The OPTIC trial was designed with the intent to investigate what is the optimum dose of ponatinib. Ponatinib was approved with a standard dose of 45mg daily, highly effective, but then we recognised the issue of the arterial occlusive events. There was some suggestion that these were related to the dose that was being used in the patients.

So this study was then a randomised study where patients that had been refractory or intolerant to prior tyrosine kinase inhibitors were randomised to receive ponatinib at a starting dose of either 45mg, again the standard, 30mg or 15mg. The primary endpoint was to achieve a BCR, a BCR-ABL, of 1% or less at 12 months. Another important element of the design is that patients who achieve that endpoint, if they were receiving 45mg or 30mg they were mandated to reduce to 15mg daily dose so eventually everybody would be getting a 15mg dose.

This is an interim analysis, so 77% of all the patients are being included – everybody who has reached the 12 month mark or who has discontinued therapy. The final analysis will be when everybody reaches the 12 month mark or discontinues therapy. 99% of the patients, 98% of the patients, had received at least two tyrosine kinase inhibitors, 50% had received at least three tyrosine kinase inhibitors. Really, all but one of the patients were resistant to therapy with the prior tyrosine kinase inhibitors.

So what the results show is, number one, in terms of efficacy do the three dose levels work equally? The primary endpoint, as I said, was to have BCR-ABL of 1% or less at 12 months and this occurred in 39% of the patients that started at 45mg daily but only in 27% of the patients who started at either 30mg or 15mg, actually those two were exactly the same. So that suggested that the 45mg daily dose was superior to the other doses.

More importantly, is that when you look at it by mutations this included patients with any mutations, so the subset of patients that had T315I mutation, the difference in response rate was even larger. So at 45mg it was 42%, at 30mg it was 24% and at 15mg it was 8%. There was a difference also in the patients that did not have T315I, although those differences were smaller.

So, overall all of these suggest that there was a benefit with the higher doses. It’s also important to notice that the dose reduction that was mandated per protocol, there were a few patients who lost their response but essentially these responses when they were lost they were lost early. Nobody who has maintained their response at 90 days has lost their response after the 90 days. Of course, we need more follow-up but that seems to suggest that this lowering the dose is safe.

In terms of safety, no big surprises here. Thrombocytopenia was the most common adverse event; in terms of the non-hematologic adverse events hypertension was the most common in 24% of the patients but only 7% of them had a grade 3. There were also 6% of the patients had a grade 3 elevation of lipase but no real pancreatitis, that was not a significant problem. But the big question is the arterial occlusive events that occurred during the trial. To evaluate these arterial occlusive events we had a panel of independent cardiologists and neurologists and vascular experts to assess every reported case to make sure that they completed the criteria for the American College of Cardiologists and the American Heart Association of an arterial occlusive event.

The incidence of any arterial occlusive event that met these criteria was 5% for the 45mg cohort, 4% for the 30mg and 1% for the 15mg cohort. So there was some trend also for more with the 45mg cohort compared to the 30mg but that difference was relatively small. So certainly what the results appear to show, a conclusion of this interim analysis, is that although there is a correlation between dose and both efficacy and safety, the gain that you have with the 45mg daily dose is much greater than the increased risk that you have by going to the 45mg. Certainly it’s good to see that all these doses are effective, they are all safe. It’s also good to know that this reducing the dose according to response seems to lower the incidence of these arterial occlusive events.

So I think these results provide good guidance on how we should manage patients with this drug that is very effective but that we have been struggling to try to find that right balance between efficacy and safety.