Targeting CD47 in MDS: Reviewing the CD47 Pathway and Key Trial Data

EP: 1.An Introduction to MDS: Initial Diagnosis and Patient Risk Stratification

EP: 2.Clinical Insights on the Treatment of Patients with High-Risk MDS

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EP: 3.Targeting CD47 in MDS: Reviewing the CD47 Pathway and Key Trial Data

EP: 4.The Future of Treatment for Patients with MDS

Dr. Naval Daver: CD47 is a very important immune pathway, that cancer cells actually leverage to protect themselves from phagocytosis by macrophages. So the CD47 is expressed heavily on the surface of tumor cells, especially MDS and AML leukemia blast, and this interacts with sopalpha on the surface of macrophages. And this interaction is actually an inhibitory interaction. It shuts down macrophages so they cannot do their normal function of attacking phagocyting tumor cells and leukemia cells. So by blocking this negative interaction, we actually release the inhibitory signal to macrophages. The macrophages are then unleashed and can attack the MDS or AML cells successfully. So this is the rationale of course. This is a very simplified version. This has been published in extensive detail by the group at Stanford, Ravi Maje IRV Weissman. And what is interesting is also that the expression of CD47 on tumor cells seems to be very high, especially in myeloid malignancies, both in AML and myelodysplastic syndrome and higher expression is also associated with an inferior prognosis. So all of these kind of hinted towards the importance of CD47 biology in escaping, anti-tumor immune response in MDS and AML and has now led the efforts to use CD47 or sopalpha antibodies to increase the macrophage attack against the MDS and AML cells.

The rationale for doing the combination of CD47 antibody magrolimab with Azacitidine was actually based on very elegant preclinical work that was done by the group at Stanford where they actually showed that Azacitidine, which is a hypomethylating agent, increases the expression of pro-phagocytic markers like calreticulin. And in fact, this leads to a very nice synergy because the increase in pro-phagocytic markers enhances the macrophage homing and attack against the MDS and the AML cells. So this actually led to this combination approach. Also importantly, Azacitidine has single agent activity of its own in AML and MDS and has been used historically for the last two decades in the frontline setting. So it was a very logical next rational combination to combine Azacitidine with CD47 antibody magrolimab in newly diagnosed MDS as well as frontline AML patients.

This rationale led to the frontline study combining Azacitidine with CD47 antibody magrolimab. This was a large phase one B study looking at both frontline higher risk MDS that included intermediate high, very high risk IPSSR patients. As well as there was a separate cohort that looked at frontline newly diagnosed AML, especially TP53 mutated AML patient population. We recently published the MDS High Risk Frontline Cohort in the Journal of Clinical Oncology. This was in March of this year, 2023. What we saw overall, this was across about 94, 95 patients were that the combination of Azacitidine with CD47 antibody magrolimab was very well tolerated. We did not see a high rate of hematological neutropenia, thrombocytopenia, or prolonged myelosuppression. Importantly, we do see anemia signal. This is well known with CD47 antibody magrolimab and it's actually an on-target anemia because of removal of CD47 antibody coded RBCs by the reticular endothelial circulation. So it is very important to monitor for this anemia in the first seven to 10 days. That is when it is most pronounced. And because of this we do an intra-patient dose ramp-up escalation to avoid having severe early onset anemia. In spite of that, we can see in about 5% to 10% of patients a hemoglobin drops of two grams or more. So it's really critical in that first seven 10 day to monitor closely transfuse, and then after that, this regimen seems to be quite well tolerated. We did not see any significant cardiac pulmonary, hepatic, renal or other toxicities. From the efficacy perspective, we looked at these patients in two subsets. One was TP53 wild type, which was the majority of the patient population about 70 patients, and then we had a TP53 mutated about 25 patients. What was good to see is that in both subsets the CR-rates were close to 33% to 35%. In fact, in the TP53 mutated, the true CR-rate was 40%. This is much better than the CR-rate we have seen with HMA alone. Azacitidine alone, for example, the CR-rates are about 15 to 18% in previous phase three and phase two studies. And also, when you look at the survival in the TP50 mutated population, survival was not met, and in the TP53, sorry, in the TP53 wild type population, the survival was not met and the TP53 mutated, the survival was 16 and a half months, which is also better than any survival we have seen in frontline TP53 mutated population. So of course, this was a single arms large study, and this has to be now confirmed in an ongoing randomized global phase three study of Azacitidine magrolimab versus Azacitidine placebo. This is called the enhanced phase three study. This study has completed enrollment recently and we hope to get the results in the near future and if positive, of course, will lead to approval in the frontline space for magrolimab with Azacitidine, which is what we hope.

The main adverse events in this study were anemia. This was most prominent in the first 10-day period. What we found is that almost 90% of the significant anemia events hemoglobin drops of greater than 1.52 occurred in that first 10-day period. So because of this, we now have incorporated an intra patient dose ramp up where we do one milligram per kilogram of magrolimab on day one for then we go up to 15 milligram per kilogram on day eight, and then we escalate to 30 milligram per kilogram on day 11. This intra-patient ramp up significantly mitigated the early anemia, but we still did see it. And so for this, we now have included into the protocol parameters for transfusion. And these include having the hemoglobin above 8.5 before the first two to three doses of magrolimab and checking the hemoglobin within 6 to 12 hours after the magrolimab for the first two to three doses so that if there is some early significant anemia, we will capture that in those patients and transfuse them. Other than that, it has been a very well-tolerated therapy. We have not seen any significant cytopenia or toxicity or prolonged myelosuppression or hepatic or renal events with this combination beyond what would be expected and has been seen with Azacitidine alone. And all in all, I think the regimen is actually quite well toleratable.

At this point in the treatment landscape of frontline high risk MDS, we really have been struggling for the last few decades. Unfortunately, in spite of many, many efforts trials, basic translational research, we have not had major breakthroughs in approvals. The single agent, HMA based therapy, Azacitidine, Decitabine, have remained standard of care for the last 25 years, and now we have an oral version, oral Decitabine also called ASTX727, which is a better delivery formulation we like to give oral, that's nice, patients like it, but the survival and response rates remain the same. So it's a replacement of IV for oral. The hope is now that the combinations we're evaluating in frontline MDS, these include Azacitidine with magrolimab but also others Azacitidine with Venetoclax, Azacitidine Sintilimab will move us to the next level, move the survival curve up. We're hoping that we can start moving into higher CR-rates. Single agent HMAs give only about 15% to 20%, can we now move to 35%, 40% CR-rate? And also, eventually the most important thing is of course to improve survival. So if the study is positive, the enhanced study, the randomized phase three global study of AZA magrolimab versus AZA placebo, this will lead to a full frontline approval of Azacitidine magrolimab as a new doublet standard of care for higher risk MDS. And this will be very exciting, and I think it will have a huge uptake across the community in the frontline MDS population. Of course, then we still need to see how transplant fits into this, but with an effective doublet with a high response rate followed by transplant, I think we could really improve the cure rates for our MDS patients quite dramatically. So this is the hope.