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A Deep Dive Into JAK2 Inhibitors and MPNs

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Published on June 3, 2020

Key Takeaways

  • JAK1 mutation is involved in T-cell production and other cell types. JAK2 mutation is involved in red blood cell production and white blood cell production in the bone marrow.
  • Ruxolitinib (Jakafi) allows MPN patients to feel better right away but can cause weight gain and needs to be used long-term.
  • Dr. Jamieson helped with the approval of fedratinib (Inrebic). Side effects may include nausea and vomiting, which can be alleviated by taking the pill at night instead of in the morning.

What are JAKs? What does this gene mutation mean for me and my myeloproliferative neoplasm (MPN) care? What medicines are available to target my specific MPN?

In this segment from our recent town meeting, Dr. Catriona Jamieson from UC San Diego Moores Cancer Center answers these questions. She also shares the history and creation of JAK2 inhibitors along with the differences between the two approved medications. Watch now to learn from an MPN expert.

This program is sponsored by Bristol Myers Squibb. This organization has no editorial control. It is produced by Patient Power in partnership with Bag It, MPN Advocacy and International and MPN Research Foundation. Patient Power is solely responsible for program content. ​

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Transcript | A Deep Dive Into JAK2 Inhibitors and MPNs

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

So let's get into the JAKs. So you mentioned in 2005 you all identified the gene that was a driver gene, 2007 I guess you were studying it. There was an early development of Jakafi—ruxolitinib—2011 it's approved.

I was diagnosed in 2011 so thank goodness for the people who were in trials that led to an approved drug that I could get as I needed it in them last year, and as you said, Dr. Scott, Dr. Jamieson was very much involved in the development and approval of fedratinib, Inrebic as the trade name is. So we have to, so first of all, Dr. Jamieson, what are we inhibiting? You've mentioned JAK, Dr. Scott rattled off JAK2 V617F you've mentioned calreticulin, Dr. Scott mentioned MPL. So these driver genes, and where did these medicines come in to kind of tamp it down?

Dr. Jamieson:

Yeah, so in 2005 four groups described a mutation in the JAK2, J-A-K-2 gene. That gene was first discovered by Andrew Wilkes in Australia in 1989, and he thought his career was over and he called JAK, Janus kinase. He almost stopped working as a scientist, because he thought it was useless. And then he said, "Wait a minute, this seems to determine what stem cells are going to be going to do in the body and the bone marrow in particular and whether they're going to become," and it was a main driver of red blood cell production. And so people started to look at is that gene JAK2? There's JAK1, which is more involved in T-cell production and other cell types, JAK2 that's very involved in red blood cell production, and white blood cell production in the bone marrow.

So a lot of groups started to look at JAK2 where's the mutation, 2005 William Vainchenker in France discovered that there was a mutation in JAK2. There was availing to acetaminophen (Tylenol) mutation at amino acid position 617 which is why we call it V617F, very long waited way to say, "That was cool." And three other groups discovered this in close succession. There were four papers that came out within a few weeks of each other. And so the bottom line is the mutation for JAK2 is in the switch part of the gene where it normally shuts itself off, and that's the pseudo kinase domain. And because that's mutated, JAK2 can't turn off. It keeps signaling there are no breaks for this pathway and people who've mutated JAK2, and it turns out the level of the JAK2 mutation actually matters.

So when Dr. Scott and I look at the somebody's next-generation sequencing results, we look at what's called the variant allele fraction or mutation burden. So how much JAK2 mutation do they have? Is it 70 percent, is it 5 percent it actually determines not just your prognosis without treatment, but may actually determine your response to therapy. So people with a JAK2 mutation tend to respond quite well to JAK2 inhibitors. A calreticulin mutation was discovered a few years later, and it turns out that can also activate JAK-STAT signaling. And then as Dr. Scott alluded to, there's another mutation that's in 1.5 percent of people called the MPL mutation. And that's the thrombopoietin receptor. We see that more in essential thrombocythemia, because it tends to drive platelet production, which is the big thing that we see with essential thrombocythemia. So with the JAK2 inhibitors, we've got ruxolitinib—Jakafi—and we've got now Inrebic—fedratinib.

