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Anonymous Feb 07

Interview: Developing Novel TNF/TNFR-based Compounds in the Fight Against Cancer

Interview: Developing Novel TNF/TNFR-based Compounds in the Fight Against Cancer

Thomas Hoeger, Ph.D., has been Chief Executive Officer of Apogenix since November 2005. Previously, he worked as a biotech analyst for DZ Bank in Frankfurt, Germany, for five years. From 1997 to 2000, he headed the 'central nervous system' research at BASF AG and Knoll AG. During the previous six years, he held various research and management positions at BASF AG.

Q: Apogenix is developing novel TNF/TNFR-based compounds in the fight against cancer. How do these products stimulate the immune response against tumours?

A: Apogenix is pursuing different strategies to trigger an optimal immune response against tumours:

Our most advanced drug, asunercept, specifically binds to the CD95 ligand. Binding of the ligand to its receptor can induce apoptosis (a.k.a. programmed cell death) of the receptor-carrying cell. This has been shown to play a key role in the regulation of the immune system, e.g., to eliminate autoreactive or to delete useless T cells. It has also been shown that the majority of solid tumours express CD95L, and there is increasing evidence that T-cells attacking tumour cells are killed upon binding to CD95L expressed by tumour cells. By preventing this interaction by asunercept, we reckon that we can protect T-cells, therefore restoring the immune surveillance of tumour cells. In a controlled phase II proof of concept trial in glioblastoma patients, we demonstrated a statistically significant increase in progression-free survival of patients treated with asunercept. Overall survival in patients carrying a CD95L-related biomarker more than doubled. This was statistically significant, too. We are currently preparing additional clinical studies in glioblastoma and other solid tumours to further substantiate the observed clinical benefit. With drug candidates developed on the basis of our proprietary HERA-platform (HERA: hexavalent receptor agonists), we can effectively and specifically stimulate (agonise) all members of TNF-receptor family. It has been shown that stimulation of receptors such as CD40 or CD27 plays a key role in mounting a strong immune response against tumours, and this is exactly what we have already shown with our HERA CD27- and HERA CD40-ligands in different model systems.


Q: An exciting component of immunotherapy approaches is the durability of anti-tumour responses observed. However, there is much work to be done to raise the survival rate. What efforts can researchers make to ensure their resources are pooled into rational trial designs, particularly in combinational approaches?

A: Clearly, a major challenge is the absence of predictive animal models to test combinational approaches. Getting there will take years and requires enormous resources given the multitude of points to consider (e.g., are the drug candidates working on human as well as on murine targets; do the drug candidates influence the murine immune system in a similar way to the human immune system; can the drug candidates strengthen an immune response in mice and facilitate migration of immune cells into the tumour etc.). In absence of these models, researchers have to create clever ways (and are already doing so) to test combinations in clinical trials - without jeopardising the health of patients. It seems as if there is a great willingness of pharmaceutical and biotech companies to jointly work on such combinational approaches in order to gain maximum clinical benefit from their drug candidates.


Q: Given that for the foreseeable future patients undergoing immune-oncology treatments will have already encountered chemo-, radio-, targeted therapy, how can we design appropriate clinical trials to recognize the success of investigative drugs in the clinic in the ‘real-world’?

A: We think that the assessment of an immunological response, e.g., by the characterisation of tumour-infiltrating lymphocytes, is very important in the design of clinical trials. There is a wealth of published data suggesting the above-mentioned parameter correlates with a clinical response, and this should be confirmed in well-designed small trials. Furthermore, the identification of new biomarkers should facilitate to design meaningful clinical trials in which surrogate endpoints should be defined which better predict an overall survival benefit.


Q: What barriers are ahead of us to enable immunotherapy to become frontline treatments?

A: In some therapeutic areas, immunotherapies are already frontline treatments. We are convinced that there is much more to come if four major challenges can be overcome:

  • Considerable toxicity has been observed especially in combination studies with two different immune-oncological drugs. Therefore, Apogenix spends a lot of effort to avoid toxicities in clinical studies. E.g., we have designed our HERA-molecules in a way that we can tailor-make their half-lives which ranges from six to 72 hours. We reckon that we can greatly reduce potential side-effects in patients based on this “fast-in, fast-out” approach.
  • We hope that meaningful biomarkers will be identified and pertinent companion diagnostic assays developed to identify patients responding best to a certain drug. This might also be helpful to avoid treating patients in which a combination treatment leads to serious adverse events.
  • New trial designs and new clinical endpoints have already been developed in close cooperation between trial sponsors and regulatory authorities. Both, trial designs and clinical endpoints must be further refined to optimally assess the clinical efficacy resulting from the new immunological mode of action to these drugs. Regulatory authorities have been very responsive and helpful in defining new and faster paths towards approval if a clear clinical benefit has been demonstrated.
  • We also have to think about drug pricing. If the future standard therapy of cancer patients comprises of a treatment with two or even more immunotherapeutic drugs, we have to embark on discussions about a sustainable reimbursement scheme with health authorities soon. 
Thomas Hoeger, Ph.D., Chief Executive Officer of Apogenix
Thomas Hoeger, Ph.D., Chief Executive Officer of Apogenix