Beyond Ruxolitinib: Exploring the JAK Inhibitors Landscape

In 2011, the U.S. Food and Drug Administration (FDA) approved ruxolitinib as the first therapy to treat myelofibrosis (MF), one of the group of bone marrow (BM) disorders known as myeloproliferative neoplasms (MPNs). Ruxolitinib has since become a standard of care for the treatment of intermediate- and high-risk primary MF, post–polycythemia vera (PV) MF, and post–essential thrombocythemia MF. In December 2014, the FDA extended the approval of ruxolitinib to a second type of MPN, for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea.

The drug was also the first Janus-associated kinase (JAK) inhibitor to receive regulatory approval. This class of drugs inhibits the activity of one or more of the JAK family of enzymes, interfering with the activation of the JAK-STAT (signal transducer and activator of transcription) pathway.1 Tofacitinib was the second JAK inhibitor approved by the FDA for rheumatoid arthritis in 2012. Recurrent activating mutations in JAK2 activating JAK-STAT signaling were simultaneously discovered by four research groups in 2005.2-5

“The development of JAK inhibitors for MPN came out of research to find out what makes these diseases tick,” explained Aaron Gerds, MD, an assistant professor of medicine at the Taussig Cancer Institute of the Cleveland Clinic, who specializes in the treatment of myeloid malignancies. “What we [learned in 2005] was that activation of the JAK-STAT pathway is a hallmark of this group of diseases. That opened up a whole new world of treatment possibilities because, at the time [of that discovery], there were no approved therapies for MPNs.”

ASH Clinical News spoke with experts in MPN treatment about the role of ruxolitinib, as well as several investigational agents under development.

A Mainstay of Treatment

The FDA’s decision to approve ruxolitinib for MPN was based on two phase III clinical trials – COMFORT-I and COMFORT-II – in which treatment with the oral JAK1/2 inhibitor significantly reduced symptom burden and was associated with an improvement from other therapies with respect to the number of patients with reduced spleen volume of at least 35 percent from baseline.6,7

Based on these results, ruxolitinib quickly became a standard treatment for this patient group with limited treatment options. “In my practice, I would use ruxolitinib for every patient with MF who has symptoms of the disease,” said Claire Harrison, DM, professor of MPNs and deputy clinical director at the Guy’s and St. Thomas’ Hospital in London, who was the principal investigator of the COMFORT-II trial.

In a five-year update of the COMFORT-I trial, ruxolitinib also modestly prolonged median overall survival (OS), compared with placebo, even though many patients initially assigned to placebo eventually crossed over to the ruxolitinib arm (hazard ratio = 0.69; p=0.025).8 “Partly because of the crossover design of the trial, the question of whether ruxolitinib allows patients to live longer is still a controversial topic,” Dr. Gerds noted, “but patients certainly are living better.”

For John Mascarenhas, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, who specializes in the treatment of MPNs, the modest survival benefit conferred by ruxolitinib is likely based on “improvement in symptoms, reversal of cachexia, and improvement in performance status.” However, he added, “we don’t generally see that survival is correlated with a reduction in the mutant JAK2 allele burden or resolution of fibrotic changes within the BM.”

Investigational JAK Inhibitors

Of course, ruxolitinib isn’t a silver bullet. A patient’s disease can stop responding to ruxolitinib, or the patient can become intolerant to the JAK1/2 inhibitor, often because of thrombocytopenia or anemia – the most common adverse events (AEs) associated with the drug. Clinicians are also uncertain whether ruxolitinib should be relegated to patients with intermediate- and higher-risk MF who were studied in the COMFORT trials, or might also have a role in lower-risk disease. In addition, clinicians are interested in combining ruxolitinib with other agents like phosphoinositide 3-kinase inhibitors or hedgehog inhibitors, which could improve outcomes without increasing toxicity.

“Ruxolitinib doesn’t clearly impact the disease course, it doesn’t [consistently induce] pathologic remissions in the BM, and it doesn’t normalize patients’ hemoglobin and platelet counts,” Dr. Mascarenhas added.

So, despite the drug’s unquestionable place in the MPN treatment armamentarium, researchers are now looking to newer JAK inhibitors to see if outcomes can be improved.

