Use of AB1 to Upregulate Fetal Hemoglobin in Patients With Sickle Cell Disease
In this podcast, Nirmish Shah, MD, discusses an overview, the results, and the preclinical and clinical impact of the study titled "Preclinical and Clinical Use of AB1, a DNMT1 Protein Depleter, to Upregulate Fetal Hemoglobin in Townes Sickle Cell Disease (SCD) Mice and Patients with SCD." Dr Shah also presented on this topic at the American Society of Hematology’s 2023 annual meeting in San Diego, CA.
Additional Resources:
Shah, N, Raval G, Kutlar A, et al. Preclinical and clinical use of AB1, a DNMT1 protein depleted, to upregulate fetal hemoglobin in Townes sickle cell disease (SCD) mice and patients with SCD. Paper presented at: American Society of Hematology's Annual Meeting & Exposition; December 9-12, 2023. Accessed December 19, 2023. https://ash.confex.com/ash/2023/webprogram/Paper188165.html
For more coverage of ASH 2023, visit the newsroom.
TRANSCRIPTION:
Jessica Bard:
Hello, everyone, and welcome to another installment of Podcast 360, your go-to resource for medical education and clinical updates. I'm your moderator, Jessica Bard, with Consultant360, a multidisciplinary medical information network. Dr Nirmish Shah is here to speak with us today about his team's research presented at ASH 2023 titled Preclinical and Clinical Use of AB1, a DNMT1 Protein Depleter to Upregulate Fetal Hemoglobin in Townes Sickle Cell Disease Mice and Patients with Sickle Cell Disease. Dr Shah is the Director of the Sickle Cell Transition Program and the Director of Clinical Research in Benign Hematology at Duke University School of Medicine in Durham, North Carolina. Thank you for joining us today, Dr Shah. Please provide us with an overview of this research.
Dr Nirmish Shah:
Yeah, so this is a lot of exciting work that's recently been undertaken by both myself and Dr Betty Pace, who leads a lab at Augusta University. So the overall goal here is this understanding that within sickle cell disease, the issue really comes down at its root cause to the sickling itself. The sickle cells go through the sickling process. That causes all these downstream issues. It causes hemolysis and destruction. It causes vaso-occlusion and adhesion issues.
So if we could get to the root cause, which is the sickling, and try to stop that sickling, then we would hopefully have a lot of potential benefit from that. And we actually have historical evidence that that actually can occur by using and leveraging fetal hemoglobin. So fetal hemoglobin is baby blood, and if we could upregulate fetal hemoglobin through a medication, in this study AB1, then we could potentially have a therapeutic option.
So the overview really is to see if AB1, and an AB1 is a DNMT1, a DNA methyltransferase 1 protein depleter, which then upregulates and increases fetal hemoglobin. And we tried this in a study within Townes mice, which is a good example and a basis for the sickle cell drugs that we try. And then we also tried this as a proof of concept in sickle cell patients.
Jessica Bard:
What were the results of this study?
Dr Nirmish Shah:
So I'll kind of separate the results since we did focus on both the Townes mouse model and then patients. And so I'll start with the Townes mouse model. Very quickly we had a couple cohorts of mice that we looked at, and we treated them with a placebo, which was water. We either otherwise had a treatment arm with hydroxyurea alone. And then finally, we had a treatment arm with AB1. And this also included an arm in which AB1 was dose-escalated. The treatments were all for about six weeks.
Really, the crux here is that the results that we're looking at were in a couple of different ways. One is on a lab level, did we have upregulation of fetal hemoglobin? We did this by looking at gamma globulin levels. Then we also looked at fetal hemoglobin itself and F-cells. And finally, we looked at organs, in particular the spleen, and we looked to see if there was any difference in the spleen at the conclusion.
So on those three levels we did find an increase at six weeks, which was the total treatment time, we did find an increase in gamma globulin and F-cells across all the treatment arms, including hydroxyurea with AB1, as well as AB1 alone. We did also, interestingly, look at the smear of the sickle cells after they've been put under hypoxic conditions. And you again see this protective effect of the sickle cells not sickling as much when put under hypoxic conditions. That ultimately led to the spleen, which when we look at the spleen as another method of seeing potential protective effects on the organs, the spleen and those that were treated like the control arm were very large. There was actually a lot of ischemia and damage to the spleen, so it was actually quite large. But for those that were on treatment with hydroxyurea or AB1 or both, we actually found areas that first off the spleen was small and then we found areas where there was erythroid hyperplasia. We actually saw areas where the spleen itself was actually trying to make blood, which is very protective.
