Oncology Live®
April 2013
Volume 14
Issue 4

JAK2 Inhibitor Shows Promise in Myelofibrosis

The strategy of targeting aberrant signaling in the JAK pathway appears promising thus far for SAR302503, an oral agent in development for the treatment of myelofibrosis.

Tal Zaks, MD, PhD

Vice President

Head of Development

Sanofi Oncology

Cambridge, MA

The strategy of targeting aberrant signaling in the Janus kinase (JAK) pathway appears promising thus far for SAR302503, an oral agent in development for the treatment of myelofibrosis. Recruitment for the phase III JAKARTA trial is complete, and initial results are scheduled to be reported later this year, according to Sanofi, which is developing the drug.

SAR302503 is a selective inhibitor of JAK2, a member of the JAK family of nonreceptor tyrosine kinases whose activity can promote cancer-causing processes, including proliferation. The drug is being evaluated in patients with primary myelofibrosis, polycythemia vera (PV), or essential thrombocythemia (ET).

Mutations in the JAK2 gene are found in approximately half of patients with primary myelofibrosis, 50% of patients with ET, and 95% of patients with PV, researchers have indicated.

In the JAKARTA trial, 225 patients with high-risk or intermediate-risk level 2 disease were randomized to receive either 400 mg or 500 mg of SAR302503 once a day for six 28-day cycles, or a daily placebo on the same dosing schedule (Figure). The primary endpoint is the response rate, defined as the proportion of patients who have achieved a ≥35% reduction in spleen size volume at the end of cycle 6.1

Figure. JAKARTA Study Design

Key Patient Criteria

  • Primary MF, post-PV MF, or post-ET MF
  • High-risk or intermediate risk level 2 disease
  • Spleen palpable ≥5 cm below costal margin
  • ECOG status 0-2
  • No splenectomy
  • No prior JAK2 inhibitor treatment




75 patients

75 patients

75 patients

500 mg SAR302503

once a day for

six 28-day cycles

400 mg SAR302503

once a day for

six 28-day cycles


once a day for

six 28-day cycles

End of cycle 6

Crossover to

400 mg or 500 mg


End of cycle 6 or

disease progression

End of treatment

ECOG indicates Eastern Cooperative Oncology Group; ET, essential thrombocythemia; MF, myelofibrosis; PV, polycythemia vera.

The JAKARTA trial. Sanofi Oncology website. Updated January 2012. Accessed March 27, 2013.

The rationale for continued development of SAR302503 was supported by phase II trial results in a similar patient population, according to research presented during the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH), held in December in Atlanta, Georgia.2

During the meeting, OncologyLive sat down with Tal Zaks, MD, PhD, vice president and head of Development for Sanofi Oncology, to learn more about SAR302503 and its potential to help patients with cancer.

The design of targeted therapies for hematologic malignancies is blossoming, Zaks noted, “because we can now understand which pathways are activated in which diseases and the reasons for that activation, and then fit the drug to that disease, enabling a much more rapid and rational drug development than we’ve had in the past. A significant part of our portfolio is now directed toward these diseases, and the coming years will be very exciting in terms of our ability to bring novel therapeutics to this space.”


Why are JAK inhibitors such a hot topic in oncology?


It’s really a convergence of our understanding of the genetic lesions in these cancers and their clinical spectrum. The JAK2 mutations were cloned in 2005, and they were found to be prevalent in the myeloproliferative neoplasms, which include three types of clinically distinct diseases. Two have to do with overproduction in the bone marrow—either the production of too many red cells, which is PV, or of too many platelets, which is ET. The third disease is myelofibrosis, which is actually the opposite clinical spectrum, where the bone marrow isn’t producing enough blood.

It turns out that the JAK2 signaling pathway is hyperactivated in the cells of all these patients, and by inhibiting that pathway with a tyrosine kinase inhibitor, you can ameliorate the symptoms of the diseases. The observation that inhibiting this pathway gives clinical benefit to patients is what’s generating all the excitement.


Treatments are limited for patients who have myelofibrosis. Besides palliative care, the only option is stem cell transplant following chemotherapy. Does this create a need for new and better treatments?


If you look at the patient population that suffers from myelofibrosis, they tend to be more elderly, sometimes with comorbid illnesses. This is a life-threatening disease with an average survival of roughly five years, so to offer such patients a treatment as aggressive as bone marrow transplant is often difficult, because you can have a significant toxicity, and even mortality upfront just from the treatment. It’s critically important to find treatments that are much gentler and yet provide benefit to patients.


In the phase II study, 31 patients with primary myelofibrosis, post-PV myelofibrosis, and post-ET myelofibrosis who took SAR302503 at doses between 300 mg and 500 mg experienced meaningful reductions in splenomegaly and improvements in symptoms. What were the study’s endpoints and conclusions?


When we treat patients with myelofibrosis, we’re looking to achieve two things. One is to reduce the spleen size. When the marrow is not productive, the body generates blood where it knows how to, which is the spleen, and that leads to large spleens. Those large spleens cause a lot of symptoms: They interfere with the absorption of food, they cause fatigue, and they cause pain.

