5 Questions... with Charles Morris, MD, VP of Worldwide Clinical Research, for Cephalon Oncology

1 Why are self-survival and self-renewing pathways such promising areas of discovery at this time for Cephalon?

If we can understand the methods and the pathways by which cells are able to either prolong their survival or sustain their own proliferation as tumors grow, then, by identifying targets along those pathways, we have the opportunity to develop drugs to interfere with and block those pathways, leading to cell death, or at least prevention of the growth of the tumors. What this means at the patient level, of course, is that if we understand the molecular pathways, we can get treatments that are much more targeted toward the tumors rather than the healthy cells so that we hopefully can get more accuracy with less toxicity than we’ve experienced with drugs in the past. Most of monoclonal antibodies are clearly directed at single pathways within cancer cells, and they have been very therapeutically successful; and most of them are pretty well tolerated. And then you have the smaller molecule approaches—Gleevec perhaps being everyone’s favorite example of a drug where by targeting a very specifi c known molecular mechanism, you’re seeing very strong results in fairly specifi c tumor types with relatively low toxicity. That has become an approach that many researchers are seeking to emulate for many targets. It’s a very fruitful area for drug discovery, and hopefully it’s a very fruitful area of therapeutics for cancer patients.

2 How would you characterize Cephalon’s current hematologic cancer research and treatment efforts?

One of the reasons that companies like Cephalon and others are engaged in hematology research now is that we have a good understanding of the molecular mechanisms. In a sense, it’s the same reason why people are going after smaller indications like GIST and renal cell carcinoma. Because we understand those mechanisms, we can develop successful agents in areas of

considerable medical need. One of the things I really enjoy about working for Cephalon is the opportunity to look beyond breast, prostate, lung, and the bigger tumor targets, and instead focus on some of these areas that have historically been underserved by drug development and really look for opportunities to bring new therapeutics forward. That’s good for the company, good for patients, and hopefully good for physicians to have more options for their patients.

3 Is Cephalon involved in any awareness or educational eff orts to promote clinical trials and make people more aware of the benefits of enrolling in a clinical trial?

I think that is an area where we do need to give more consideration. Part of the challenge across the industry and across academia, and anywhere where we’re doing clinical research, is that the results of clinical trials always make big news, but unfortunately I’m not sure if people are adequately aware of the process that actually goes into getting those trial results. In the information age, where all new therapies can be found by people very quickly, there seems to be great reluctance to accept the uncertainty that goes with a clinical trial. I think that there’s a lot we need to do—industry needs to work with investigators, with academia, and particularly with the patient groups. I think publications like yours have a role in this as well, to really help people understand the importance of clinical research, because without the trials, the experimental drugs don’t become the new therapeutics that we need. It’s a struggle to recruit patients in the US, so we are looking to use international data to a much greater extent. There are economic reasons to do that and time reasons to do that, but I think we also know that people will always feel more comfortable with a significant proportion of US data within the clinical trial programs, so we really have to do everything that we can to support that.

4 What can you tell our readers about Cephalon’s near-term pipeline?

We have Trisenox and Treanda now marketed, and a second indication for Treanda for refractory non-Hodgkin’s lymphoma is currently under review at the FDA. That is the next drug that we will hopefully bring to market; we will also continue to develop Treanda for a number of other indications related to chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL).

5 What else is Cephalon focusing on?

We’re particularly interested in understanding the potential of Treanda in combination therapy, at least with rituximab, which is such an important agent in this area. We will be doing studies in CLL in combination with rituximab, and we’re completing a frontline study with Treanda and rituximab for NHL [results of which were recently published online in the Journal of Clinical Oncology].

The next drug we hope to bring to the end of phase III is CEP-701 (lestaurtinib). This drug, among other activities, inhibits a number of kinases, including one called FLT-3, which is expressed and gives a poor prognosis to a subgroup of about 25—30% of patients with acute myeloid leukemia (AML). CEP-701 is currently in a phase III study in patients with relapsed AML. We hope to complete the recruitment for that study this year, and if that’s positive, we hope to submit to the FDA for consideration during 2009. That drug also has activity against a target known as JAK2/STAT, which has become widely known as an important target in myeloproliferative disorders such as polycythemia, essential thrombocytosis, and myelofibrosis. It is currently in phase II in that setting. Earlier in the pipeline is CEP-11981, which is targeted at the VEGFR receptor and the TIE-2/pan kinase receptor. TIE-2 is another angiogenesis pathway, and we’re hoping that by targeting more than one angiogenesis pathway, we may be able to see greater efficacy relative to the other smallmolecule angiogenesis inhibitors. CEP-18770 is in phase I testing. It is a proteasome inhibitor that we hope to explore in programs focusing on myeloma therapy. Also in the pipeline, the next IND that we hope to submit would be for a PARP inhibitor, which we would see as a potential chemosensitizer for solid or hematologic malignancies.

The next program after that is an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor that we hope will have efficacy in a subgroup of patients with lymphoma and, interestingly, in a subgroup of patients with small-cell lung cancer. Overall, we are looking broadly at anti-proliferation targets and survival pathway targets that will take us into a broad range of both solid tumors and hematologic malignancies. The sheer amount of effort that is going into this area at the moment is starting to really bear some fruit, and the emphasis on the pathways that we’ve talked about and the technologies that are coming through means that there isn’t any single answer to what is the most promising approach. There is so much focused research going on leading to greater understanding of the unmet medical needs and an improved understanding of the genetics and biology of the disease that we really are making some progress. All the new science that has become available over the last 20 years is now translating into new therapeutics for patients. I think that is really exciting.