Andrew Schorr: Dr. Young, for patients receiving initial treatment could you discuss the findings comparing horse ATG and rabbit ATG?

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1 What s New in Aplastic Anemia Treatment American Society of Hematology Meeting December 2011 Dr. Neal S. Young Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion with your own doctor, that s how you ll get care that s most appropriate for you. Dr. Young here at this major medical meeting, ASH, American Society of Hematology, what do you feel is an important finding related to aplastic anemia? So I think that the most important new finding in aplastic anemia over the course of the last year has really been this growing relationship between telomeres and their relationship with bone marrow failure, aplastic anemia and other diseases. And presented at this year's ASH as well as published over the course of last year is the prognostic importance of short, shorter telomeres of white cell and the outcome in patients with aplastic anemia. Telomeres are the ends of the chromosomes. They get shorter naturally as we age, and we know that there is a subset of aplastic anemia that is inherited that's due to genetic defects in telomere repair. We also realize that patients even who have normal telomeres but are shorter, in the shorter range, those patients don't do as well as patients who have telomeres that are longer, normal, still in the normal range but longer than this very short group. And that has an enormous prognostic significance and also potentially will help patients choose therapy and even develop new therapies. Dr. Young, for patients receiving initial treatment could you discuss the findings comparing horse ATG and rabbit ATG? Yes. So there have been a number of studies actually mainly of horse ATG alone or rabbit ATG alone. And some of the smaller studies when rabbit ATG was introduced into the American market for other purposes, not for aplastic anemia, some of the smaller studies suggested that rabbit ATG might be better than horse ATG for the treatment of patients. And there are some reasons to think that rabbit might be superior because it's a more potent immunosuppressant. It works better for example in the setting of renal transplant, both preventing rejection and treating rejection. And it also has some interesting properties in the test tube, for example stimulating cells that we think are good cells in immune disease like T regulatory cells. So we at NIH in our hospital where we do see patients with aplastic anemia wished to compare these two treatments. We actually had a three-arm study to begin with actually a third drug as well, which we were not able to continue. So we performed a full study to look at whether rabbit or horse were better as inducing hematologic responses. That's 1

2 the important factor in how well patients do, whether they can respond to immunosuppressant therapy, and we were very surprised at the result. Actually, it was completely opposite of that which we hypothesized. Rabbit was significantly inferior to horse, almost half of the response rate to rabbit compared to horse. We actually had powered the studies statistically to show that sort of difference but expected rabbit to do better than horse. So horse won the race. So that's standard therapy in the United States, horse ATG, and will remain standard therapy. As you alluded, unfortunately, horse ATG, which is produced actually in Michigan by Pfizer's horses that are immunized up there, horse ATG is not available in other parts of the world, and so that is a major problem for Europe and for Asia. Now, an abstract that was presented as a poster here at ASH this year suggested that maybe in Asia that doesn't make a difference, and there may be ethnic differences, and patients seem historically to do as well with rabbit now as they did with horse in the past. But there are other studies from South America and from Europe here at ASH that although they weren't randomized trials like the one that was performed at Bethesda they've looked again at how patients are doing with rabbit now compared to how patients did with horse before, and they're actually even worse than our results that patients are really doing much more poorly with rabbit in Europe and in South America than they are--than they did with horse. So there are efforts at the moment, some of them successful, to bring horse ATG back, to import it back into Europe, and that's been achieved in Italy and a couple of other countries. I think those efforts are continuing. Obviously having a paper published that's a randomized trial is going to be helpful, but there is going to have to be a shift in terms of how patients are treated based on this randomized trial. Tell us about newer immunosuppressant drugs. Well, Campath really hasn't been tested adequately in patients at the outset of their disease, so I don't think we actually have to go beyond Campath at the moment. We have to figure out whether Campath actually may work as first treatment because that would avoid what's often problematic for patients, with is cyclosporine, and it probably could be given to patients as an outpatient. Some small studies in Europe suggested that Campath was effective. We certainly think it's effective in patients who have relapsed or have refractory disease. When we did our big triple-arm study we didn't see Campath work very well, which is why we dropped it, but I think Campath deserves another look, maybe in older patients, patients who can wait a few months to see whether they respond and where treatment is not urgent. So I think Campath actually remains as a potential immunosuppressive agent. The horse-versus-rabbit study, laboratory data that were associated with that study suggested that T regulatory cells, which are a very popular subject of laboratory study in mice and in humans and a lot of different diseases from cancer to autoimmune diseases, the T regulatory cells were actually very low in the patients who were treated with rabbit, 2