In the study, we demonstrated that, at the end of cycle 3, the median reduction in spleen volume was 26% in the group taking a 300-mg dose, 31% with 400 mg, and 38% with 500 mg. A spleen response at the end of cycle 3 was seen in 30% of patients in the 300- mg group, 50% in the 400-mg group, and 64% in the 500-mg group.

We showed a very good correlation between the dose of the drug and the effects on inhibiting the pathway, as well as on symptoms. We showed that, as exposure increases, there’s an increase in the ability to inhibit the JAK2 pathway, and that response rates in the spleen go up.

A second important endpoint is whether the patients feel better. And, in this study, patients who started out with symptoms reported an improvement by more than 2 points, or a total abatement, of those problems. The improvements came in the areas of night sweats for 93% of those patients, itching for 71%, early satiety and abdominal pain for 56%, and abdominal discomfort for 50%.

The drug did cause some grade 3/4 anemia, which occurred at a rate of 55% in the group dosed at 500 mg. Less frequently, we saw thrombocytopenia. The other side effects primarily had to do with GI toxicity—mainly diarrhea, which, by and large, was manageable. These are side effects that medical oncologists are used to and comfortable managing.

The final piece of this study was that we demonstrated the pharmacological properties of the drug. We confirmed that it has a long half-life and can be given with once-daily dosing, all of which are things you look for when you’re trying to devise a treatment that will be appropriate for patients to take long term.


Sanofi has enrolled a pivotal phase III trial of SAR302503. What are the design and endpoints of that study?


We are testing doses of 400 mg and 500 mg, and placebo, so that we can compare and see what the effects of the drug are. We are doing that in patients with high-risk myelofibrosis, who have risk factors that would lead to an adverse outcome in the long run. The design is to treat them for six months, and then measure carefully what’s happening to their spleens, what’s happening in their bone marrow, and what their symptoms are. At that time, patients who have been randomized to placebo will have the opportunity to cross over to get active drug.


Will SAR302503 be tested in additional patient populations?


This, for us, is just the beginning. Since JAK2 alteration has also shown activity in PV and ET, we have, ongoing, a phase II study that is looking at the doses appropriate for those diseases. We’re looking at additional studies and additional indications in which it makes sense to inhibit JAK2. Once we have a full understanding of efficacy and toxicity in myelofibrosis, PV, and ET, we’ll have a much better roadmap as to the appropriate way to continue the development of this drug.


JAK inhibitors are also being developed by other companies. One such drug, ruxolitinib (Jakafi), was approved by the FDA in November 2011 with an indication in myelofibrosis. What are the differences and similarities between the JAK inhibitors?


There are significant differences between the drugs being developed. One is available on the market, and it’s pretty clear that, while there’s considerable benefit, there’s a population of patients who do not benefit. It’s also clear that, over time, some patients will either become resistant or intolerant to that drug.

We’ve started a phase II study looking at patients who come off approved therapy and then take our drug, to see whether we can demonstrate that our drug will be effective in cases where others have failed. Our drug is also different because it’s given once daily, and its side effect profile seems to be different. As more drugs get into patients in the clinic, we will get a better understanding of the differentiating factors between them.


Might any of these JAK inhibitors be used in combination to treat patients?


You probably don’t want to combine two JAK2 inhibitors, because if you’ve got one that potently inhibits its pathway, you probably have the most benefit you can. The question is: Can you combine inhibition of this pathway with the inhibition of a related pathway to achieve a synergistic clinical benefit? There are examples in some solid tumors where people have done that successfully, and that insight is spurring a lot of preclinical work by our company, by others, and sometimes by companies together.

Researchers are trying to use well-characterized pathway inhibitors in chronic myeloid leukemia to see whether inhibiting the JAK2 pathway would add benefit in treating that disease. There are similar preclinical experiments in other diseases trying to combine JAK2 inhibitors with other pathways.

While we’re just starting the journey of understanding in this area, we can already see the acceleration of the pace of science.


Do you use patient-reported symptom assessment in trials of SAR302503?


We do. If you are designing a treatment that will alleviate patient symptoms, the best way to answer that is to ask the patient: “Are you feeling better?” It’s not trivial; one has to build a validated questionnaire, and we’re using a form of a questionnaire that has been validated and accepted by the regulatory authorities that is specifically appropriate for myelofibrosis.

To accomplish this, we’re employing an electronic capture record that allows patients to use a little gizmo to report their symptoms over time. This is the first time we’re doing this in a multinational study, and it’s an interesting experience to deploy this tool to many different countries in many different languages. But I think the ability to capture the patients’ symptoms right at the source, right when they have them, without any translation through paper or clinicians, will make this a very accurate and powerful tool to demonstrate the differences in symptoms.


  1. Phase III study of SAR302503 in intermediate-2 and high risk patients with myelofibrosis (JAKARTA). website. NCT01437787.
  2. A phase II randomized dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF. Blood (ASH Annual Meeting Abstracts). 2012;120(21): abstr 2837.

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