We looked at oprozomib which is an oral proteasome inhibitors which is structurally related to carfilzomib, a currently FDA approved drug. The drug oprozomib has got advantages in that it is an oral proteasome inhibitor and oral drugs are certainly of great potential in patients with myeloma which is slowly turning out to be a chronic disease. With oprozomib in this trial we looked at a phase I dose escalation scheme; in the early part of the study a capsule formulation was used twice daily. What was seen at that time was gastrointestinal toxicity. At that point the formulation was switched to a tablet given once daily and the majority of the cohort that I reported on was accrued thereafter. A further amendment was subsequently made more recently when the formulation was changed once again to an extended release formulation based on FDA guidelines for reduction of variability in the solution profile of the drug. Also, a stepped up dosing was introduced and the trial that I presented was showing how the story has evolved over this period of time.

Could you tell me about the patient group that you were looking at here?

This patient group was once again heavily pre-treated, nearly all patients had been exposed to probably some inhibitors and immunomodulating drugs. Quite a few of them were refractory to bortezomib and also to carfilzomib proteasome inhibitors and also quite a few were refractory to even pomalidomide and certainly a lot of patients were refractory to lenalidomide.

So what were the study arms that you looked at?

The study was a dose escalation study; there were two different dosing schedules. The drug was given in two week cycles; in one schedule it was give two days every week, in the other schedule it was given five days out of every fourteen days.

And what happened?

What we saw, again, as I alluded to earlier was at the beginning there was gastrointestinal toxicity with the first formulation. With the second formulation of the drug, which was a tablet form given once daily, there was still gastrointestinal toxicity. What emerged was that with the introduction of the stepped up dosing perhaps a signal of better tolerability on gastrointestinal tract and certainly the drug is active. The drug showed responses in a significant proportion of patients, even in the phase I portion of the study, so once again the drug is something that continues to be studied in a further cohort of patients that will give us a better sense of the tolerability and the efficacy.

What should doctors read into this in terms of the feasibility of using a proteasome inhibitor, or this one in particular, in the setting of multiple myeloma?

This study provides us the first evidence that the drug can be delivered in a manner that can be tolerated by most patients. It also shows us evidence of activity; there was activity even in a carfilzomib refractory population. So going forward I believe that the drug has the potential to become a drug in the next few years that could provide oral proteasome inhibitor potential in a convenient manner.

But how big an improvement could we hope to see because these are patients who have failed lots of different treatments?

Correct. The thing is that, as I alluded to the fact, a lot of these patients have failed bortezomib and carfilzomib as well so the fact that about 18% of patients in a carfilzomib refractory population responded suggests that it has the potential to be active when our currently active agents have failed. But the data is preliminary and we need a larger cohort of patients to be conclusive about these findings.

And your very brief take home message for doctors?

Stay tuned with oprozomib, further data on single agent and combination activity will be emerging and it has the potential as an oral proteasome inhibitor to potentially make the lives of patients easier for long-term administration.