DDW Editor Reece Armstrong speaks to Howard Davis, CEO of clinical stage oncology company, Akamis Bio, about its work in developing a gene therapy to treat pancreatic cancer.
In February this year, Akamis Bio announced an expansion of its ongoing partnership with the Parker Institute for Cancer Immunotherapy (PICI) to include a clinical collaboration with the Cancer Research Institute (CRI). The partnership is focused on evaluating Akamis Bio’s lead compound – NG-350A – an immuno-stimulatory tumour gene therapy that could work as part of combination therapies to treat pancreatic cancer.
NG-350A has already shown preliminary evidence of clinical activity in patients in two open-label studies and is now being investigated as part of the REVOLUTION clinical study – a platform clinical study examining novel therapeutic combinations for the treatment of previously untreated metastatic pancreatic cancer.
DDW: What have been some of the challenges so far in developing therapies for pancreatic cancer?
Davis: Despite many decades of research and numerous clinical trials, pancreatic cancer remains one of the most difficult to treat tumour types. The disease often presents at an advanced stage which means that curative treatments like surgery are not viable options. Pancreatic cancers are also often resistant to standard forms of chemotherapy, and even in those patients that do respond, the responses are often relatively short-lived. Typically, only 20% of patients survive for more than one year after a pancreatic cancer diagnosis.
Targeted therapies for individual pancreatic cancer mutations have also met with only limited success because this tumour type tends to harbour a wide range of gene mutations versus having a single dominant mutation which could serve as a common drug target. Pancreatic cancer also generally has a very high level of stromal content – connective or fibrotic tissue that sits in between the cancer cells – which can prevent both therapeutics and immune cells from reaching the cancer. Given this, immunotherapies have also generally been ineffective in the treatment of pancreatic cancer.
Thus, despite enormous progress for cancer therapeutics generally over the last 20 years, pancreatic cancer has remained extremely challenging to treat.
DDW: Why is pancreatic cancer so difficult to treat using a single therapy?
Davis: Given the multiple barriers to treatment that pancreatic cancer cells possess – chemotherapy resistance, diverse gene mutations within the tumour, high stromal content, exclusion of immune cells – single therapies aimed at any one of these barriers individually have had only very limited (if any) success. [This is why] approaching treatment of pancreatic cancer with multiple different therapies, each targeting a different mechanism of resistance, makes strong scientific and clinical sense.
DDW: What do you hope to achieve from your continued partnership with the Parker Institute for Cancer Immunotherapy (PICI)?
Davis: Developing new cancer treatments is complex and collaborating with PICI has provided Akamis Bio with the opportunity to work with the leading clinician scientists and top cancer centres around the world to increase our odds of positively impacting the lives of people living with cancer. The financial support from PICI and access to the deep pool of immuno-oncology talent present in their network is accelerating our efforts to investigate our T-SIGn tumour gene therapies in the clinic.
DDW: Through the partnership, you’ll be working with the Cancer Research Institute (CRI). How will they be involved and how can they help you advance novel treatments for pancreatic cancer?
Davis: CRI are operational and financial supporters of the REVOLUTION study, and they have contributed extensively to the study’s design while also providing a large proportion of the funding for execution of the study. CRI’s commitment to cancer research and the clinical development of novel therapeutics is central to the continued success of REVOLUTION.
DDW: You’re exploring NG-350A in the study. Why can its mechanism of action potentially drive an anti-tumour immune response?
Davis: Akamis Bio is developing a portfolio of solid tumour-targeted T-SIGn therapeutics which aim to enable a patient’s own immune system to recognise, attack, and clear their cancer. NG-350A is an intravenously delivered T-SIGn therapeutic which is capable of driving intratumoural expression of a secreted CD40 agonist monoclonal antibody. NG-350A’s mechanism of action is based on CD40-mediated activation of antigen presenting cells (APCs) resident in a solid tumour and its draining lymph nodes; once activated, the APCs recruit T-cells into the vicinity of the tumour to deliver a potent anti-tumour immune response. NG-350A has the potential for use in both the monotherapy setting, as well as in combination with other immuno-oncology agents.
DDW: If used as a monotherapy, can NG-350A target other cancers?
Davis: The mechanism [described above] is broadly applicable to many tumour types where there are potential tumour antigens, but an inadequate engagement and activation of the immune system. Thus, there are many tumour types where NG-350A monotherapy may be able to help overcome immune resistance (so called ‘cold’ tumours). Akamis Bio is also exploring NG-350A in combination with checkpoint inhibitors, to overcome tumour resistance to these agents.
DDW: Through the partnership with PICI and CRI, will you be exploring other therapies targeting pancreatic cancer?
Davis: The REVOLUTION study is our first clinical partnership with PICI and CRI. As the partnership advances over the coming years, we will continue to explore other potential innovative approaches to the treatment of pancreatic cancer in an effort to address the enormous unmet need associated with this disease.
DDW: Could you tell us about the REVOLUTION clinical study?
Davis: REVOLUTION is an ongoing Phase 1 study in newly diagnosed advanced pancreatic cancer patients, exploring novel immunotherapy combinations. The study has recruited a series of different cohorts of patients, each examining a novel approach to rationally combining therapies to treat pancreatic cancer. The cohort that NG-350A is part of (“Cohort C”) is testing whether a combination of standard chemotherapy (gemcitabine / nab-paclitaxel), a CTLA-4 checkpoint inhibitor and NG-350A, given sequentially in several cycles, can improve treatment outcomes in this patient population. The study was initiated by PICI, and is now also supported both operationally and financially by CRI.
DDW: You’re also exploring NG-350A in two open-label studies. What insights have these studies generated and can you explain what stage each study is at?
Davis: The Phase 1a FORTITUDE study is evaluating the safety, tolerability and preliminary efficacy of NG-350A as monotherapy in patients with metastatic or advanced epithelial tumours. This study has established a maximum tolerated dose for NG-350A monotherapy in cancer patients which will inform our dosing approach in future clinical studies.
The Phase 1a FORTIFY study is evaluating the safety, tolerability and preliminary efficacy of NG-350A in combination with pembrolizumab in patients with advanced or metastatic epithelial tumours. This study is seeking to establish a safe and optimal dose of NG-350A in the combination therapy setting, while also exploring the safety and preliminary efficacy of multiple cycles of NG-350A dosing.
Akamis Bio also anticipates the initiation of an expansion cohort study for NG-350A in early 2024 to demonstrate clinical proof-of-concept in a patient population with a single type of epithelial-derived solid tumour.
