Just before the American Society of Hematology (ASH) meeting last December, I posted an overview of the JAK2 pathway and pipeline inhibitors in development. Things have changed a bit since then, with TargeGen's inhibitor, TG101348, being licensed by sanofi-aventis and the advent of new phase I/II data being published this week in the New England Journal of Medicine on the leading compound in this category, INCB018424 (Incyte/Novartis).
I loved this simple overview from Verstovsek et al., which is hard to improve on for simplicity and logic:
"Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor."
Here's what the pathway looks like, for those interested:
Source: Cell Signal
Currently, there are no approved therapies for the treatment of myelofibrosis, so using a targeted inhibitor is a worthwhile approach to determine whether any clinical benefit will result.
In this study, patients were preselected for one of the following characteristics:
- JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis
- post–essential thrombocythemia myelofibrosis
- post–polycythemia vera myelofibrosis.
In all, 153 patients were given INCB018424 as oral therapy for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated dose (MTD).
Additional doses were also examined, with a clear rationale emerging for a 15 mg twice daily starting dose.
Skimming through the results section, my attention was immediately drawn to the following:
"61 of 140 patients with an enlarged spleen at study entry (44%) had an objective response (clinical improvement), based on a reduction of 50% or more in palpable splenomegaly within the first 3 months after therapy."
Interestingly, the response rates were highest in patients who took their therapy BID, whereas none of the patients who took INCB018424 once daily showed any clinical improvement.
The researchers went onto note:
"A total of 28 patients who received 25 mg twice daily or 15 mg twice daily (the most active regimens for splenomegaly reduction) were transfusion-dependent at enrollment. After a median treatment duration of 12 weeks, 4 patients (14%) had transfusion independence (clinical improvement according to the International Working Group) for a median duration of 20 months."
One of the many problems people with myelofibrosis experience is a poor quality of life, so it was reassuring to see some real improvement in practical real life tests.
A small proportion of the patients underwent the 6-minute walk test, with the following improvement in their ability to walk as follows:
- 34 m after 1 month
- 57 m after 3 months
- 71 m after 6 months
I couldn't find the baseline, but we can reasonably assume that it was 34 m or less, judging from this positive trend.
When considering the patients with (n=61) and without (n=11) the JAK2 V617F mutation, there was no difference in response between the groups in the patients who received the most effective doses (ie 15 mg twice daily or 25 mg twice daily). The response rates were 51% and 45%, respectively.
In addition, people with primary myelofibrosis (n=37) had a response rate of 49%, while those with polycythemia vera (n=22), 45%, suggesting that the overall response rates were in the general 45-51% range, irrespective of the type of myelofibrosis.
With regards to serious adverse events, 59 people were affected by JAK2 therapy, of whom 12 had serious adverse events that were considered to be at least possibly related to treatment. Additionally, 3 patients had transformation to AML, but whether this was treatment related, or part of the natural disease progression, wasn't clear from the article.
The improvements in clinical benefit (response rates, reduction in splenomegaly and exercise endurance) look promising enough for phase III trials to begin. Understanding the mechanisms behind the inflammatory responses and reduction in splenomegaly will be important as more research is undertaken.
In the previous post on JAK2, we discussed how inhibiting JAK2 may influence or block cytokine signalling, which is thought to be responsible for the myelofibrosis. In this study, normalisation of the inflammatory cytokines was noted with INCB018424, suggesting that JAK1 and JAK2 inhibitors may possibly have clinical efficacy in inflammatory diseases such as rheumatoid arthritis (RA).
Indeed, a trial with another JAK2 inhibitor, INCB028050, from Incyte is ongoing in RA and has already completed recruitment. The results from this trial may offer proof of concept for JAK2 and cytokine normalisation in inflammatory disease.
The future though, may well involve some form of combination rather than single agent therapy, as the accompanying editorial pointed out:
"One disappointing finding in the trial was the minimal effect on the burden of the V617F-mutated clone; however, this was not entirely unexpected considering the lack of specificity of INCB018424 for mutated protein. Yet, one may question whether the disappearance of the V617F-mutated clone is a reasonable end point for JAK1 and JAK2 inhibitors without causing excessive toxicity, given the essential role of JAK1 and JAK2 in the normal immune system and hematopoiesis."
It is very good news to see that a single agent JAK2 inhibitor has some early efficacy, so we can hope that the phase III trials (COMFORT I and II) will also be positive and confirm the initial phase II results when the data is available in the first half of 2011. In the long run, though, combination approaches may well produce even better outcomes.
Vannucchi, A. (2010). From Palliation to Targeted Therapy in Myelofibrosis New England Journal of Medicine, 363 (12), 1180-1182 DOI: 10.1056/NEJMe1005856
Verstovsek, S., Kantarjian, H., Mesa, R., Pardanani, A., Cortes-Franco, J., Thomas, D., Estrov, Z., Fridman, J., Bradley, E., Erickson-Viitanen, S., Vaddi, K., Levy, R., & Tefferi, A. (2010). Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis New England Journal of Medicine, 363 (12), 1117-1127 DOI: 10.1056/NEJMoa1002028