Friday, February 25, 2011

HiJAKing the JAKs in Myeloproliferative Disorders


Myeloproliferative neoplasms (MPNs) are characterized by uncontrolled proliferation of differentiated myeloid cells in the bone marrow, and have an underlying clonal genetic change.  They often evolve into acute myelogenous leukemia (AML).  MPNs with chromosomal translocation t(9;22) BCR-ABL, also called Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), have a very good prognosis.  Imatinib (Gleevec; Novartis) is a very effective inhibitor of BCR-ABL kinase.  On the other hand, Ph-negative MPNs, until recently had lacked targeted approaches.  This changed in 2005 with the discovery of a dominant gain-of-function somatic mutation in Janus Kinase-2 (JAK2) of a significant proportion of MPNs, wherein guanine-to-thymidine substitution results in a valine-to-phenylalanine change at position 617.  

Jack of all trades (all in the family)

JAK2 belongs to a family of four members: JAK1, JAK2, JAK3 and TYK2.  JAK proteins bind the cytoplasmic tails of cytokine receptors (which lack intrinsic tyrosine kinase activity) and transduce signal by activating STAT family of transcription factors .  The ligands for these  cytokine receptors include numerous interleukins, interferons, GM-CSF, erythropoietin (EPO), thrombopoietin (TPO), growth hormone  (GH) and prolactin (PRL ).  JAK-STAT are key regulatory pathways in hematopoiesis and lymphopoiesis.  Constitutively active JAK2(V617F) activate several signaling pathways, including STAT3, STAT5, MAPK, ERK, PI3K-AKT, bypassing cytokine receptor and thus, allowing cytokine- or growth factor-independent growth.  JAK2(V617F) also translocates to the nucleus, and phosphorylates  histone H3 at tyrosine41 (H3Y41), disrupting binding of transcriptional repressor HP1-alpha.  This JAK- H3Y41-HP1a pathway leads to the activation of pro-hematopoietic and pro-lymphopoietic genes (such as, lmo2) and also cause genomic instability, increasing oncogenesis. However, the significance of JAK2(V617F) to disease severity remains controversial [read here, here].  Nevertheless, as described below, large number of companies are targeting multiple JAK kinases.


(Figures from: Nature Reviews Drug Discovery, February 2011, 10(2):127-140 | Abstract | )

The jackpot

Many compounds targeting JAK kinases are in development.  Progress has been slow, and only now, some Phase III data has started to emerge.  Ruxolitinib (aka  INC424  or INCB018424 or INCB18424; Novartis; early development by Incyte Genomics) is ahead of the pack and is the only one to have cleared Phase III.  It is an orally bioavailable JAK inhibitor (IC50 values for JAK1, JAK2 and JAK3 are 3, 5 and 332 nM, respectively).

On Dec, 20 2010, Novartis announced that a pivotal Phase III trial for Ruxolitinib, oral JAK2 and JAK3 inhibitor, met its primary endpoint of significantly reducing spleen volume in patients with myelofibrosis (MF).  The study, called COMFORT-1 (COntrolled MyeloFibrosis Study with Oral JAK Inhibitor Therapy), showed treatment with INC424 provided a statistically significant reduction in spleen size in patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF). The study also met the secondary endpoint of symptomatic improvement as measured by the modified Myelofibrosis Symptom Assessment Form Diary.  [ read press-releases here, here]  The results were published in the Sept. 16, 2010, issue of New England J of Medicine (Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis)

Jack and the beanstalk, I am not far behind
Phase II
  • Lestaurtinib (JAK1, JAK3); aka  CEP-701; developed by Cephalon, Inc., Frazer, PA.
  • TG101348 (JAK1, JAK2 inhibitor; IC50 in low nM); Sanofi-aventis (original discovery/development by TargeGen, San Diego) [news, ..., ...]
  • Tasocitinib (JAK1, JAK2, JAK3); aka CP-690550 (Pfizer) is in Phase II/III
  • XL109 (JAK1, JAK3), from Exelixis was dropped due to toxicities 
Phase I or I/II
  • AZD1480 (JAK1, JAK2, JAK3); AstraZeneca
  • CYT387 (JAK1, JAK2); YM BioSciences, Inc., Mississauga, Ontario, Canada (NYSE Amex: YMI, TSX: YM) [news, ..., ...]
  • GLPG0634 (JAK1, JAK2); Galapagos NV (Euronext: GLPG) [news, ...]
  • INCB028050 (JAK1, JAK2, TYK2); Incyte Genomics [news, ...]
  • ONX0803 (JAK1, JAK2, TYK2); aka SB1518; Onyx Pharmaceuticals (original discovery/development by S*BIO Pte Ltd, Singapore) [news, ..., ...]
Preclinical
  • INCB16562 (JAK1, JAK2, JAK3, TYK2); Incyte Genomics
  • NVP-BSK805 (JAK1, JAK2, JAK3, TYK2); Novartis
  • PRT062070 is a Syk-Jak inhibitor; Portola Pharmaceuticals. South San Francisco, CA. [...]
 Other companies with JAK inhibitor programs include, Ambit Biosciences, Deciphera Pharmaceuticals, Eli Lilly, Onconova Therapeutics (ON 044580), SuperGen (SGI-1252) and SGX.

Primer (Myeloproliferative neoplasms)

The WHO 2008 classification characterizes myeloid malignancies into five categories: (a) AML, (b) myelodysplastic syndrome (MDS), (c) MPN, (d) MDS/MPN, and (e) PDGFR-rearranged or FGFR1-rearranged myeloid and lymphoid neoplasms associated with eosinophilia.

