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Two JAK Inhibitors for Myelofibrosis

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Published on December 22, 2020

An Overview of Ruxolitinib (Jakafi) and Fedratinib (Inrebic)

The two approved JAK inhibitors, ruxolitinib (Jakafi) and fedratinib (Inrebic), have offered more options and new hope to myelofibrosis patients. What are the differences between ruxolitinib and fedratinib? Under what conditions should a myelofibrosis patient be on one or the other? Are there financial considerations Dr. Catriona Jamieson, MD, Ph.D., of the Catriona Jamieson Laboratory in the Department of Medicine at UCSD, joins her patient, Patient Power co-founder, Andrew Schorr to discuss how each of these two drugs has impacted treatment, the manageable side effects and the future of treatment for each of these drugs in combination with others.

This program is sponsored by Bristol Myers Squibb. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.


Transcript | Two JAK Inhibitors for Myelofibrosis

Andrew Schorr: Hello, it's Andrew Schorr from Patient Power, in the San Diego area, and I want to introduce you, once again to my Doctor who's at UC San Diego, Dr. Catriona Jamieson. Hello, Doctor and tell everybody what your title is there in San Diego.

Dr. Jamieson: Yeah. Thank you so much, Andrew, for having me on again to Patient Power. This is such a great format for delivering the newest news in hematology and cancer clinical trials. I am the Director of the Sanford Stem Cell Clinical Center and Deputy Director of the Moores Cancer Center here at UC San Diego, so it's a pleasure to join you today.

Andrew Schorr: Thank you. So, Dr. Jamieson, we have two approved JAK inhibitors: ruxolitinib (Jakafi) and fedratinib (Inrebic). You've been very involved in the early development of fedratinib. So we're hearing now about combination studies with ruxolitinib. We wonder, might that happen, other drugs being layered on top of fedratinib or Inrebic. And also how you decide, which JAK inhibitor might be right for which patient?

How Do You Decide Which JAK Inhibitor is Right for a Patient?

Dr. Jamieson: Yeah. That's the fundamental question right now. It's great to have choice. So I think in the myeloproliferative neoplasm field, we're in much better shape for physicians, and most of all, for patients. In terms of the difference between ruxolitinib and fedratinib, or Jakafi and Inrebic as they're known commercially, Jakafi is both a JAK1 and a JAK2 inhibitor. The JAK2 inhibitory part is going to cause some anemia. It's going to really have a detrimental impact on platelets if it's not working effectively. And that's been the main issue we've had with Jakafi where it's been underdosed and people aren't going by the label because they're worried about potential toxicity.

The other thing, because of the JAK1 inhibitory part, it can be immunosuppressive and it's actually used for treatment of a post-transplant disorder called graft-versus-host disease, so it's quite immunosuppressive. The difference between that and fedratinib, fedratinib is a combination drug that targets both JAK2 and this other gene called F-L-T-3, FLT3. FLT3 is actually turned on by cells as they start to become leukemic.

It's very important for cells called leukemia stem cells to be able to clone themselves. So, by targeting both JAK2 and FLT3, this drug, fedratinib also known as Inrebic, is slightly more potent in intermediate two and high-risk disease in terms of trapping the disease in the bone marrow. The way I put it to patients, because they're both approved frontline for myelofibrosis, whether it's primary myelofibrosis headboard has progressed from polycythemia vera or essential thrombocythemia to myelofibrosis, is all about symptoms and the side effects that people are willing to put up with. So I just present the case and say if you have an inflammatory disorder auto-immune disease, then Jakafi maybe a better option for you.

 If you don't have a problem with that and are willing to put up with a little bit of nausea and intermittent diarrhea for the first six weeks, then Inrebic may be a better choice for you than Jakafi. So it's a patient choice, and we were in this very good position several years ago with Gleevec (imatinib) versus Sprycel (dasatinib), where Gleevec was not as potent, but very well tolerated, Sprycel more potent, not as well tolerated or so it seemed initially from a respiratory standpoint. And then as it turned out, Sprycel ended up being extremely well-tolerated over the long-term, just harder to get initially and more expensive initially. So, I think the major hurdle we have to overcome for patients with MPNs, is getting rid of the financial toxicity of these medications and ensuring that people don't have massive copays and that they do have access to their medication, whether they're an inpatient or an outpatient.

