By Jalaja Potluri, MD
How can this study help modify myelofibrosis? Navitoclax is the investigational drug, which is not currently approved. It is being studied in a condition called Myelofibrosis. It's a bone marrow disease where there's changes in the blood counts and patients are symptomatic, with enlarged spleen. It is being studied in a phase 2 program, and the data that are being discussed are from this ongoing phase II study. It has multiple cohorts. The data that was just presented represents a population that has not yet received the current standard of care Ruxolitinib, and we're combining Navitoclax the investigational agent with the standard of care Ruxolitinib.
The current standard of care is with what we call JAK inhibitors, and they have been the standard of care with the approval of Ruxolitinib in 2011. It's an oral drug that's taken twice daily and it controls improvement in spleen size and symptoms of the patient, which are. The general presentations for patients with this disease and what's important for this combination is while patients do benefit, majority of them do benefit from improvement in their symptoms and the size of their spleen.
This combination, it not only increases the these responses, but also has more in-depth response, meaning some of the things that we're noticing could impact the natural history of the disease. By that, what we call it as potentially disease modifying trying to control some of the hallmarks of the disease, meaning the fibrosis and the bone marrow, improving their blood counts, and also trying to suppress some of the genetic abnormalities that are seen in association with this disease. So that's why we're excited with the combination, improve upon the current standard of care.
This is a phase 2 study, it was developed to understand how this combination would work in patients. We did have some preclinical data that supported that the two agents can be synergistic and therefore the Navitoclax trial was begun in patients who already received the standard of care Ruxolitinib. So we added Navitoclax in the earlier cohort of 34 patients, and we presented that data and there's a publication as well, and once we had the data that were very encouraging, we expanded the trial into different cohorts and we have shared those data in patients who had add-on Navitoclax to an ongoing Ruxolitinib. And also now this particular cohort is looking at patients who have not yet received the current standard of care, but starting both of these medications at the same time that we're calling it as JAK inhibitor naive population.
Ruxolitinib, the pivotal or the registration trial showed patients who have improvement in spleen in about 40% of the patients, and the similar number of patients had improvement in their symptoms, which are very key for patients who experienced this disease. What we have seen in this cohort of patients in this phase 2 study are about 60% of the patients are having that improvement in the spleen, and about 40% of the patients have improvement in their symptoms.
What's exciting now is not only there's incremental improvement in the spleen with this combination, we're also seeing what I just mentioned regarding, the potential disease modification with improvement in that bone marrow change is called marrow fibrosis grade. So we're seeing improvement in the marrow fibrosis grade in about a third of the patients.
So we're very excited that this potentially could help alter the natural history of the disease. And that's the exciting data that we have shown and it's seen across the board, regardless of which type of prognostic group of patients are enrolled and have received this combination. It's a small sample size, but we're excited with the emerging data that we have.
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It is a synthetic, orally accessible, small-molecule antagonist of a subset of the B-cell leukemia 2 (Bcl-2) protein family with potential antitumor efficacy. ABT-263 binds specifically to apoptosis suppressor proteins Bcl-2, Bcl-XL, and Bcl-w and blocks their binding to the apoptotic effectors Bax and Bak proteins, which may induce apoptosis in tumor cells overexpressing Bcl-2, Bcl-XL, and Bcl-w. Bcl-2, Bcl-XL, and Bcl-w are widely overexpressed in numerous malignancies, including those of the lymphatic system, breast, lung, prostate, and colon, and have been associated with tumor therapeutic resistance.
Is a treatment for myelofibrosis (is a cancer of the bone marrow in which the bone marrow is replaced by scar tissue and causes decreased blood cell production). It is also used to treat polycythemia vera (PV; a slow-growing blood malignancy in which the bone marrow produces too many red blood cells) in patients who did not respond to hydroxyurea. Ruxolitinib is also used to treat acute graft versus host disease (aGVHD; a complication of hematopoietic stem-cell transplant [HSCT; a procedure that replaces diseased bone marrow with healthy bone marrow] that typically develops within the first few months after HSCT) in adults and children 12 years and older who were treated unsuccessfully with corticosteroid medications. It is also used to treat chronic GVHD (cGVHD; a consequence of HSCT that typically arises at least 3 months after HSCT) in adults and children 12 and older who have been unsuccessfully treated with one or two prior treatments. Ruxolitinib belongs to the class of drugs known as kinase inhibitors. It treats myelofibrosis and PV by inhibiting the impulses that promote the multiplication of cancer cells. This prevents the spread of cancerous cells. It treats GVHD by inhibiting the signaling of the cells responsible for GVHD.
The Navitoclax study is a phase 2 trial the primary endpoint is spleen volume reduction. And this is unlike a registration or a phase 3 trial. This is not a trial where we would have a study designed to meet its statistical significance. Therefore, I would say the objective has been met, but I can't say that there is a statistical significance. The data are definitely very compelling compared to the historic data. We can't compare cross trial, but, based on the available data from the pivotal Ruxolitinib trials, and what we're seeing in our combination is definitely we think that the clinical study has met the objective, but in terms of did it meet the endpoint will be determined in later more randomized clinical trials.
When you add new drugs we have to think about their tolerability and how long can they receive the drug and what incremental benefit they might receive. More importantly in terms of the incremental benefit, definitely it's a 60% and higher response rates At week 24 is when we measure. The outcome of the spleen volume in this particular disease.
When we leave patients to continue to receive the drug, we're seeing improvement in that spleen volume upwards of 70%. So that's very encouraging, compared to what has been published that we know of for Ruxolitinib, and that's the data that we share with our oncology colleagues. The second thing is the safety. This is a drug called BCL-XL inhibitor, and that's a, based on its mechanistic mechanism of action. It does target certain blood cells, so it does lead to what we call thrombocytopenia or decrease in platelets. It's a common signal and it is something that we do want physicians to be careful, monitor the patients more closely.
So that's a safety aspect that we continue to remind all of our investigators that are participating in the Navitoclax trial. One thing to note is, it is very well tolerated with all the modifications of the dosing that we implement into the trial and without any problems to the patients. It's the numerically, the numbers, do drop, but they're well managed with the dose adjustments. So those are the key things that we communicate with our investigators.
I am a hematologist myself, I'm very excited for a lot of new innovative targeted therapies for patients with a lot of these chronic but very debilitating conditions. And so there's a lot of signs that's advancing in myelofibrosis, and I think the patients do, deserve better. We need to improve upon their outcomes. So looking forward to advancing the science and being part of this development of Navitoclax in combination treatment with Ruxolitinib.
Dr. Jalaja Potluri is a board-certified hematologist and oncologist who has worked in the pharmaceutical industry for over 15 years. She has experience in both clinical practice and cancer research thanks to her participation in national cooperative cancer clinical trials. Extensive expertise in the pharmaceutical industry is required for the design, development, and execution of Phase 1 to 3 clinical trials, including the approval of new medications for a variety of indications on a global scale. She currently holds the position of Executive Medical Director at AbbVie.
NIH - Navitoclax. NIH, 2022
Medline Plus - Ruxolitinib. Medline Plus, December 15, 2021