MPNs are further divided into eight types:
  1. CML (Ph+)
  2. Polycythemia vera (PV)
  3. Essential thrombocytopenia (ET)
  4. Primary myelofibrosis (PMF)
  5. Chronic neutrophilic leukemia
  6. Chronic eosinophilic leukemia
  7. Systemic mastocytosis
  8. MPN unclassifiable
  •  #2-#8 fall into MPN (Ph-negative) group 

PV, ET and PMF constitute the majority of Ph-negative MPNs, effecting nearly 100,000 patients in US.  Current standard of care does not change the natural history of MPN; most interventions prevent thrombotic and hemorrhagic complications.  For example, phlebotomy, aspirin or hudroxyurea are used to manage hematocrit and thrombotic complications (such as, thromboembolisms and transient tissue ischemias) in PV or ET; anagrelide is used to lower platelets in ET; corticosteroids or EPO to improve cytopenia in PMF; splenectomy, irradiation or hydroxyurea help deal with splenomegaly in PMF.  Penalidomide (aka Revlimid) also improves anemia and splenomegaly in a limited number of PMF patients.  However, none of these supportive therapies change the natural course and median survival.  In PMF, the median survival is 3-5 years.  Allogenic stem cell transplantation is currently the only curative option available.

"JAK Frost is gonna provide options; he's the coolest! ..."


Readings and references:
Disease classification and management
  • The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. James W. Vardiman et al. Blood, 30 July 2009, 114(5):937-951 | FreeFullText | DOI | Scholar |
  • Prognostic Markers for Myeloid Neoplasms: A Comparative Review of the Literature and Goals for Future Investigation. T. A. Juopperi et al.  Vet Pathol, January 2011, 48:182-197 | Abstract | DOI | (not free access) 
  • Myelodysplastic syndromes: A practical approach to diagnosis and treatment. Afsaneh Barzi. Cleveland Clinic Journal of Medicine, January 2010, 77(1):37-44 | FreeFullText | DOI |
  • Treatment of MDS: something old, something new, something borrowed. Mikkael A. Sekeres. Hematology 2009 (American Society of Hematology Education Program Book) pg.656-663 | FreeFullText |
  • Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®).  National Cancer Institute | wwwLink
 JAK2 and JAK2(V617F) biology and target
  • JAK2V617F allele burden in polycythemia vera correlates with grade of myelofibrosis, but is not substantially affected by therapy. Richard T. Silver, et al. Leukemia Research, February 2011, 35(2):177-182 | Abstract | DOI | (not free access); read press summary here 
  • JAK Inhibitors in Myeloproliferative Neoplasms. Ayalew Tefferi, July 1, 2010, The Hematologist (American Society of Hematology) | FreeFullText |
  • Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis. Srdan Verstovsek, New Engl J Med, Sept. 16, 2010, 363:1117-1127 | Abstract |
  • Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Alfonso Quint├ís-Cardama, et al. Nature Reviews Drug Discovery, February 2011, 10(2):127-140 | Abstract | DOI |
  • Inhibition of JAK–STAT signaling by TG101348: a novel mechanism for inhibition of KITD816V-dependent growth in mast cell leukemia cells. T Lasho, et al. Leukemia, July 2010, 24:1378-1380 | Abstract | DOI |
  • JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors Alexandra Dusa, et al. PLoS ONE, June 16, 2010, 5(6):e11157 | FreeFullText | DOI |
Recent news and blogosphere:
  • JAK2 inhibition in hematologic conditions.  Sally G. Church, Pharma Strategy Blog, December 3, 2009 | wwwLink | (good comprehensive post)
  • JAK inhibitor quells symptoms linked to myelofibrosis. Cancer Nerwork, December 30, 2010 | wwwLink
  • JAK Inhibitors Producing Significant Response in Myelofibrosis Patients. ScienceDaily,Dec. 6, 2010 | wwwLink |

3 comments:

  1. Update on CoMFORT-II Phase Trial of the investigational Janus kinase (JAK) inhibitor INC424 (ruxolitinib). ///\\\ (press release) ///\\\ BASEL, Switzerland, March 15, 2011 - Novartis announced today that a pivotal Phase III trial of the investigational Janus kinase (JAK) inhibitor INC424 (ruxolitinib) has met its primary endpoint of significantly reducing spleen size in patients with myelofibrosis (MF). INC424 is a potent, selective inhibitor of the JAK1 and JAK2 tyrosine kinases.

    The European study, called COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy), showed treatment with INC424 provided a statistically significant reduction in spleen size in patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF), when compared with best available therapy, administered at doses and schedules determined by the investigator. The safety profile of INC424 was consistent with previous studies. Complete study data will be submitted to an upcoming medical meeting.

    These results support findings from another large Phase III clinical trial (COMFORT-I) conducted by the collaboration partner, Incyte Corporation, in the US, Canada and Australia comparing treatment with INC424 to placebo in patients with MF at 24 weeks. In addition, a Phase I/II study published in the September 16, 2010 issue of The New England Journal of Medicine showed that treatment with INC424 resulted in marked, fast and durable clinical benefits in patients with MF.

    [ LINK: http://www.drugs.com/clinical_trials/second-phase-iii-study-novartis-jak-inhibitor-inc424-meets-primary-endpoint-patients-myelofibrosis-11317.html , OR USE URL, http://goo.gl/E4tDN/ )

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  2. more discussion on INC424 clinical trial data and related issues: Helping People. Working System?
    By Jessica Wapner Posted: March 16, 2011 (http://blogs.plos.org/workinprogress/2011/03/16/helping-people-gaming-system/ , OR USE URL , http://goo.gl/bzMYi/ )

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  3. backtrack http://blogs.plos.org/workinprogress/2011/03/16/helping-people-gaming-system/

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