural damage in the joint. In addition, RBM showed anti-T cell proliferative features that can be of benefit in modulating arthritis pathogenesis.

– The planned mechanistic investigations will utilize modern platforms that will help to identify the specific cellular and molecular targets of Rabeximod. Our data analysis approach is a targeted one and we hope we can identify and validate the most relevant assays for Rabeximod’s mode of action. The optimized assay will be used in patient samples treated with Rabeximod as a next step. Its mode of action in addition to its oral availability and safety profile make Rabeximod a potential ideal therapeutic for RA.

– There is a large unmet need, due to the significant potential side effects of Methotrexate, nausea, feeling unwell for two to three days post-dose that leads to poor compliance in many patients. If a drug is made available even with the same efficacy as Methotrexate but with a better safety/tolerability profile, it would fill a large unmet need.

Clinical trials in RA are being transformed with your methods using biopsies – why do you think synovial biopsies could be important for the development of Rabeximod?

– In-depth characterization of the synovial tissue in rheumatoid arthritis will bring deeper understanding of the cellular and molecular features of the disease in the individual patients, as well as an insight into the pathology of the disease in the joint that cannot be detected by other readouts. This approach can lead to improvement in the response rate to treatment in future trials by matching the use of Rabeximod to the specific patient groups showing better response.

– Rabeximod is a drug with very special properties and with a unique mode of action acting on a subset of immune cells and on a pathway central to the pathogenesis in RA. The inflammatory macrophage is known to be the key cell type responsible for the joint damage which occurs in RA and this is where Rabeximod exerts its effect.

Finally, you have been a part of redesigning the phase IIb study, what differs from the previous design and how do think this will increase the likelihood of a positive readout?

– In my opinion the phase IIa study results showed a promising trend in efficacy even though the study did not meet its 12-week endpoint. The results at 16 weeks showed two important things: Firstly, a significant improvement over the methotrexate alone arm and secondly durability in efficacy since no drug was administered between 12-16 weeks.

– I do not see the delay in the effect as a barrier, since RA is a lifelong chronic disease that lasts years, if not decades, the delay in four weeks is not important if the drug can prevent joint destruction in the long run. I also see that there is much room for improving the signal by focusing on patients who will benefit from the mode of the action of the drug.

– The phase IIa trial included a wide range of patients benefitting and not benefitting from the drug. By omitting as much as possible those patients likely not to benefit from Rabeximod there is a likelihood that the positive signal at 16 weeks will be much higher.

– Finally, we wish to include a subset of patients from whom joint biopsies will be taken so we can analyse the status of the immune cells within the joint of patients before and after treatment with Rabeximod. This will allow us to evaluate the effect of our drug down to a cellular and molecular level to further elucidate the mode of action and our understanding of the biomarkers which define which patients actually do benefit from Rabeximod. This is the first step toward a precision medicine approach for Rabeximod in RA patients.

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