Ruxolitinib Extended-Release Could Mitigate Risk/Increase Compliance for Patients With MPNs

Aaron T. Gerds, MD, MS

According to an FDA complete response letter, additional requirements are needed to grant approval to ruxolitinib (Jakafi) extended-release tablets for the treatment of patients with myeloproliferative neoplasms (MPNs).

Ruxolitinib was the first JAK1/JAK2 inhibitor to gain an FDA approval for patients with myelofibrosis. Now, the agent has approvals to treat a number of diseases, including for patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea as well as steroid-refractory acute and chronic GVHD after failure of 1-2 lines of systemic therapy. Topical ruxolitinib is approved for non-segmental vitiligo.

However, the currently approved oral formulation of ruxolitinib is dosed twice daily. This often results in patients missing a dose, which then can lead to a rebound of symptoms and adverse events.

According to Aaron T. Gerds, MD, an extended-release may help mitigate that risk and increase compliance in patients since taking medication once a day is easier to remember.

In an interview with Targeted Oncology^TM, Aaron T. Gerds, MD, MS, associate professor in Medicine (Hematology and Medical Oncology) at the Cleveland Clinic, provided an in-depth discussion on the complete response letter issued to ruxolitinib extended-release, and why continued evaluation of the agent could be beneficial for patients with MPNs.

Targeted Oncology: Can you explain the background info regarding ruxolitinib for patients with MPNs?

Gerds: Ruxolitinib is the first ever approved JAK inhibitor, initially developed in the myeloproliferative neoplasms field. A nice abstract initially presented a couple years ago and published this past Octoberin the Annals of Hematology, showed that survival dramatically increased in patients with myelofibrosis after the regulatory approval of ruxolitinib, even in those who did not get ruxolitinib, suggesting a systemic benefit to patients beyond simply just treating disease. For those of us who are MPN junkies, this is a huge pivotal point in the history and the treatment of MPNs.

It's also been approved to treat graft-versus-host disease, which makes sense because JAK inhibitors are anti-inflammatory drugs. Other JAK inhibitors have been approved to treat rheumatologic conditions, but ruxolitinib was the first one. Then of course, from a business perspective, the exclusivity for ruxolitinib is going to run out soon, so that's a big risk for the company. One of the tactics that has been used in the past is to come up with a new version drug that is the same, but still new, a strategy also known as secondary pharmaceutical patents. One famous example was when omeprazole was followed up by esomeprazole. The drugs are different enough to extend periods of exclusivity and where the FDA says they can market the second compound as new.

From the clinical strategy, ruxolitinib is a twice daily drug. It has a very short half-life of 2 to 3 hours, meaning that it is cleared from the body quickly, and so when patients miss a dose, 2 doses, and certainly 3 doses, they can begin to feel the effects of it right away. If they do not get treatment for a day or a day and a half, they start having rebounding symptoms, or worse a kind of cytokine storm that can occur when they immediately stop ruxolitinib without tapering it.

How would an extended-release help when treating patients with MPNs?

An extended release would help mitigate that risk and increase compliance by being a once daily medication vs a twice daily medication. Conesus in the published literature supports the concept that there is an inverse relationship between how often you have to take a drug in a day and compliance with the medication. So, with a medication that is taken 3 or 4 times a day, people increasingly miss doses just because we're human and not perfect. Medications taken one per day tend to have much higher compliance rates.

From a clinical standpoint, that's the interest for a once-a-day medication. Better compliance combined with a longer half-life, so patients are less likely to fall off this cliff if they miss a dose, immediately stop it, or run out of medication.

Can you discuss the NDA submitted to the FDA for ruxolitinib extended-release? How did this play a role in the FDA issuing a complete response letter?

There was a new drug application for extended-release ruxolitinib that Incyte submitted to the FDA. The FDA issued a complete response letter, which means that they have looked at the application, considered it, and are not going to move forward with it. It is a full stop for this application in its current form. It was notable that in the 2 trials which serve as the basis for this new drug application, they show that the extended-release did hit a target area under the curve as compared with the original twice daily dosing formulation, meaning that the amount of available drug in the bloodstream was similar with the two versions of ruxolitinib. Which is important because that's exactly what you're supposed to show in these types of studies.

There weren't any specifics in the press release regarding the reasons why the FDA did issue this letter. What Incyte can now do now is take the feedback the FDA provided in the letter, and they resubmit the application with that additional information in it to address the shortcomings of the application. This may be information already available for analysis or may need to be generated with additional clinical studies.They can also, with additional information, submit an entirely new application. Either way they do have the option to resubmit, so it's not dead in the water, but at least with the data that was sumitted so far, they do need to retool in order to get the application to proceed down the avenue of regulatory approval.

Do you think it's important for the company to resubmit this application?

That question can be answered from multiple points of view, from a business perspective and from a clinical perspective. It also heavily depends on what the FDA pointed out as the reasons for issuing the letter. If there are small things that can be easily overcome, or it requires maybe a small study to be done, then it makes a lot of sense to do this, both clinically where this drug could be of advantage, and from a business standpoint, where financial input would be limited. What could be a big challenge is a requirement for a larger trial. Large trials take a long time and consume considerable resources. So even if a large randomized non-inferiority trial comparing ruxolitinib with ruxolitinib-extended release would move the new formulation forward, it may not be prudent in the company’s eyes.

What are the next steps for evaluating ruxolitinib extended-release?

Again, it depends on what was in the letter and the specifics to why the application was denied. The next steps would be to look at the feedback given by the FDA, and try to formulate a strategy to overcome that by providing the data requested in order to approve it. Without having the specifics, it's kind of hard to say.

The next big wave in the treatment of myeloproliferative neoplasms is combination therapy. We're taking ruxolitinib and adding in pelabresib [CPI-0610], navitoclax [ABT-263], parsaclisib, and other medications to improve and deepen responses to ultimately improve patients’ lives. Once daily dosing could be an advantage in these combination therapy studies, not only for compliance with the ruxolitinib, but less pill burden for patients. If we have an extended-release form of ruxolitnib serving as the backbone for these strategies, we may get better pharmacokinetics and pharmacodynamics with synergistic combinations as well. As a clinical investigator, I would be interested in having extended release ruxolitinib to partner with other drugs as we embark on combination therapies. Now, all the combination studies are using the already approved and available twice daily ruxolitinib.

For the community oncology audience, what is important to know about this complete response letter and moving forward in the MPN space?

For the everyday practicing oncologist, ruxolitinb twice daily is still a standard of care. It has been for a long time. However, there are now other JAK inhibitors available including fedratinib [Inrebic], pacritinib [Vonjo], and potentially momelotinib, which has a PDUFA date of June 16, 2023.

Certainly, the treatment landscape for myeloproliferative neoplasms is rapidly getting more complicated, but I think if available today, extended-release ruxolitinib would be used in a similar fashion as the currently available formulation of ruxolitinib. But it would provide a more convenient dosing schedule for patients. So, for the everyday practicing clinician, it may not change what they do very much. However, I do think we are on the cusp of some major developments in the field of MPNs that are going to bring bigger changes, including combination therapies, and even immunotherapies that are even further down the pipeline, but are incredibly exciting.