3 whereas they returned to normal levels in the horse ATG-treated patients. And there are some specific cytokines that may induce T regulatory cells. So that's one direction that we will probably go at the NIH, starting with patients who either have relapsed or have refractory disease. So giving for example low doses of some of these cytokines again potentially in the outpatient setting, may be helpful to now more specifically modulate the immune response. I'll mention just one other agent that we reported here at ASH that isn't working on the immune system but is exciting because it's actually working on the bone marrow directly, and that's a drug called eltrombopag. That's actually a drug that's marketed now in the United States, approved by the FDA for the treatment of patients with idiopathic thrombocytopenic purpura. This is a very low platelet count due to immune causes. And we did a study in some of our most refractory patients, a couple of dozen of those patients, who had not responded to any immunosuppression and a lot of other therapies, and we were actually quite amazed that almost half of these patients showed significant improvements in their blood counts and also amazed that it was not restricted to platelets. So there it appears that this drug actually can affect the hematopoietic stem cell. And in some of these patients as we showed in one of the oral sessions, in some of these patients the bone marrows that were obtained at six months were actually normal in their cellularity, which is quite different from what we see in immunosuppression. So we're quite excited about actually having an agent that may work directly on the stem cell in addition to having drugs that can reduce the immune attack on the stem cells. And the hope is if the company is willing that we'll actually now start a new trial with standard immunosuppression and with the addition of this very well tolerated oral agent and be able to work on both sides of the immune system and on the bone marrow. We got a question from Gail in New Rochelle, New York. She wants to know is there any better understanding now of the cause of aplastic anemia. Unfortunately not. I think that the causes that most patients think about are environmental, that there's a drug that they have taken or a chemical that they might have been exposed to that caused their aplastic anemia, and I think there's actually been very little new information that would allow patients to go back and say, I know for sure that this is what led to my disease. Really, in most patients we see it's very hard to identify any environmental exposure with a singular exception, which is hepatitis, and some proportion of patients, probably between five and as many as 20 percent of patients who have aplastic anemia had a preceding hepatitis, usually a month or two before the onset of their aplastic anemia. And I think once we understand what that hepatitis is about we'll know a lot about aplastic anemia, but it's not the normal sort of hepatitis due to hepatitis A virus or hepatitis B or hepatitis C virus. There's no known viral agent. We're looking for that as are other groups. But that's really the most distinct preceding trigger for whatever happens to the 3

4 immune system. Otherwise, in most patients there's no distinct history, and this often occurs in young people who are not taking any medical drugs or have any unusual exposures. And in that respect I think it's quite similar to many other immune-mediated diseases. Multiple sclerosis, inflammatory bowel disease, these also tend to occur in older children, young adults, and we don't think that those are caused by a specific chemical. There is something that does lead to an imbalance of the immune system and to a targeted attack on an organ, but really knowing exactly what that is has been elusive. Dr. Young, we got this question from Alise in Brooklyn, wants to know if there's a difference in response rates for people who have relapsed receiving Campath versus ATG. Actually, we've just published a paper. It's online in Blood now, which is a randomized study looking at the effectiveness of rabbit ATG and Campath in our patients at NIH, and they're about equivalent. So in our hands between 30 and 40 percent of patients who are refractory to horse ATG will respond to a second round of immunosuppression with rabbit or with Campath. And Campath we think may be easier to give because it doesn't require cyclosporine and again probably can be given in the outpatient department. In patients who have relapsed we've observed that many, more than half of patients who have relapsed will respond so Campath. So these drugs look to be about similar in their ability to rescue hematopoiesis, rescue bone marrow function in aplastic anemia patients. Dr. Young, you've been at this a long time. When you look at aplastic anemia are you encouraged with how we're doing now? Oh, I'm tremendously encouraged, but I have a long perspective, which is not often the perspective of somebody who has this disease and is ill and wants to get cured and be sick any more, especially young people who were fine a month or two earlier. When I first started to see aplastic anemia patients, which is a long time ago, back in the 1980s, the mortality rates were astronomical. Virtually everybody died, and they died very early on in the course of their disease. That's actually very rare now. It's really remarkable that--i think it's one of the great success stories in modern hematology that we've been able to take a disease that was uniformly fatal in my professional lifetime and convert it to one in which most patients can expect to do well with many different modalities, immunosuppression, bone marrow transplant, which has now been expanded for unrelated donors, other therapies, like the growth factors that I mentioned, so there would be--the survival rates, the response rates are actually most patients are going to do well. That's not everyone, but most patients are going to do well. And in addition we have stunning new laboratory data that come from the genetics of the immune system but especially of the hematopoietic system that will I think allow us to 4

5 really understand in individual patients much better what's driving the bone marrow failure and obviously be able to treat it. Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion with your own doctor, that s how you ll get care that s most appropriate for you. 5