There are a number of additional JAK-targeting agents that have been tested in MPN, several with circuitous development paths, according to Dr. Harrison, who referred to the development of other JAK inhibitors as “a bit of a rollercoaster.”

Fedratinib

A prime example is the story of fedratinib, a selective, oral JAK2 inhibitor under investigation for the treatment of MF. In 2013, results from the phase III JAKARTA MF study with fedratinib suggested that the drug significantly reduced splenic volume and MF-associated symptom burden, compared with placebo.9 Later, the phase II JAKARTA-2 study, which evaluated fedratinib in patients with intermediate- or high-risk MF who were intolerant to ruxolitinib, met its primary endpoint of splenic response.10

Despite these encouraging results, further development of fedratinib stalled in November 2013 when the FDA placed a full clinical hold on fedratinib trials. Eight of 877 participants exposed to fedratinib in a total of nine trials showed signs possibly consistent with Wernicke’s encephalopathy, a serious neurologic condition linked to thiamine (vitamin B1) depletion. The manufacturer of the drug, Sanofi, halted further development.11

In August 2017, though, the FDA lifted the clinical hold following a careful review of the suspected cases of encephalopathy. At the 2017 ASH Annual Meeting, researchers reported that the incidence of Wernicke’s encephalopathy was actually lower than previously published levels for a patient population of similar size, and cases were either misdiagnosed or attributable to thiamine depletion related to malnutrition, which was probably preexisting in some cases.11

The incidence of encephalopathy among the fedratinib trials was less than 1 percent, and only one patient had clinical signs and MRI findings that clearly supported the diagnosis of Wernicke’s encephalopathy. Their findings suggest that the drug does not increase the risk for thiamine deficiency, “beyond its potential to exacerbate malnutrition through poor management of preventable gastrointestinal (GI) AEs,” the authors wrote.11

“The results from the follow-up analysis of the fedratinib studies were convincing and suggested that the encephalopathy was not caused by the medication,” Dr. Gerds said. “Certainly, we should still be careful about malnutrition in our patients, but for the vast majority of patients, there is likely no increased risk of Wernicke’s encephalopathy.”

“Fedratinib is an efficacious drug that had strong results in clinical trials,” said Dr. Harrison, who was involved with the phase II JAKARTA-2 trial. “It can cause some GI toxicity, but it is particularly efficacious as second- and third line treatment, although we don’t yet know how it would compare directly with ruxolitinib as a firstline treatment.”

Four years after the initial clinical hold, Impact Biomedicines – a company founded by some of the scientists who initially developed fedratinib – acquired fedratinib from Sanofi; in 2018, Impact Biomedicines was acquired by Celgene. Earlier this year, Celgene announced that “based on the reported benefit-risk profile of fedratinib from the JAKARTA-1 and JAKARTA-2 clinical trials, regulatory applications in MF are planned, beginning in the middle of 2018.”12

Pacritinib

Another JAK inhibitor, pacritinib, which binds JAK2 and FMS-like tyrosine kinase 3 (FLT3), had a similarly rocky road to development. The drug was evaluated for the treatment of MPN in two phase III trials: PERSIST-1 compared pacritinib and best available therapy in patients with MF; PERSIST-2 tested the drug’s efficacy in patients with thrombocytopenia who were considered poor candidates for ruxolitinib treatment.13,14 Results from the trials were mixed.  In PERSIST-2, for example, pacritinib significantly reduced spleen volume but did not consistently improve symptom burden.

Then, in February 2016, the FDA pulled the investigational new drug application for pacritinib, halting the ongoing PERSIST trials. In their decision letter, the agency noted that the interim OS results generated from the unblinded PERSIST-2 data suggested a detrimental effect on survival for patients treated with pacritinib, consistent with the results of PERSIST-1. There also was excess mortality among patients who crossed over to the pacritinib arm. The deaths in PERSIST-2 in pacritinib-treated patients were due to intracranial hemorrhage, cardiac failure, and cardiac arrest.15

The FDA hold was subsequently lifted in January 2017, after the drug’s manufacturer, CTI BioPharma, conducted additional dose-exploration studies and failed to find a significant increase in risk of these complications among pacritinib-exposed patients. In May 2017, the company initiated the PAC203 trial, a dose-finding study looking for the optimal dose to balance pacritinib’s safety and efficacy among patients with primary MF whose disease has failed to respond to ruxolitinib.

