Saturday, September 22, 2007

My old company announced some very good news this past week: their Phase III trial for Velcade in newly diagnosed multiple myleoma had halted early because the experimental arm was performing so much better than the control arm. The trial tested a standard combination of myeloma drugs, melphalan and prednisone, vs the same pair of drugs with added Velcade.

The structure of the trial is a good illustration of how cancer chemotherapy most frequently moves forward: an agent which shows activity alone is tried in combination with existing chemotherapy regimes in the clinic. This is a conservative approach and has moved therapy forward, but it also has several glaring shortcomings. For example, it is very unlikely that compounds lacking single agent activity will be tried, though it is certainly possible that there exist compounds which would work only in combination. Another example is that this is just one of many combinations being tested; there really aren't good ways to determine which combinations to try, other than trying them. Pre-clinical cancer models aren't particularly good other than for very rough estimates, and small trials might miss effects -- particularly if only a defined subset of patients would benefit from a particular therapy.

Myeloma therapy has advanced greatly in recent history, with Velcade being an important contributor to that. The other big new drug in myeloma is Celgene's Revlimid, which is a follow-on to thalidomide. Thaliomide is, of course, one of the worst horror stories of drug history, having caused scores of severe birth defects when used as a morning sickness drug. Thalidomide's resurrection as a chemotherapy drug was impressive, as is Celgene's business cleverness in getting a monopoly on an off-patent drug, by patenting the safety system designed to present a re-play of the birth defect catastrophe.

Millennium was once positively giddy about Velcade's commercial prospects -- at one internal class the person in marketing gleefully exclaimed that 'our competition will be thalidomide and arsenic' (arsenic trioxide being another newish drug for myeloma). Revlimid's rapid ascent was a rude surprise, and since it is an oral drug and Velcade an injectable, a difficult competitor -- particularly when there is really not any rational way to determine which drug should be used in which patients (or whether they should be combined, which has looked promising but will bankrupt any payer). The fierce competition is one reason Millennium all but erased my department last year.

It's worth noting that our therapeutic ignorance is really pretty great for both. For Revlimid, the molecular target isn't known. A microarray paper (PNAS open access) this summer suggested an underlying reason for its utility in another blood malignancy, but the results are far from ironclad. Whether they apply in other malignancies is a question. On the other hand, we know the molecular target of Velcade (the proteasome), but why tumor cells -- and why particular types of tumor cells -- are sensitive to this remains a mystery. The literature is full of hypotheses, but again none are really nailed down in a convincing way. Given that ignorance of mechanism, it isn't surprising that we are in the dark as to how to combine the drugs or pick out diseases (or disease subsets) to use them in.

Will we ever move from incremental, conservative, empirical approaches to some rational, mechanistic hypothesis-driven approach? I wouldn't be optimistic for the short term -- there is still too much we don't know. But perhaps in a decade-or-so time frame, perhaps we will really get a handle on the mechanisms of the disease. That's a wild guess & perhaps pessimistic, but on the other hand we are just now starting to get therapies (e.g. Iressa, Gleevec) from the oncogene research that emerged from Nixon's War on Cancer (when I was but a wee lad) -- which makes a decade time frame wildly optimistic.

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