Compelling presentation made by Dr. Elias Jabbour in the recent Analyst/Investor day...
"Well, here the story is. First of all, we have a clear relationship between dose and safety. In fact, every time you reduce your dose by 15 milligram, from 45 to 30 for example, you reduce the risk of vascular events by a third. So if you go from 45 to 30, a third. From 30 to 15, another third. So we are making progress in that sense. And more importantly, am I jeopardizing efficacy? The answer is no. In fact, when we had the PACE trial and we had to reduce the dose after all these problem for safety concern, and we have a two years to three years follow-up since we did reduce the dose, we did not see loss of responses.
Meaning patients maintained their responses despite the fact we had to reduce the dose. So I'm quite confident today that in CML, lower dose of ponatinib is good. It is as effective as a higher dose and way safer. And I must confess to you: I never ever use ponatinib above 30 milligram in a chronic phase CML patient.
Now why I am confident as well of CML and ponatinib? Because of what is happening [nearly]: ALL. So another disease where we are making cancer history. I don't have my slides. In fact, I want to give you -- I will give you a reference if you need later on. In fact, survival at one year of this disease is only 10%. 90% of our patients will die within one year of treatment. One year. 10% only will make it. So we have a way to improve. I want to give you my whole message to you right now. Today, we went from 10% at one year to 80% at three years, even without transplantation, just by adding ponatinib to the chemotherapy. So what we've shown is when you add TKI starting with imatinib and dasatinib, we improve the outcome. And here on the slide is our experience using dasatinib. It's recommended by NCCN, an expert today in CML. I want to highlight two things at least from the slide here. One: the CMR -- what we called complete molecule response, meaning no disease left
whatsoever -- by adding chemo to TKI is 60% and the three-year survival is 60%. So great progress, but still, we are not the 80%, 90%. And more importantly, we are seeing patients relapsing. Why? Because they acquire the 359 mutation. A third of our patients did progress and acquire this mutation. Therefore, therefore if we want to improve the outcome, I need to prevent this mutation from happening. I need to suppress this mutation. And second, I need to have deeper responses. If I can have deeper responses -- if I can improve the CMR from 60% to 80% and suppress this mutation,
my patient will be cured. Will be cured. 10% survival to cured? It's amazing, correct? So we need options. Based on this data at MD Anderson in 2010, we embarked into adding ponatinib to the chemotherapy. Guess what? We were accused to be crazy because who will do that? Well, some crazy people need to be there to do that because that will advance the field. You have to take risks, okay? And if you don't try, you don't get anywhere. So what about these details? But what I'm trying to say to you is we use ponatinib plus chemotherapy and we use 45, for example, there at the
beginning because that is the dose that was found in a PACE trial in a Phase 1. Now guess what? We had two deaths happening on this trial from vascular events. Then what we did, we went back to the FDA and we revised everything; we went deep into the data. And then we used [a cradle] approach dose. We went from 45 for two weeks and then 30 milligram and then 15. 45, 30, 15.
Guess what? Since we amended our protocol, we enrolled 30 patients moving forward and we had zero deaths, zero vascular events. Better than CML. So by using [a cradle] approach of the dose from 45 to 30 and 15, we minimize safety. We had zero adverse events, and guess what? We maintained efficacy all along. And today, we are curing these patients. In fact, look at the results never heard before. I'm not making this data, by the way. A lot of people asked me oh, are you crazy? We don't [happen
to see] these results. Yes, these are real results. In fact, the CMR rate is 80%. The best data you have in Europe, 20%, [does that] at MDS that nobody can ever use 60%? We are at 80% CMR. Complete molecular response, meaning no disease left whatsoever. 80%. Broadly, that is zero. And then we have a great outcome.
Well, before they go to survival, because that is where the money is, vasc safety concern, as I said to you. From the minute we amended our study to use lower dose, we had zero events -- zero vascular events. So that is quite reassuring to the FDA, to you, and to everybody."
