Hesham Abdullah, MD, MSc, of GSK, discusses myelofibrosis treatment options, including recently approved Ojjaara (momelotinib).
Transcription:
My name Hesham Abdullah, senior vice president, global head of oncology within R&D at GSK. So I oversee what is the end to end strategic research and development activities for oncology at GSK. I would say that we have a few key prioritized disease areas of interest for us in oncology. Those include hematological malignancies. And within hematological malignancies, myelofibrosis is certainly a key area of interest for us as an organization.
Myelofibrosis is really an incurable cancer that is kind of grouped within this set of disorders that affect the bone marrow. It’s basically a progressive disease that is caused by chronic inflammation impacting the marrow, which ultimately results in fibrosis of the bone marrow over time. This results in decreased bone marrow function and ultimately a decrease in what is the production of red blood cells, but also platelets as well too. So decreased erythropoiesis, oftentimes requiring blood transfusions, and also decreased thrombopoiesis, or decreased platelet production as well too, by the bone marrow.
There is a few different, I’d probably say, elements to the disease. There is what is the cytopenias that it causes, which I’ve just described. There are the organomegalies, or increases in the size of certain organs, specifically those that help produce or compensate for the decrease in red blood cell or platelet production. So what we call extramedullary hematopoiesis, and that includes enlargement of the spleen and other organs.
And that kind of, in some ways, results in this red blood cell sequestration that takes place in these organs and specifically the spleen. And then finally, there is a third element, which is the constitutional symptoms that patients experience as a result of the cytopenia, the splenomegaly. And these include fatigue, bone pain, night sweats, pruritus, cachexia and fever as well, too. The disease, at least certainly in the US, impacts around 20,000 patients. And unfortunately, the disease, like I said, has a median survival of about maybe four to six years.
And in some ways, certainly, of course, has this fatal long term outcome. So in turn, it continues to have areas of key unmet need, especially for agents that could help address all three elements. The cytopenia, the splenomegaly, but also the symptoms or constitutional symptoms of the disease as well, too. I think I’d probably say, in terms of diagnosis, it is one of these areas where it’s important for patients to have the appropriate workup, to be able to make the appropriate diagnosis. There is also an element of how each patient is managed and when intervention takes place, therapeutic intervention takes place as well too.
But yes, you’re absolutely correct. It’s one of these areas where appropriate diagnosis is important and screening as well, in terms of identifying some of these early symptoms, but also signs through laboratory assessments and evaluation of the bone marrow as well too. So these patients are probably, say, as of now, typically managed through treatment with JAK one two inhibitors. The JAK stat pathway, if I may call it that, is a key pathway. In a large portion of patients with myelofibrosis, there’s typically aberrant or abnormal signaling that takes place through this pathway, which results in more downstream activation of key mediators of inflammation in the body.
This inflammation or these inflammatory factors then continue in certainly causing some of this progressive bone marrow fibrosis over time. And so what we’ve seen over the past several years is the development of agents that selectively target JAK one two in order to help address that. But part of the challenge is that some of these agents also are associated with certain cytopenias as well, too. So there is the anemia that’s caused by the disease itself, but then could also be exacerbated by some of the existing agents as well too, if that makes sense. So while these agents address the splenomegaly and address the constitutional symptoms, they don’t necessarily address the anemia, and at times could potentially exacerbate it as well too.
And this is where, of course, being able to have an agent that helps address all three elements, the anemia, the splenomegaly and the symptoms, becomes important. And that’s where actually the mechanism of action of momelotinib comes into play. So not only does it address JAK one two signaling and help address the chronic inflammation that is caused by the inflammatory signals that are activated and factors as well, too. But it also addresses through its mechanism what is ACVR one alc two signaling, and it inhibits that. What does that do?
Well, it helps, certainly, in terms of managing better regulating what is iron homeostasis, and in turn helps address the anemia that is caused by the disease as well too. And based on the data that we’ve seen across the development program and the studies that have been conducted, this is something that we’ve seen manifest itself in terms of its impact on anemia and transfusion independence in these patients. Interestingly enough, there was actually data that was presented from a few key studies from across the development program as well too. And these are basically subgroup analyzes of patients that were enrolled in three different studies, specifically two second line studies, momentum and simplify two, and then a first line study which was called simplify one. I’ll start off first with the data that was presented recently at ASH from simplify two.
And it was specifically looking at a subgroup of patients who required red blood cell transfusion on the control arm of that trial. And the control arm of the study was actually patients could have continued on an existing JAK one two inhibitor that they were receiving, or best supportive care as well, too. And then those patients could have been switched over to momelotinib later on. And specifically in those patients that actually switched over to momelotinib on the control arm. What we saw was the ability of momelotinib to deliver higher splenic volume reductions, transfusion independence, and certainly total symptom score response rates as well, too.
This is certainly important in terms of being able to again demonstrate the impact that momelotinib has on the anemia and certainly on maintaining transfusion independence and also helping certainly improve outcomes for those subgroup of patients as well. Why is this important? Well, it’s important because 40% of myelofibrosis patients actually, at the time of diagnosis, have moderate to severe anemia. And over the course of the disease, the majority of patients develop anemia as well too. And we also know that the anemia is actually, at least based on published data linked to prognosis and long term outcomes, including survival as well, too.
And so the ability to be able to address that is important. And like I said, this is where certainly some of this data that’s being generated with momelotinib is important as well, too. The second data set that was presented was actually from the simplify one study, which was a first line frontline study, and then also a second line study, momentum. Again, all three studies, simplify one, simplify two, and momentum were phase three studies. And what I would say for simplify one and momentum.
This analysis actually looked at transfusion burden in those patients across these two studies. Simplify one and momentum, and specifically looking at ways that patients on the momelotinib arm, either one, began requiring zero units of transfusion at baseline and maintained that, or a higher proportion of them maintained that over time relative to those that were on the control arm. And then the second really was more around looking at the proportion of patients that had some level of transfusion requirement at baseline, but over time required zero units of red blood cell transfusion as well, too. And we saw that there was a higher proportion of patients on the momelotinib arm that had zero red blood transfusions requirements at baseline and maintained it relative to, of course, the control arm as well, too. So these data, of course, certainly demonstrate that momelotinib was associated with better maintenance of red blood cell transfusion intensity and zero red blood cell transfusion status relative to the control arm in these trials.
So again, why is this important? I think it’s certainly another piece of data evidence that helps give us better insight into further characterizing the effect that momelotinib has on anemia in terms of looking at transfusion burden in patients with myelofibrosis and ways that it could potentially help address some of this key unmet need in anemic myelofibrosis patients. The only thing that I would just add is we’re continuing to, of course, at this time await certainly additional regulatory outcomes. As you may be aware, of course, in the US, momelotinib has gained approval for a line agnostic indication in myelofibrosis in anemic patients, and then also in Europe. We’re awaiting the commission decision on its authorization and we look forward to hopefully additional regulatory outcomes in 2024 across different countries and regions across the globe.
We’re continuing to look at and evaluate additional opportunities for combinations exploring momelotinib and combination partners again to help address continued areas of unmet need and patient segments. And that is an area that we’re going to continue to evaluate and assess moving forward as well too.
To learn more about myelofibrosis and other rare cancers, visit https://checkrare.com/diseases/cancers/
