Efter att ha uppnått det primära effektmåttet i fas II-studien OPTIMIZE-1 med mitazalimab i bukspottkörtelcancer kan Alligator Bioscience nu börja förbereda fas III. Bolaget presenterade nyligen resultaten i mer detalj i ett webbseminarium för Key Opinion Leaders. BioStock pratade med Alligators CMO Sumeet Ambarkhane för att få veta mer.

Bukspottkörtelcancer är en av de dödligaste cancerformerna, med en medianöverlevnad på cirka sex månader och en femårsöverlevnad på cirka 10 procent. En del av problemet är att bukspottkörteln är ett organ som ligger djupt inne i kroppen, och dagens screeningmetoder kan inte fånga upp tidiga tecken på malignitet. När symtomen uppstår är cancern redan i ett sent skede, där konventionell behandling i stort sett är ineffektiv.

Totalt sett är endast 20 procent av patienterna berättigade till operation. Det innebär att så många som 80 procent av patienterna inte har möjlighet att erhålla kirurgi och behandlas istället med cellgifter. Det betyder att det medicinskt behovet är stort för denna indikation.

Alligator Bioscience når primärt effektmått i fas II

Alligator Bioscience är fast beslutna att de har hittat en lösning – mitazalimab som är en antikropp som binder till CD40-receptorn som finns på celler i immunsystemet. När receptorn väl har aktiverats förbättrar den immunsystemets antigenpresentation och attackerar cancerceller selektivt.

Det svenska bioteknikbolaget har publicerat top-line-data från fas II-studien OPTIMIZE-1 som utvärderar mitazalimab som första linjens behandling i kombination med FOLFIRINOX – den mest effektiva cellgiftsbehandlingen för patienter med bukspottkörtelcancer. Data visar en objektiv responsfrekvens (Objective Response Rate, ORR) på 40 procent, vilket uppfyller det primära effektmått som fastställts för denna studie och bekräftar den kliniska nyttan av mitazalimab som sågs i interimsdatan.

“Varaktighet av behandlingssvaret sticker ut”

Ytterligare viktiga datapunkter i denna analys är 12,5 månaders varaktighet av behandlingssvar (Duration of Response, DoR), 7,7 månaders progressionsfri överlevnad (PFS) och 14,3 månaders total överlevnad (Overall Survival, OS). Alligator höll ett KOL-webbinarium nyligen för att diskutera resultaten mer i detalj. Utöver bolagets vd Søren Bregenholt och CMO Sumeet Ambarkhane bjöd Alligator in Dr Zev Wainberg för att ta del av hans expertinsikter. Dr Wainberg är co-director för UCLA GI Oncology Program och klinisk konsult för det kliniska utvecklingsprogrammet för mitazalimab. Han har varit huvudprövare för flera kliniska prövningar inom gastrointestinal onkologi, inklusive bukspottkörtelcancer.

Enligt Dr Wainberg är DoR det som verkligen sticker ut från Alligators studiedata.

»That’s never been shown before in metastatic pancreatic cancer. The median duration of response reported with gemcitabine combined with nab-paclitaxel of FOLFIRINOX regimens range between 3 – 6 months across the published studies. The median DoR in the OPTIMIZE-1 study appears more than two times better, translating in better overall survival for these patients. So, the fact that there are still 51 per cent of the patients still ongoing in the study, and with 32 per cent of patients still on treatment, would suggest that, in fact, we are going to end up seeing quite a bit longer duration of response and survival as the data matures.« — Dr Zev Wainberg, co-director of the UCLA GI Oncology Program

Alligators vd Søren Bregenholt besökte BioStock Studio för en exklusiv intervju rörande resultatet. Se intervjun här.

Förberedelser för start av fas III 2025

Alligator Bioscience har i diskussioner med FDA kunnat etablera en tydlig väg för utveckling och godkännande för mitazalimab i bukspottkörtelcancer. Mot bakgrund av nya data från  fas II-studien har den amerikanska läkemedelsmyndigheten dessutom godkänt att Alligator kan gå vidare till en fas III-studie efter OPTIMIZE-1, som Alligator planerar att inleda i början av 2025.

Kommentarer från CMO

BioStock kontaktade Alligators CMO Sumeet Ambarkhane för att få hans syn på resultaten samt en djupare förklaring av Dr Wainbergs kommentarer.

Sumeet, what is the overall take-home message from these results?

