ASH 2020 | Prof.Srdan Verstovsek: New drugs for myelofibrosis are emerging, and JAK inhibitors are promising
Q1: Could you please summarize the challenges for treatment of Myelofibrosis
Dr Verstovsek: Challenges in the therapy of myelofibrosis are multiple. But typically, we encounter three main problems when treating patients with myelofibrosis. These problems are with anemia, problems with an ever-enlarging spleen, and problems with a poorer quality of life. These are usually targets in the development of new therapies. We aim to obtain good control of the symptoms of the disease and eventually make people live longer. This has been proven to be possible already with the first ever approved medication for myelofibrosis, ruxolitinib, but it doesn’t work in everybody and it doesn’t work forever. Almost everybody fails on treatment after 1-3 years and there is a need for another therapy after that. So now we consider second-line therapy as the number one need for our patients with myelofibrosis, and when we talk about the quality of response (control of anemia, splenomegaly, quality of life). We would also like to have medications that are curative, but at the moment, that is hard to achieve and those quality of response aspects are the focus of our efforts.
Q1: At ASH meeting,we’ve seen a lot of thematic session，Could you please highlight the latest studies released in ASH for Myelofibrosis ?
Dr Verstovsek: Understanding that the main problems in myelofibrosis are anemia, splenomegaly and poor quality of life, you usually utilize JAK inhibitors - ruxolitinib, and in the US, fedratinib - both approved to control the symptoms and the spleen in patients with myelofibrosis. We don’t have any medication to control the anemia. We would like this to have a long duration of action, but unfortunately, it doesn’t. So we are looking to develop new medications in the second-line setting as a priority, after ruxolitinib or fedratinib. In this setting, we have a number of new developments in the field. Medications such as KRT-232, or imetelstat, or CPI-0610 and several others, have been studied in the second-line setting after ruxolitinib and shown some activity in controlling the spleen, symptoms or anemia. In that setting also, another JAK inhibitor, momelotinib, has been studied and shown some activity as a single agent after ruxolitinib. The alternative is to boost the response that can be achieved on the spleen and symptoms with JAK inhibitors by using combinations. We can give patients with a suboptimal response to ruxolitinib another agent. In that setting, we have combination studies reported at this ASH meeting, combining CPI-0610 (a BET inhibitor) to ruxolitinib in suboptimal responders, or adding navitoclax (a BCL-2 inhibitor) to ruxolitinib, or luspatercept added to patients suffering from anemia while being treated with JAK inhibitors. This is an area of significant possibilities for enhancing our ability to properly treat patients for splenomegaly, symptoms and anemia - adding on to suboptimal responders another agent or an agent that will bring different anemia benefits to patients. Finally, there is another level of possibilities to enhance outcomes, and this is to combine medications from the outset at the time of diagnosis and where there is a need for myelofibrosis therapy. We can be envisage combinations from day one. In this setting, the most attractive approach perhaps was using CPI-0610 in combination with ruxolitinib from the very beginning. This has not been tried previously. In that setting, it seems the combination of these two drugs works better than ruxolitinib alone. This is only exploratory at the moment, but for any of these new drugs I have mentioned, we should have phase III studies underway soon to prove whether they are sufficiently beneficial for our patients to earn approval.
Q3: Could you please introduce the study design and result of Momelotinib in JAK Inhibitor Naïve and Previously JAK Inhibitor Treated Intermediate/High Risk Myelofibrosis Patients?
Dr Verstovsek: Momelotinib is a JAK inhibitor that has been in clinical development for quite some time as both a JAK1 and JAK2 inhibitor. There were phase III studies recently concluded and published. The phase III studies are called the SIMPLIFY studies. The SIMPLIFY-1 study compared momelotinib to ruxolitinib in the first-line setting on day one when patients needed to control the spleen and symptoms. They were randomized to momelotinib or ruxolitinib and compared for their ability to control the enlarged spleen. They were about the same. In terms of quality of life, ruxolitinib performed better than momelotinib. The third goal of the trial was control of anemia. In that setting, momelotinib appears to be better. The SIMPLIFY-2 study was a phase III study in the second-line setting in patients previously treated with the JAK inhibitor, ruxolitinib. Patients were again randomized either to best available therapy including the continuation of ruxolitinib, or momelotinib as a comparison. In this setting, control over the spleen was about the same in both arms. The quality of life improvement was better with momelotinib. And the anemia benefit was better with momelotinib. Unfortunately, because the studies were not perfect in every aspect, therapy using momelotinib has not yet been approved in the United States or globally. We hope that the next step - comparing momelotinib to danazol in the second-line setting (currently underway in a phase III study focused on the spleen, symptoms and anemia, the MOMENTUM study) - will lead to the approval of momelotinib in the near future.
Q4: Could you please explain the difference between the Momelotinib and other Jak inhibitor?
Dr Verstovsek: Momelotinib is a JAK inhibitor that is quite similar to ruxolitinib, the drug that is approved, but there are significant differences. These differences are related to momelotinib possibly affecting iron metabolism in the body of patients. This medication can actually lower hepcidin. When levels are high, hepcidin prevents the availability of iron from being present in the body for hemopoiesis. So due to ACVR1 inhibition and hepcidin lowering, momelotinib may have additional clinical benefits as a result. This was seen previously in the phase III studies that compared momelotinib in the front-line setting to ruxolitinib, and momelotinib to best available therapy in the second-line setting. In those settings, momelotinib was active on the spleen and symptoms, and active against anemia as well. Unlike other JAK inhibitors, this is the qualitative difference with momelotinib that is worth exploring in the future. In fact, the ability to improve anemia is the goal of the ongoing MOMENTUM phase III study in the second-line setting after ruxolitinib, where momelotinib is compared to danazol. If that study is successful, we will have access to a drug that is able to control symptoms, anemic and the spleen as well. Lastly, a presentation at the ASH meeting suggested that with momelotinib, we may achieve a life prolongation beyond what we have for ruxolitinib. So I think there are good prospects for momelotinib if it is approved based on the MOMENTUM study, particularly in the second-line setting after ruxolitinib.