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Replies to post #171029 on Biotech Values
So the -- there were 2 other patients in the other category that we should talk about. The first one was a patient who transformed on study to CMML and ultimately did have an off-study death to AML. And both of those events were considered unrelated to imetelstat by the investigator. Ironically, Ayalew had 2 patients with CMML that we're going to go into the study about the time that this patient developed CML and now we decided -- or he decided not to put them in but I think this is a pretty common transformation, unfortunately, in some of these patients.
The -- there was another patient in this Arm A other column who simply discontinue due to lack of response. I don't have any more data about that patient.
So now to the 2 death. One I think was a death that was certainly considered unlikely to be due or not due to imetelstat. It's a sort of unfortunate tragic story that goes along with this disease. Many patients with long-standing hepatomegaly develop portal hypertension and varices disease. And this patient had a pre-existing varices. The patient had, I believe, it was 39-day something like that into the study had a catastrophic variceal bleed, coagulation parameters were normal, the platelets counts were normal. So this patient was not considered to be a study or a trial -- an imetelstat-related death.
The other patient who was in Arm B actually tells us a lot and taught us a lot and we should talk about it. So this patient was an elderly gentleman with all -- almost all of the signs and symptoms of later-stage myelofibrosis. He came in and he was allocated, he was the 10th patient allocated to the Arm B which remember is 4 doses of imetelstat, 1 a week and then going to the Q3 weekly dosing. And as you'll see actually in some further slides, he -- at the time that he came in, he tolerated the first and second dose quite well. He had some myelosuppression on the third. At the time he came in for the fourth dose, he had a very steep fall in his neutrophils and in his platelets. By protocol at that time, we had a limit of about 30,000 platelets under which we would not treat or Dr. Tefferi would not treat -- or continue treatment. However, at the time there also was the hint that patients who had more myelosuppression might be getting a deeper response and so Dr. Tefferi thought about this. He and his colleagues thought about it and they wouldn't have been treated the patient. This patient became aplastic and subsequently died after severe -- obviously, complete myelosuppression. The patient was supported with platelets and growth factors unfortunately to no avail, the patient develops a febrile neutropenia. We assume the patient became infected and subsequently, had a CNS bleed and died. The platelet counts were very low, the white counts were very low. It was a very difficult moment for all of us. But we certainly learned that patients whose platelets were falling rapidly and also down to those levels really shouldn't be treated. This was followed by a patient who doesn't show up here but it was followed by the 22nd patient. And this was a woman who had massive hepatomegaly. Her liver was down into her pelvis. She had already had a splenectomy. She was a young women. She was dying of myelofibrosis. And she was treated and had a very a similar clinical course, a similar decision was taken because we haven't seen the effects or Dr. Tefferi hadn't seen the effects on the previous patient. And this time, however, very fortunately through I think very, very outstanding medicine, she did survive. And after prolonged myelosuppression, her platelet counts did come back, her neutrophils did come back. She eventually regained normal platelet and neutrophil counts. Her spleen shrunk up to basically a normal-size spleen or a very close to it and she has done very well. She continues on drug today. So I think that we learned that the rate of fall and also the absolute fall in particularly in platelets but also in neutrophils was a very important thing. You heard Dr. Tefferi say that this was a very potent drug and we completely agree with this. And I do think that we have used this opportunity -- unfortunate opportunity to learn about the drug and also to change a lot of the ways or some of the ways that we treat patients. I'll end up with some of those comments perhaps.
So let's move on to the -- let's move on quickly to the safety, the appropriate safety. So here, we wanted to make sure we were as up to date as possible as I told you. We don't have the data from the patient from 23 through 33. So we are going to just simply repeat Dr. Tefferi's slides because I think they're very well done and quite illustrative. So this is Cohort A and is equal to 11, Cohort B as before. Now what we are going to do as he described, we were going to do a Cohort C which is going to be weekly, but after seeing the myelosuppression that occurred after weekly dosing, this was not a difficult decision. Dr. Tefferi made it but we were in complete agreement that this was -- that these patients could not be treated weekly. And so these patients were reallocated to either Cohort A or Cohort B. The patients who got into Cohort A were patients that had mutations in particular splices on mutations that might have suggested that they would be more sensitive. I'm not sure if that's true or not but it was a theory at the time and these patients were thought not to be as sensitive.
You saw this. This is the patient disposition. There's really nothing new to talk about. It's collated to slightly different way, but there have been no additional deaths, no additional transformations. We're unaware of any other changes, a lack of response and this is more updated that you can't pick and tie, guys. This is a more recent data set because he has access to those data. These are all of the grade 3 for non-hematologic adverse event that he showed today. He commented that these were not attributable to the drug in his view and these are the treatment related myelosuppressive toxicities and it ticks up with the picture that we've seen over and over again. I will tell you right now most hematologists who treat these disorders do not worry too much about grade 3, but they do worry about grade 4. And I think this is the very important finding in this and is equal to 33. The patients in the B -- group B treatment paradigm have clearly a higher grade 4 thrombocytopenia and neutropenia than the patients in grade 1 where there was no grade 4 thrombocytopenia and no grade 4, only 1 patients with grade 4 neutropenia. So this has certainly given us these observations that myelosuppression is principal dose-limiting toxicity. We think it's a theory that it's on-target toxicity due to effects on progenitor cells. I think most of the academics believe that to be the case. It's clearly manageable through dose hold rules and dose modifications. And to mitigate against the risk of severe persistent cytopenias, the Mayo Clinic protocol has been amended to raise the hematologic thresholds for retreatment and include more stringent monitoring and dose adjustment criteria. And the non-hematologic adverse effects have been generally not very much to write home about. So this -- these are the conclusion. We just simply reiterate the efficacy and safety conclusions. And so I think that I will end there, and we will open the floor to questions.
AI
