At the beginning of the year, Alligator BioScience presented promising interim data from its OPTIMIZE-1 phase II study in metastatic pancreatic cancer. To put further emphasis on the study design and importance of these results, the Swedish biotech hosted a webinar featuring Alligator’s CMO Sumeet Ambarkhane and Jean-Luc Van Laethem, who is Principal Investigator for the study. BioStock spoke with Dr Ambarkhane to learn more.

Pancreatic cancer is one of the deadliest forms of cancer. The high death rate has remained unchanged for at least half century according to Pancreatic Cancer UK. The five-year survival rate globally is currently around 10 per cent, and median survival is around 6-months.

The pancreas is so deep within the cavities of the body that current screening methods are unable to pick up any 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, and the other 80 per cent are treated with chemotherapy. So there is a huge unment medical need for this indication.

Alligator Bioscience in phase II with CD40 agonist

Determined to make a difference, Alligator Bioscience is developing an antibody drug candidate called Mitazalimab – a CD40 agonist. Activation of the CD40 receptor on dendritic cells enhances the immune system’s antigen presentation, thus selectively attacking cancer cells.

The candidate is currently being evaluated in a phase II trial in combination with FOLFIRINOX – the most common chemotherapy for pancreatic cancer patients. Alligator published interim data from the OPTIMIZE-1 study at the beginning of the year, and CEO Søren Bregenholt came to the BioStock Studio for an exclusive interview to talk about the results. You can watch the interview here.

KOL webinar

To give even more insight on the study’s design and overall goals, the company recently hosted a webinar featuring Alligator’s CMO Sumeet Ambarkhane and Principal Investigator of OPTIMIZE-1 Jean-Luc Van Laethem.

During the webinar, these two explain the interim efficacy results from OPTIMIZE-1 and put them into context with current treatment options. Dr Van Laethem talks about the primary endpoint in the study – the objective response rate (ORR).

»I think the most important takeaway from the interim analysis is the strong signal it has generated, indicating clinically meaningful activity of Mitazalimab when added to the chemotherapy backbone FOLFIRINOX« — Sumeet Ambarkhane, CMO Alligator Bioscience

Dr Van Laethem points out that the ORR of 52 per cent observed with the combination was significantly higher than the previously measured ORR of approximately 30 per cent relating to FOLFIRINOX alone. He also emphasises on continuing mitazalimab’s development in this patient population, as well as other tumour types and potential treatment combinations. The webinar can be viewed here.

CMO comments

To learn more about the phase II results and the scope of the webinar, BioStock got in touch with Dr Sumeet Ambarkhane for an interview.

Dr Ambarkhane, the last time you spoke to BioStock, which is when you had just started in your role as CMO at Alligator, you said “I am convinced we will deliver very interesting data in the next 12 months.” Now, only 6 months since your statement, are you prepared to say, “I told you so?”

– Absolutely. And this is pretty evident with the interim results that we have reported at the start of the current year. Mitazalimab in combination with mFOLFIRINOX chemotherapy demonstrated an encouraging ORR of 52 per cent in this preplanned interim analysis of our ongoing OPTIMIZE-1 clinical trial. This response rate, although preliminary, is quite impressive in light of the approximately 30 per cent response that has been reported with FOLFIRINOX alone as a frontline treatment for patients with pancreatic cancer.

From your perspective, what are the key takeaways from the OPTIMIZE-1 phase II interim results?

– I think the most important takeaway from the interim analysis is the strong signal it has generated, indicating clinically meaningful activity of Mitazalimab when added to the chemotherapy backbone FOLFIRINOX. The results met the predefined statistical threshold, such that the study passed futility and is now continuing to complete its recruitment in a timely manner. It needs to be acknowledged that these are preliminary data, and other results such as duration of response, progression free- and overall survival are not mature at this stage. Mitazalimab combined with FOLFIRINOX is associated with a very manageable safety profile, indicating the clinical feasibility of this regimen. These results provide additional confidence about the relevance of CD40 as a therapeutic target in this very difficult-to-treat patient population.

During the webinar, Dr Van Laethem talks about the interim results and the primary endpoint, the objective response rate. Could you tell us more about the significance of this endpoint?

– As Professor Van Laetham mentions in the webinar, the primary endpoint of the OPTIMIZE-1 clinical trial is the ORR, measured according to the RECIST 1.1 criteria for solid tumours. These assessments comprise of sequential imaging of the tumour burden for each patient at periodic intervals as a part of the trial. An objective response is assigned only if there is substantial (at least 30 per cent) reduction in the total size of the tumour, demonstrated on two consecutive scans. Thus, this is a rather stringent method of assessing efficacy and rules out a transient effect that may not be associated with much clinical benefit.

Could you talk about the secondary endpoints and when you expect to reach them?

– Indeed. The study includes analysis of all standard secondary endpoints which are routinely performed in the context of oncology clinical development. These include duration of response, progression free survival, overall survival as well as assessment of safety and tolerability, pharmacokinetics and pharmacodynamic effects, and evaluation of other exploratory biomarkers. As mentioned earlier, the overall duration of treatment, as well as follow up of patients for progression free and overall survival, had not been long enough at the time of this interim analysis. Generation of these data is continuing as the study is progressing, and we are positive that more mature and meaningful results will be available later this year – these results will inform about the longevity of the effect and clinical benefit, in addition to the response rate itself.

During the webinar, you talk about how pancreatic cancer is “immunologically cold.” What do you mean by that?

– Tumours which are associated with infiltration by cytotoxic T-cells are regarded as immunologically warm, and these tumours are often responsive to immunotherapy. Classical examples are melanoma and some lung and renal cancers. Whereas, pancreatic cancer does not have this feature and thus is considered immunologically cold. On top of that, it has a lot of fibrotic stroma, which makes the penetration of treatments to the tumour cells difficult. Due to these features, classical checkpoint inhibition has not been able to improve outcomes in pancreatic cancer patients and the overall prognosis remains dismal.

What is it about mitazalimab that makes cancer cells more vulnerable to immune attacks?

–  Mitazalimab targets CD40 in the tumour microenvironment. It activates dendritic cells resulting in a better antigen presentation that leads to a higher influx of T-cells with tumour cell-killing properties. It also converts the macrophages in the tumour microenvironment to a more pro-inflammatory subtype, further increasing the antitumour effect. With the addition of chemotherapy, these effects of mitazalimab are further enhanced due to the release of antigens from dying cancer cells, resulting in a lasting effect.

What comes next for the study?

– As mentioned, we remain on track to complete the patient recruitment for this trial. Importantly, the treatment and follow up of the patients are ongoing, and additional results will be available later in the year. Topline results from the main (primary) analysis of the trial will be available at the latest in the first quarter of next year. We are also collaborating with key experts in the field to better interpret these data and explore the possibility of identifying patient subgroups that may preferentially benefit from this therapeutic combination. So there is much more to come on the results front.

Finally, will Alligator continue the preparations for phase III and the dialogues with potential partners, as well as initiate discussions with regulatory authorities on possible accelerated development pathways?

– As a clinical-stage biotech, the mitazalimab programme is Alligator’s highest priority. We are taking all the efforts in laying down a solid path for the confirmatory development and first regulatory approval for mitazalimab in pancreatic cancer. It is very likely, that additional and much larger randomised studies will be required in this process, which is where partnering the programme for a seamless execution of confirmatory development will be of key importance. Since the unmet medical need in this patient population is very high and there are not enough promising therapeutic approaches in development, acceleration of overall clinical development of mitazalimab is on the table and will be a part of our upcoming discussions with regulatory authorities worldwide.

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