Alligator prepares for phase III with CD40 agonist
Having met the primary endpoint in its OPTIMIZE-1 phase II trial with mitazalimab in pancreatic cancer, Alligator Bioscience can now start preparing for phase III. The company hosted a KOL webinar to explain the results in detail. BioStock spoke with Alligator’s CMO Sumeet Ambarkhane to learn more.
Pancreatic cancer is one of the deadliest forms of cancer, with a median survival of around six months and a five-year survival approximately 10 per cent. Part of the problem is that the pancreas is an organ located so deep within the body, and current screening methods are unable to pick up early signs of malignancy. By the time symptoms occur, the cancer is already in its late stages, where conventional treatment is largely ineffective.
Overall, only 20 per cent of patients are eligible for surgery. This means as many as 80 per cent of the patients do not have the option of a surgical cure and are treated with chemotherapy. So there is a huge unmet medical need for this indication.
Alligator Bioscience meets primary endpoint in phase II
Determined to make a difference, Alligator Bioscience is developing mitazalimab – an antibody that binds to the CD40 receptor found on cells of the immune system. Once activated, this receptor enhances the immune system’s antigen presentation, attacking cancer cells selectively.
The Swedish biotech has released top-line data from the OPTIMIZE-1 phase II trial evaluating mitazalimab as a first-line treatment combined with FOLFIRINOX – the most effective chemotherapy for pancreatic cancer patients. The data show a confirmed objective response rate (ORR) of 40 per cent, thus meeting the primary endpoint set for this study and confirming the clinical benefit of mitazalimab seen in the interim data readouts.
“Duration of response stands out”
Additional key data points of this analysis are 12.5 months duration of response (DoR), 7.7 months progression free survival (PFS), and 14.3 months overall survival (OS). Alligator held a KOL webinar last week to discuss the results in more detail. In addition to the company’s CEO Søren Bregenholt and CMO Sumeet Ambarkhane, Alligator invited Dr Zev Wainberg to give his expert insights. Dr Wainberg is the co-director of the UCLA GI Oncology Program, and clinical consultant for the mitazalimab clinical development programme. He has served as principal investigator on several clinical trials in gastrointestinal oncology, including pancreatic cancer.
According to Dr Wainberg, DoR is what really stands out from the data.
»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
Alligator’s CEO Søren Bregenholt came to the BioStock Studio for an exclusive interview to talk about the results. You can watch the interview here.
Preparing for a start of phase III in 2025
In discussions with the FDA, Alligator Bioscience has been able to establish a clear development and approval pathway for mitazalimab in pancreatic cancer. Moreover, in view of the emerging data from this phase II study, the US regulatory authority has endorsed OPTIMIZE-1 as a phase III enabling study, which Alligator plans to initiate in early 2025.
CMO insights
BioStock reached out to Alligator’s CMO Sumeet Ambarkhane to get his view of the results and elaborate on some of Dr Wainberg’s comments.
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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