The last few weeks have seen several emails from Pharma Strategy Blog readers and clients asking about JAK2 inhibition and it's importance in cancer, so we thought it was a good time to summarise the pathway with ASH imminent.
Here's how the JAK2 (Janus) pathway connects strategically in the wider scheme of things:
As the chart shows,blocking JAK2 may block cytokine signaling, which is associated with the build up of fibrosis in myelofibrosis disorders.
Why is JAK2 relevant in hematology?
According to the Oregon Health Sciences University (OHSU) Molecular Diagnostic Center (downloadable PDF), patients with myeloproliferative disorders carry a V617F JAK2 mutation:
- 74 – 97% of patients with polycythemia vera (PV)
- 33 – 57% of patients with essential thrombocythemia (ET)
- 35 – 50% of patients with myelofibrosis (IMF)
- Also present infrequently (3-5%) in myelodysplastic syndrome (MDS) & CMML
- JAK2 V617F mutation (auto-inhibitory domain) activates the kinase
Testing for the mutation also helps confirm these clinical diagnoses.
Drugs in development
There are several compounds targeting the JAK2 mutation in development. They include:
- INCB018424 (Incyte/Novartis)
- TG101348 (TargeGen)
- CEP-701 (Cephalon)
- AZD1480 (AstraZeneca)
- XL019 (Exelixis)]
- WP1066 (Calistoga)
- CYT-387 (Cytopia)
Incyte recently signed a licensing deal with Novartis, for the JAK2 inhibitor, which has completed phase II trials. According to the company, the compound works by blocking cytokine signalling:
Interestingly, in the article by Garber (below), Dr Moshe Talpaz, a world recognised hematologist, was quoted as saying that the JAK2 inhibitors, "Preclinical was much more impressive than clinical" based on his experience with TargeGen's agent because fibrosis was not reversed.
At the ASH meeting this weekend, the leading JAK2 company, Incyte, will be presenting three key papers on INCB018424, the compund they are developing with Novartis:
- A Phase II Study of INCB018424, An Oral, Selective JAK1/JAK2 Inhibitor, in Patients with Advanced Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory to Hydroxyurea
- Significant Activity of the JAK2 Inhibitor, INCB018424 in Patients with Secondary, Post-Myeloproliferative Disorder Acute Myeloid Leukemia: Results of An Exploratory Phase II Study
- Long-Term Follow up and Optimized Dosing Regimen of INCB018424 in Patients with Myelofibrosis: Durable Clinical, Functional and Symptomatic Responses with Improved Hematological Safety
What is the potential impact of JAK2 for people with myelofibrosis?
More information will be reported from ASH meeting on this blog as the data is presented in New Orleans over the weekend.
It will be interesting to see how good the agent is and what exactly Novartis, who are leading the commercial development, have on their hands. In case anyone is wondering, both PV and ET are rare orphan diseases, meaning they affect less than 200,000 people per year, with an approximate prevalence of around 40-50K each in the USA, if memory serves me correctly.
Garber, K. (2009). JAK2 Inhibitors: Not the Next Imatinib But Researchers See Other Possibilities JNCI Journal of the National Cancer Institute, 101 (14), 980-982 DOI: 10.1093/jnci/djp216