And then moving on to the clinical side. The exciting part is that the mouse model showed a signal. It showed that we did have upregulation of fetal hemoglobin, so we now take that leverage to try this in patients with sickle cell. And so we designed a phase 1-2 dose-escalating study where we actually took low-dose AB1 at levels that we would not necessarily expect to have any clinical benefit, but really wanted to just monitor safety in pharmacokinetics, pharmacodynamics. And we started two and four and moved our way. Our max dose is ultimately going to be 32, but the results here in this portion, the clinical portion, is that we've enrolled six patients, two on the 2 milligrams, two patients on the 4 milligrams, and two in the 8 milligrams, although one has come off study.
And so the results show that from a pharmacokinetic pharmacodynamic level, by the 8 milligrams, we're starting to see a little bit of movement, and we see fast absorption within all of the different cohorts. So we're optimistic that we'll see more of the same as we get to higher doses. And ultimately, the biggest result to kind of highlight here is that at 2 and 4 milligrams, we're actually starting to see an increase in fetal hemoglobin, and we weren't expecting that at all. We actually thought that this was a very low dose. So we don't have the F-cell or fetal hemoglobin values for 8 milligrams yet because one patient came off for an infection, colitis that was deemed not due to the drug. The patient was actually off the drug for seven days before that developed. It has not restarted. So we're still enrolling in the 8-milligram cohort. So we're just really excited to see where this goes from here.
Jessica Bard:
And why would you say this topic is important to study?
Dr Nirmish Shah:
As I kind of started here, the reason this is important to study is that fetal hemoglobin has been shown in many different ways to be very protective for sickle cell, so much so that actually one of the gene therapies, which is of course a hot topic in sickle cell disease, which is just approved for sickle cell now just a week ago, one of the treatments with gene therapy is actually causing an edit to the gene to upregulate fetal hemoglobin. And so we know that fetal hemoglobin in a natural history way, in a gene therapy way, can be protective to patients with sickle cell. So in this effort to try to use an oral agent, to try to upregulate fetal hemoglobin, it really seems like a viable and very hopeful option for patients with sickle cell to have a protective option.
Jessica Bard:
And what would you say is next for research on this topic?
Dr Nirmish Shah:
So now I think the next step is probably twofold. One is how far can I push fetal hemoglobin? Can I get fetal hemoglobin to a value that is as protective as what gene therapy seems to be indicating so far? And so really trying to see to what degree I can do this in a safe and effective way. The second thing to consider as the next step is if I'm not able to really hit the home run and make it so that I'm completely making patients asymptomatic, but getting near to that, how do I integrate this therapy with other therapies that are also beneficial? We now have many therapies that are beneficial to sickle cell, and so can I combine these therapies with hydroxyurea, with these other therapies with different mechanisms of action that all then encompass a good multi-drug therapy to help our patients?
Jessica Bard:
What would you say are the overall take-home messages from your presentation?
Dr Nirmish Shah:
Yeah. I think the take-home is that we can be optimistic that fetal hemoglobin, in general, is a good option for patients. And from the results that we're presenting, we don't see any safety concerns so far. We were already starting to see a signal where we have an increase in fetal hemoglobin despite us having a very low dose. So I'm actually quite optimistic to see what the next several cohorts show us because I think very soon we'll actually be in the dose ranges that we actually would expect the difference, and it'd be nice to see what kind of fetal hemoglobin responses we get.
Jessica Bard:
Is there anything else that you'd like to add that you think that we missed?
Dr Nirmish Shah:
I would encourage researchers who are looking at novel therapies such as fetal hemoglobin and other mechanisms of action to consider, how this fits into the opportunities that we now have for patients. We actually used to just have hydroxyurea. I'm talking to patients all the time about when you have a very complicated disease, do you have diabetes that's not controlled, congestive heart failure that's not controlled? We use more than one drug. That's actually the expectation to use more than one drug. And we haven't really had a lot of studies to do that within sickle cell yet. We're all working on therapies that in one way or another showing that one therapy is good. Most are really showing it with hydroxyurea, which is great, but now we have all these other mechanisms of action. It would be great to think ahead and see how we can do these studies to show that all of these drugs can be complementary.
Jessica Bard:
Dr Shah, thank you so much for joining us on the podcast today.
Dr Nirmish Shah:
Of course. Absolutely. Thanks again for having me.