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INTERESTED IN LEARNING MORE? PLEASE CONTACT DAVID QUERRY @ [email protected]

Myelofibrosis and JAK InhibitionHas development been a swing and a miss?By David Querry

As a former brand manager working in the

myeloproliferative disorder/neoplasm (MPN)

market, I have been keenly interested in the development and potential of JAK inhibition.

This tumor type is often considered an

“oncologic orphan” – a rare group of diseases

that challenge every hematologist but is

oftentimes viewed more as a condition rather than a malignancy. They are a slow-burning

collection of stem cell disorders that have

clinicians handcuffed when it comes to offering

meaningful interventions – limiting their

treatment approaches to phlebotomy, hydroxyurea, and other supportive care options.

Finding the “drugable” target?

In early 2004 there was a great deal of

excitement with William Vainchenker’s discovery of the Janus kinase or JAK 2 (JAK2 V617F). Dr

Vainchenker subsequently associated the

JAK-2 mutation with BCR-ABL1-negative

myeloproliferative neoplasms. However, what

has been found is that the JAK-2 oncogene mutations are not MPN-specific nor can they be

traced back to ancestral clone. Instead these

mutations are “phenotype-modifying subclones

that do not necessarily contribute to leukemic

transformation.”

JakafiTM—a base hit, but no home run!

In November of 2011, ruxolitinib became the

first-in-class selective JAK1 and JAK2 inhibitor to be FDA approved for use in patients with

high- and intermediate-risk myelofibrosis. The

approval was based on two phase 3 studies;

COMFORT-I and COMFORT-II. While the

studies served the purpose of satisfying regulatory requirements for FDA approval, they

unfortunately interjected as many questions as

answers around the pathogenic contribution of

the JAK-STAT pathway and the V617F

mutation. In short, these studies confirmed the role of ruxolitinib in terms of partial response in

splenomegaly and alleviation of constitutional

symptoms (interestingly regardless of the V617F

mutation), but failed to demonstrate any

histopathologic, cytogenetic, or molecular remissions. In addition, ruxolitinib was more

likely to cause anemia and thromobocytopenia

instead of improving it. Finally, because of a

failure to risk-stratify at randomization, a true

survival benefit cannot be supported in either study. In fact, the lack of survival benefit was

also suggested by another phase1/phase 2

long-term study of the drug performed at the

Mayo Clinic. As a result, it is fair to say

ruxolitinib is not the home run we were hoping for, but it improves disease-related

symptomatology, and is therefore a solid single.

CORTHOUGHTS

…a slow-burning collection of

stem cell disorders that have clinicians

handcuffed when it comes to

offering meaningful

interventions.

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INTERESTED IN LEARNING MORE? PLEASE CONTACT DAVID QUERRY @ [email protected]

Marketing implications for future

JAK inhibitors

Like it or not, the approval and data supporting ruxolitinib will form the basis of expectations for future second and third generation JAK inhibitors in development. Future molecules leveraging this pathway and seeking to improve patient outcomes in MPNs will need to consider the following:

1. Help the market better understand the

disease pathology, diagnosis, and treatment options for this group of diseases

Break the “oncologic orphan” syndrome.

MPNs are often still considered a nebulous

mixed bag of symptoms. To ensure maximum

penetration, pre-marketing programs directed at aiding in the recognition, diagnosis, and

sense of urgency to intervene in this

malignancy will result in the recognition of a

larger patient pool and more rapid uptake at

launch. The myelodysplastic syndrome (MDS) market is a perfect analog demonstrating the

importance of this step in the commercial-

ization process. As the agency of record

launching Vidaza®, The Navicor Group believed

that elevating the severity of the condition, aligning it as a malignancy, and demonstrating

the therapy as the first "active" treatment for

MDS was critical to its early and continued

success. We believe Incyte left this door wide

open, and the company that steps into this opportunity will end up defining and owning

the market.

2. Manage customer expectations and

the storyThe most basic tenet of advertising and

launching brands! There are a small group of

KOLs who influence this market – you need to

work with all of them, especially the Mayo

Clinic. Trial designs that fail to look at risk stratification and compare against placebo are

not real-world and will limit the commercial

story and value proposition. For example, data

reported in October 2011 in N Engl J Med

reported no overall survival benefit for ruxolitinib

as compared to standard therapy across

different DIPSS criteria. In addition, while the data support the reduction in spleen volume,

they fails to elaborate on the ruxolitinib

withdrawal syndrome” – a communication

challenge with which Incyte is most assuredly

wrestling.

3. Differentiation from initial experience

The clinical data supporting ruxolitinib reinforce

the current perception around the disease – it

is all about reduction in spleen size, symptom control, and QoL. While 93% of clinicians in a

recent survey correlate spleen size to disease

progression (reference: Life Science Advisors

Jakafu Usage Survey, Jan 2012), future entries

into this market are going to need to design trials to demonstrate a more “active” therapy

against the disease rather than another

supportive care option – particularly if the

molecule will demand a premium price.

Myelofibrosis and JAK InhibitionHas development been a swing and a miss?By David Querry

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ABOUT THE AUTHOR With a mind for strategy and a heart for science, Dave

brings the perfect mix of marketing savvy and pharmaceutical

insight to The Navicor Group. Leveraging more than

22 years of experience, he provides strategic leadership

across a variety of clients.

Are you developing a “targeted” small

molecule, an immunomodulatory agent, a cytokine inhibitor, or something

different?

Thinking through this part of the story and aligning not only the unmet medical

need but also the association of the molecule MOA to the pathway and

disease pathology is going to be critical

to future success in the MPN marketplace.

The Navicor Group, part of inVentiv Health, is a full-service oncology/

hematology-focused communications

company. We partner with clients in phase II through full commercialization

to transform products into brands and patients into survivors. Give us a call or

send us an e-mail with your challenges.

We are ready to tackle them!