Myelofibrosis Treatment Options

Hesham Abdullah, MD, MSc, of GSK, discusses myelofibrosis and the uses of momelotinib, also known as Ojjaara, to treat it.

Transcript:
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?