– As a physician-scientist in oncology drug development, I find these results extremely encouraging – most importantly for patients with pancreatic cancer, but also for the researchers across the world who strive to develop better therapies to improve outcomes for cancer patients. For Alligator as an immuno-oncology biotech, these results validate mitazalimab as the best-in-class second generation CD40 mAb that can be safely combined with chemotherapy, contributing to a further improvement in clinical benefit. This also opens up multiple development possibilities for mitazalimab, in combination with various other anticancer drugs and in multiple tumour types. All in all, these results substantially boost the value of mitazalimab and Alligator’s innovative drug development pipeline.

Regarding the objective response rate (ORR), 40 per cent deemed as “confirmed” ORR, while 51 per cent was deemed “unconfirmed.” Could you elaborate on that?

– ORR is the primary endpoint for the OPTIMIZE-1 study, which is classically the case for phase II, non-randomised trials. We have taken a more conservative approach that requires at least two consecutive CT scans that show an objective response, in order for a patient to be considered as a confirmed responder, which eventually contributes to the assessment of the primary endpoint ORR. This approach of response assessment resulted in a confirmed ORR of 40.4 per cent in the study. Whereas, the unconfirmed response rate includes all patients who had at least one CT scan showing objective response (regardless of the subsequent scan showing a response or not). This number is as expected higher, amounting to 51 per cent of the evaluable patients. Of note, the most recently reported randomised phase III study NAPOLI-3 (with NALIRIFOX as the investigational therapy) had reported “unconfirmed” ORR in their response assessment readout.

Why does Dr Wainberg consider duration of response as the most interesting result?

–  First of all, the durability of response (DoR) that we have reported is unprecedented, much longer that the response duration reported with any standard or investigational frontline therapy for metastatic pancreatic cancer. For example, the median DoR reported with FOLFIRINOX, Gemcitabine-nab-Paclitaxel and NALIRIFOX was 5.9, 3.9 and 7.3 months respectively, and as against this the 12.5 month DoR with mitazalimab+mFOLFIRINOX is more than two times longer.

– More importantly, the long DoR indicates a much longer duration for which patients remain progression free, in many cases with better quality of life. DoR has a direct positive impact on overall survival, which is a gold standard to assess clinical benefits of a treatment from a clinical as well as regulatory point of view.

The FDA has endorsed a phase III study. How are preparations for that going?

–  The preparations for a phase III study are going in full speed. The interactions with the FDA have been very positive, and we are following their guidance in this regard. These preparations mean that the Alligator team is working on all fronts, such as the preparedness in terms of manufacturing, regulatory as well as the clinical scientific and operational front. We have a globally recognised and expert panel of advisors who are extremely supportive in this regard, and we are positive that our efforts will pave the way for a timely and efficient start of the phase III trial.

Have the dialogues with potential partners intensified?

–  Absolutely. The OPTIMIZE-1 data have generated great interest across various companies, and we are looking forward to continue meaningful conversations with potential partners. In the background of these discussions, will be successful continuation of mitazalimab development in the confirmatory stage for pancreatic cancer, as well as expanding it into various other tumor types with unmet need. Just a couple of days ago, FDA has approved NALIRIFOX as the new regimen, which adds another important therapeutic option for this patient population. Developments like these further substantiate the value of mitazalimab, which due to its favorable safety profile becomes an attractive combination partner for existing and newer therapies.

Finally, on a more general note, Dr Wainberg mentioned that the oncology field is trying to move on from chemotherapy and putting more focus on immunotherapy. Does this mean that there is a future for CD40 agonists like mitazalimab as stand-alone therapies?

– Well this is an interesting perspective that doctor Wainberg shared in his talk. Indeed, immunotherapy is taking more importance in the current therapeutic landscape and is increasingly being utilized even in initial lines of treatments. This consideration will also certainly apply for mitazalimab. The data from the OPTIMIZE -1 study very clearly indicate the substantial addition to the durability of response in particular for patients where chemotherapy had an initial effect. So clearly, combination with chemotherapy or also with other immunotherapeutic drugs such as checkpoint inhibitors or cancer vaccines will remain as the main development approach for mitazalimab. Whereas we do have even more potent, third generation bispecific antibodies in Alligators early development pipeline, such as ATOR-4066 and we are working hard to bring this soon to clinical development in order to demonstrate its activity as stand-alone therapy. So, stay tuned!

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