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 how and why 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 Tisch Cancer Institute of 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 might have a role in lower-risk disease or should be relegated to patients with intermediate- and higher-risk MF who were studied in the COMFORT trials . 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 the principal investigator of the phase II JAKARTA-2 trial . “ It can cause some controllable GI toxicity , but it is particularly efficacious as a secondline 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 and inhibits JAK2 and FMS-like tyrosine kinase 3 ( FLT3 ), had a similarly rocky road to development . The drug was evaluated for the treatment of MF in two phase III trials : PERSIST-1 compared pacritinib with 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 .
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