And really, as you know, we just sit down and say, "Hey, what would you like to face as side effects?" Because they have entirely different side effect profiles so both pills, Jakafi as I call it, you take twice a day, people tend to feel really good very quickly, usually within a month. Becky and I noticed that when we started to do the clinical trials with Jakafi, it was like a happy pill. People would come in and say, "I feel great. Almost too great." It was, too happy. And I think it's because the burden of those growth factors, the cytokines is lifted and so people feel so good. Generally people do well for quite a number of years. Unfortunately, the downside is it's not quite as potent as an inhibitor of JAK2, as we had like for long-term use. And so about 25 percent of people are still on Jakafi after five years where we were hoping it would be more people.

Side effects include weight gain, it seems to make people hungry, and they tend to snack at night. So a lot of people gain weight around the middle. People don't like that in Southern California. And the other thing is a slight increased chance of infection, viral infection, because it also inhibits JAK1. And so it inhibits T cells, in other words. So that's something we really have to watch out for overall and incredibly well-tolerated drug. And I think an issue, we're probably a little too conservative about the people we selected to treat with that. So in 2011 when it was approved, we were really just keen to treat people with intermediate-2 or high-risk disease. And now we know we can treat people at slightly earlier stages of disease rather than just waiting for their symptoms to accumulate. So often symptom reduction actually goes with real disease control.

So the quality of life measures that Dr. Mesa actually developed are very good predictors of survival of overall outcome. So the more we can tackle the symptoms, the greater the chance it is that we're actually tackling the disease with Inrebic the reason we worked so hard to get that back is it's not one size fits all. Not everybody responds to Jakafi and or some people lose their responses. I mentioned only 25 percent of people are on Jakafi after five years. So it means they either didn't tolerate it or they've progressed on it. And so then we have to consider another JAK2 inhibitor, and this is why the FDA approved it frontline, because they don't want people to have to wait until they haven't responded to JAK but they want to say, "Hey, this is a choice." I think when Becky and I did the clinical trials Phase I to III, for fedratinib or Inrebic, it was quite clear that people didn't feel like they'd had a happy pill.

They didn't feel great within the first month. If anything, they didn't feel good at all. And we saw nausea, vomiting, diarrhea, lot of this was okay, take your Imodium and the meetings won't be quite so disrupted as we had a few people cursing as one who vomited all over the front of his wife's new Bentley that he bought her. So this patient told us take the pill at night and that turned out to be a really great thing because it caused her motion, sickness down, nausea in the first six weeks. I think now that it's approved at a 400-milligram dose, which is a lower dose than Becky and I used for a lot of the patients would be maintained on the five-year long extension phase study. It seems to be a bit better tolerated. Definitely a potent drug. It seems to work more on the disease and the spleen and the bone marrow as opposed to the cytokines.

Slightly different mechanism of action also targets JAK2. It's a little bit more potent in terms of inhibiting JAK2 and it takes a little bit longer to work. So generally people say, "Hey, I didn't feel good for a whole three months." And that's why I like telehealth so much because we can see people within that time period with just a quick visit. Anyway, so I think we have a chance of really having people respond to this therapy. It's been approved since August of last year and more people are getting on it. And I think what we saw with the phase one extension phase study that went on for five years was, about 25 percent of people reduce the scarring in their bone marrow and we didn't use to consider that a prognostic feature until the MIPSS70+ scoring system came along.

So we'll be looking for all of these medications via Jakafi, Inrebic or a combination of one of these two JAK inhibitors with something else to see does it produce bone marrow scarring, does it reduce mutation burden. And as Dr. Scott was alluding to and if we don't get far enough fast enough, maybe allogeneic transplantation will be an option for people sooner. We don't have to wait as long now that we've got such precise tools for determining long-term outcomes.

Andrew Schorr:

Okay. Thank you for explaining that. I just want to mention that based on one of the things I was dealing with where my platelets were trending down after seven years on Jakafi, which worked remarkably well for me, dosages had to be changed. Sometimes add bruising or other issues, but overall lived quite well. We made the decision together to change to fedratinib. And I have to tell you, I had some anxiety, Becky, maybe you heard about it, but Dr. Jamieson heard about it, switching to another powerful drug when, except for the platelets, it kind of wasn't broken and I was living well. And so when you've been on a drug seven years and it's working pretty well, even though the blood was starting to say something different, you're hesitant to change knowing how powerful these medicines are. So knowing there could be certain side effects.

I went to Rite Aid down the street and I got diarrhea medicine, I got itching medicine, dah. Guess what kids, I've been on this five months, I haven't used it for any of it. And I take the four capsules, 400 milligrams at night when I brush my teeth. So far, so good.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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