The problem with Jakafi in terms of inpatient use is you're supposed to taper off instead of stopping cold turkey if you get sick. And so people end up trying to taper, but in the ER, the medications just stopped. And so there're concerns about the on-again, off-again, effect of being on Jakafi in the setting of getting more upper respiratory tract infections, upper urinary tract infections, other types of infections because then you lose your response in the bone marrow. And it’s an excellent drug for managing symptoms. It's a really good, safe, tolerable, long-term drug for really badly in myelofibrosis in the extramedullary features of that, meaning the enlarged spleen. But it's not great in terms of people having to taper and having to take it twice a day and gaining weight on it.

So those have been issues. Other than that, I just leave it up to patients to decide, we have the NCCN guidelines. So I actually print the NCCN guidelines. It's not exactly tree-friendly, but a lot of people want to read what we've deliberated on at the National Comprehensive Cancer Network panel that meets yearly. And I think with data, people are just able to make their own decisions. So I'm not all that prescriptive about the choice, I do now go though by the next-generation sequencing panel. So if somebody is increasing their variant allele frequency, by more than 10%, I really started to watch that now. And we consider the addition of something to Jakafi like Pegasys, which is the pegylated interferon or a switch to Inrebic in that case, or a clinical trial.

Andrew Schorr: Well, so that was the one other area I wanted to just ask you about. The news out of ASH was about other drugs that may be added certainly to ruxolitinib. But do you see the possibility that these drugs might be added to fedratinib just as well? I know that we don't have the studies yet, but in other words, how is this all going to work out, sort of a one-two punch for myelofibrosis?

What Do We Know About Combination Therapies with JAK Inhibitors?

Dr. Jamieson: Yeah, I think we're getting some long-term safety data with the fedratinib, Now, [inaudible] are very present at the long-term safety data for fedratinib with no evidence of Wernicke encephalopathy and the group that they presented as a follow-on from the JAKARTA study. And now we've got a couple of clinical trials going on for Inrebic. So I think it's just looking like it's safe, it seems to be well tolerated. I think as we become more conversant with having two baseline JAK2 inhibitors, we'll be able to know how to combine them with other therapies. For example, with navitoclax, which is a BCL-2, BCL-XL antagonists, that's really hard on the platelets because of BCL-XL inhibition, which platelets need to form. That's made the combination with Jakafi difficult because Jakafi also lowers platelet counts, Inrebic doesn't lower platelet counts as much.

So Inrebic, maybe a better treatment option for a combination with something like navitoclax. For the Constellation Pharma drug that I think will be fine with Jakafi... The two pills I think we just have to look at having non-overlapping side effects as we develop these combination strategies. I think we should stay realistic; the combination strategies are really for people with higher risk features. They have high molecular risk, they've got more fibrosis in the bone marrow. I wouldn't recommend a combination strategy considering that we've got two great JAK2 inhibitors without evidence of having higher risk disease at this point because with every combination comes more side effects.

While we'll do clinical trials here, and we're excited to do that, we want to make sure that we don't make it sound like a panacea. These combinations have additional side effects, increased liver enzymes, lower platelets, things like that, that you're... as a patient, you're willing to face if you have higher risk disease or intermediate too. But I think it's going to be hard for intermediate one risk patients to take on these extra toxicities until we understand the safety profiles of the combinations. So, I agree with you, Andrew, I think there's an opportunity to combine with Inrebic or Jakafi depending on what the other drug does as a side effect.

Andrew Schorr: Okay. Well, I think you've really put it in perspective. But research marches forward... I know behind you there, you have your lab and you're doing a lot of work there. Thank you for all you do Dr. Jamieson. Thank you for what you do for me personally, and for helping us understand now some of the properties of these two JAK inhibitors in where we may go in the future. Thanks for being with us.

Dr. Jamieson: It's my pleasure. And I... Just to say a parting word, the European Medicines Agency or a CHMP has given a favorable review of Inrebic. So fortunately in Europe, they're going to have two choices as well. I think this is a testament to how hard our regulatory agencies work. And I'm really proud of our FDA for everything they've done for COVID and to keep our patients safe. And for our whole MPN community... Andrew, you see what a motivated community of patients we have and I'm really grateful for being involved with Patient Power. So just let me know how I can help in the future.

Andrew Schorr: Thank you so much. With Dr. Catriona Jamieson, I'm Andrew Schorr. Remember knowledge can be the best medicine of all.

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