Momelotinib

Momelotinib, anotherJAK1/2 inhibitor, has been studied as an alternative to ruxolitinib in the SIMPLIFY clinical trials, but these studies have also produced complicated results.

In the phase III SIMPLIFY-1 trial, momelotinib was non-inferior to ruxolitinib in splenic volume reduction and superior in reducing rates of transfusion-dependency for MF-associated anemia. However, it failed to improve disease-associated symptoms, compared with ruxolitinib.16

In the phase III SIMPLIFY-2 trial, momelotinib again failed to improve rates of splenic response, this time compared with best available therapy in patients previously treated with ruxolitinib.17 But, Dr. Gerds noted, patients did show an improvement in both spleen volume and symptoms, even if the results were not statistically significant. Additionally, some patients who were dependent on blood transfusions no longer required them, which is an important improvement for quality of life, but was not one of the trial’s endpoints.

For Dr. Harrison, results from the momelotinib trials underscore how difficult it is to improve on the ruxolitinib-induced symptom response in patients with MPNs. The approval of ruxolitinib, she said, “has drastically changed the management of these disorders.”

Moving Beyond Symptom Improvement?

Given the recent equivocal trial results with the newer JAK inhibitors, many clinicians treating MPNs agree that clinical trials should incorporate additional trial endpoints beyond symptom improvement.

For example, the pivotal ruxolitinib trials set a primary endpoint precedent of at least a 50 percent improvement in symptom burden and at least a 35 percent reduction in splenic volume. “These are arbitrary endpoints,” Dr. Gerds argued. “Symptom reduction is on a continuum. A patient who experiences a 49 percent reduction in his or her symptoms is clearly benefiting from treatment with a study drug, but not based on the bar set by the ruxolitinib clinical trials.”

According to Dr. Gerds, the MPN clinical community has to come together to help define endpoints that are meaningful to their patients and take the biology of MPN into account. “Alleviating symptom burden is not always the same as improving quality of life,” he added.

Getting to this point will require a better understanding of the pathophysiology underlying MPN. While other agents are also in development for MPN, “we are always looking for better ways to treat our patients, and JAK inhibitors remain a touchstone of care,” he added. —By Anna Azvolinsky


References

  1. Vainchenker W, Delhommeau F, Constantinescu SN, et al. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;118:1723-35.
  2. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144-8.
  3. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-61.
  4. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-90.
  5. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-97.
  6. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
  7. Harrison CN, Kiladjian J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-98.
  8. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10:55.
  9. Pardanani A, Harrison CN, Cortes JE, et al. Results of a randomized, double-blind, placebo-controlled phase III study (JAKARTA) of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis (MF). Blood. 2013;122:393.
  10. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4:e317-24.
  11. Harrison CN, Mesa RA, Jamieson C, et al. Case series of potential Wernicke’s encephalopathy in patients treated with fedratinib. Abstract #4197. Presented at the 2017 ASH Annual Meeting, December 11, 2017; Atlanta, GA.
  12. “Celgene to acquire Impact Biomedicines, adding fedratinib to its pipeline of novel therapies for hematologic malignancies.” Accessed April 5, 2018, from http://ir.celgene.com/releasedetail.cfm?releaseid=1053509.
  13. Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4:e225-36.
  14. Mascarenhas J, Hoffman R, Talpaz M, et al. Results of the Persist–2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients (pts) with myelofibrosis (MF) and platelet counts <100,000/µl. Abstract LBA-5. Presented at the 2016 ASH Annual Meeting, December 6, 2016; San Diego, CA.
  15. CTI BioPharma. “CTI BioPharma provides update on clinical hold of investigational agent pacritinib and new drug application in U.S.” Accessed April 5, 2018, from https://www.prnewswire.com/news-releases/cti-biopharma-provides-update-on-clinical-hold-of-investigational-agent-pacritinib-and-new-drug-application-in-us-300217839.html.
  16. Mesa RA, Kiladjian J, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor–naïve patients with myelofibrosis. J Clin Oncol. 2017;35:3844-50.
  17. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5:e73-81.

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