Interview

Dr Alejandro Ricart speaks to James Eslea MacDonald, Program Director for World ADC Summit, 27th-28th October 2010, Boston, MA

Dr Alejandro Ricart Associate Director, Oncology Department Pfizer

Dr. Ricart received his MD from Universidad de Buenos Aires School of Medicine (Buenos Aires, Argentina) and completed his residency training at the Hospital Militar Central (Buenos Aires, Argentina). He was a fellow at the Department of Medical Oncology at the Instituto Alexander Fleming in Buenos Aires, where he first developed an interest in Developmental Therapeutics. He completed an Advanced Oncology Drug Development Program at the Institute for Drug Development, Cancer Therapy and Research Center and at the Division of Medical Oncology, University of Texas Health Science Center at San Antonio, Texas. There, he was introduced to multiple new therapeutic agents targeting cancer in a variety of novel ways. Dr. Ricart was fascinated by the science behind tumor vascular biology, and its therapeutic targets including vascular endothelial growth factor (VEGF). Dr. Ricart has participated in several studies of small molecules and monoclonal antibodies, in all phases of clinical development. Dr. Ricarts honors include receipt of the ASCO Foundation Merit Award in 2006. He is currently an Associate Director of Oncology Development at Pfizer Inc. in San Diego, California. What led to your interest in antibody development? In my personal opinion, clinical development in oncology was mainly empirical until the end of the 90s. I was trained during this time concentrating primarily in chemotherapy. Although chemotherapy was improving, we still had a number of patients not benefiting from the therapy and suffering significant adverse events. In some ways this approach, which is very effective against some types of cancer, is still very not specific. Since then, we have seen a lot of new approaches, which collectively we can group under the title of targeted therapies. These utilize different mechanisms of action and different therapeutic approaches, such as signal transduction inhibition, anti-angiogenesis, and antibody-based therapy. What appealed to me about antibody therapies is that this approach attempts to achieve an unprecedented degree of targeting due to the affinity of the antibody to the surface cell target. Compare this to small molecules inhibitors, even when you can design very specific inhibitors, you have offtarget effects because you are inhibiting other pathways. This is quite a common problem with small molecules inhibitors. Empowered antibodies have seen a lot of investment, yet still remain very difficult to develop, why do you think this is? From a historical perspective, the technical ability to make more human variants of monoclonal antibodies made them suitable candidates for repeat treatment. The other technical aspect when considering ADCs that I think has improved significantly is the linker technology. The reason for them being hard to develop, specifically

Although chemotherapy was improving, we still had a number of patients not benefiting from the therapy and suffering significant adverse events.

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for solid tumors, is because of the scarcity of suitable tumorassociated antigens. However, we still have a few of them that look like good candidates for targeting, for example, I think HER2 and PSMA. As a community, we need to invest a lot of resources to find further targets. Within solid tumors this is specifically significant and is probably less true for hematological malignancies where there are more suitable targets at this time, however it is still an important area of research. What new technologies do you see really set to impact on ADC development? Well, there are several. I think proteomics can be used to identify and validate drug targets faster than ever. Biomarker validation is also important and is improving in the clinic. In terms of advances in antibody formats, I think that antibody fragment technology has great potential for new therapeutic opportunities. Their smaller molecular size, and potential for better penetration and better PK characteristics is very exciting, although we still need to prove this in the clinic. From a pharmacological perspective, we now have the capacity of measuring all the components of the conjugates. We can measure the whole antibody drug conjugate, the naked antibody and the free cytotoxic component, the free drug, and in this way verify conjugate stability within the plasma. In solid tumors we are using very potent payloads, even small quantities of that potent payload could produce significant toxicity if

they reach normal tissues. The whole idea behind antibody drug conjugates was to improve the therapeutic index, therefore if we have a candidate that is releasing too much free drug in the plasma, that drug might not be the ideal one to move forward. So I think with this approach we can further screen candidates in the early phases of development. In terms of clinical approaches, we are seeing better dynamic tumor imaging that will make treatment less empirical. For example PET imaging can also help us investigate the targeting properties of the antibody in the clinic. This ability to undertake scans of patients and see how the localisation of the antibody compares to the metastatic sites is a very important development. The ADC world is relatively small but holds great potential. How do think we could kick-start efforts in the wider antibody community? Over the last 10 or 15 years we have started to overcome some of the obstacles associated with solid tumors, such as understanding tumor specific antigens. My personal opinion is that the ADC targeted against HER2+ breast cancer will get accelerated FDA approval soon. This, I suspect, will spur on efforts in the field and attract attention from a wider audience. We are seeing a shift in strategy in big pharma, as they are looking to buy out and invest in biotechs, who traditionally are the ones developing these types of technology, for example, linker technologies.

This goes against the myth that the pharmaceutical industry doesnt share.

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My personal opinion is that the ADC targeted against HER2+ breast cancer will get accelerated FDA approval soon.

Also inter-company communication is increasing; the upcoming Summit in Boston is a great example of how to kick-start efforts in this field. We are going to have colleagues from different pharmaceuticals and biotech companies, along with some academic colleagues, all interested in learning more and in sharing experiences, for the ultimately benefit of cancer patients. This goes against the myth that the pharmaceutical industry doesnt share. By the way I also think that antibody drug conjugates are going to dominate the field, especially in terms of solid tumors, as opposed to radiolabeled-conjugates. How do you see the oncology sector changing over the next 5 years? Definitely I see more personalized. Oncology in general, will be one of the most important examples of personalized medicine. I base this on the fact that we have many more predictive biomarkers in oncology and this will help us to identify subsets of patients who will benefit from a particular therapy. In this way, a drug with a low response rate in an un-selected population may have significant effect in a well-defined population of patients. This is exemplified in trastuzumab in HER2 positive breast cancer and erlotinib in EGFR mutated non-small cell lung cancer. This may result in looking for large differences in efficacy in small population groups. One might dispute that this approach is not economically or technically feasible but there are strong indications that it is feasible. This will give enable us

to not only, reduce the number of patients enrolled in phase three studies, potentially also reduce late stage attrition, which is such a great problem under the current development paradigm in oncology. This will accelerate clinical development and consequently reduce costs and extend patent benefits. We may receive fewer revenues from the approval but we will need to invest less money to produce break-through therapies. Last but not least, this approach will also prevent those patients without the right molecular / genetic profile from suffering unnecessary toxicity. I also see more robust overall developmental strategies based on cutting-edge science, because there is greater investment in pre-clinical as well as early clinical development. Hopefully this strategy will reduce both the risk and the uncertainty going into phase 2/3 studies. We need to continue our efforts to build an oncology culture within industry and make use of the modern techniques to really develop more personalized medicine. Alejandro will be sharing his experiences in clinical development of ADCs at the World ADC Summit taking place in Boston, MA, 27th-28th October 2010.

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