Findings From Study of JAK2 Inhibitor for Blood Cancers
December 12 2011 - 10:24AM
UK Regulatory
TIDMLEL
Abstract #2814
Embargoed for Release: December 12, 2011
Contact: Amy Sousa, Lilly Neil Hochman, TogoRun
317-276-8478 (office) 212-453-2067 (office)
317-997-1481 (mobile) 516-784-9089 (mobile)
Email: sousa_amy_e@lilly.com Email: n.hochman@togorun.net
LILLY ONCOLOGY REVEALS FINDINGS FROM STUDY OF JAK2 INHIBITOR FOR BLOOD CANCERS
AT ASH MEETING
SAN DIEGO, December 12, 2011 - Eli Lilly and Company (NYSE: LLY) announced data
from an oncology pipeline molecule today at the 53rd Annual Meeting of the
American Society of Hematology (ASH). At the meeting, Lilly Oncology presented
Phase I data from the investigational therapy LY2784544, a small-molecule Janus
kinase 2 (JAK2) inhibitor, in development for the treatment of certain types of
myeloproliferative neoplasms (MPNs), a group of blood cancers characterized by
abnormal production of red blood cells or myeloid cells (non-lymphocyte white
blood cells).
"Research into myeloproliferative neoplasms demonstrated the importance of the
JAK2 genetic mutation as a target for potential treatment options," said
Richard Gaynor, M.D., vice president of product development and medical affairs
at Lilly Oncology. "These data show that our compound has the potential to
inhibit the JAK2 mutation and should be studied further. We hope that this
study is the first in Lilly's ongoing research and development of LY2784544 and
that our findings signal a potential new treatment for patients fighting
myeloproliferative neoplasms."
The Role of JAK2 in MPN
In 2005, researchers reported that a point mutation in the JAK2 gene occurs in
more than 95 percent of patients with the MPN subtype polycythemia vera (PV)
and the majority of patients with the subtypes myelofibrosis (MF) and essential
thrombocythemia (ET).2, The JAK2 point mutation observed in MPNs substitutes
the amino acid phenylalanine for valine (at position 617 [V617F]) of the JAK2
protein.2 The mutation makes JAK2 constantly active, triggering several
signaling pathways that cause blood-forming cells to proliferate and resist
apoptosis (programmed cell death).
Phase I Study Sought to Ascertain Safety, Tolerability
In pre-clinical study, LY2784544 selectively targeted JAK2 V617F while
minimally inhibiting wild-type JAK2 so that normal marrow function wasn't
impeded.
The primary objectives of this ongoing study were to determine the safety and
tolerability of LY2784544 and to define a recommended oral daily dose for
further study in patients with JAK2 V617F-positive MF, ET or PV. At the time of
the interim analysis, 19 patients (1 PV, 1 post-ET MF and 17 MF) were
evaluated.
Secondary objectives of the trial included determining pharmacokinetics,
evaluating patient response to therapy using criteria developed by the
International Working Group for Myelofibrosis Research and Treatment (IWG-MRT),
and evaluating symptoms using the Myeloproliferative Neoplasm Symptom
Assessment Form (MPN-SAF).
An effective MPN treatment will ideally reverse splenomegaly (spleen
enlargement)-a painful complication caused by an overabundance of blood cells
infiltrating the organ. In this study, a palpable reduction in spleen length of
at least 35 percent was seen in 13 of 17 evaluable patients (76%, including 16
MF and 1 PV). After five cycles of therapy, a reduction in severity of
bone-marrow fibrosis was observed in three of five MF patients for whom
follow-up biopsies are available.
When laboratory results were analyzed, one case of laboratory tumor lysis
syndrome (LTLS) and three cases of grade 2 clinical tumor lysis syndrome (CTLS)
were detected. TLS is a consequence of cancer treatment that encompasses
metabolic complications caused when dying cancer cells release breakdown
products. Specifically, the TLS occurrences involved one case of hyperuricemia
at the 240 mg dose and three cases of creatinine increase at the 200 mg dose,
resulting in 200 mg and 240 mg doses of LY2784544 being reported as
dose-limiting toxicities.
Based on analysis of pharmacokinetics, doses of LY2784544 associated with TLS
appear to overlap the lower boundary of the biologically efficacious dose (BED)
range predicted from pre-clinical evaluations. To permit testing of doses
within the BED, the dosing regimen has been amended to include a lower-dose
lead-in period for the purpose of reducing tumor burden, and the likelihood of
TLS, prior to further testing of dose escalation.
Assessing symptoms using the MPN-SAF questionnaire showed that most patients
reported alleviation of symptoms within the first two therapy cycles.
Fifty-nine percent of patients reported symptom improvement of = 50% in key
MPN-SAF symptoms, and 47 percent reported a = 50% improvement in
fatigue-associated parameters. At the doses tested, no reduction has been
observed in the mutant allele burden (i.e., the percentage of blood cells
carrying the JAK2 V617F mutation).
Four patients discontinued therapy, one for each of the following reasons:
adverse event, progressive disease, investigator decision and subject's
decision. Serious drug-related adverse effects were seen in four patients (4
saw grade 2 creatinine increase, 2 saw grade 4 hyperuricemia and 1 saw grade 1
hyperkalemia). Temporarily interrupting treatment allowed all adverse events to
resolve within 14 days. The most frequently reported drug-related adverse
events were diarrhea (3 patients with grade 2, 5 with grade 1); nausea (2
patients with grade 2, 4 with grade 1); transient increased creatinine (4
patients with grade 2); anemia (3 patients with grade 2, 1 with grade 1); and
hyperuricemia (2 patients with grade 4).
About Myeloproliferative Neoplasia
Over 200,000 people in the U.S. have some form of myeloproliferative neoplasm
(MPN), a category of diseases in which genetic mutations in bone marrow stem
cells cause the bone marrow to have abnormal production of red blood cells,
white blood cells or platelets. Symptoms for patients can be many or few and
not all patients will experience symptoms. Treatment of MPNs depends on the
presence and type of symptoms, and typically aims to correct the abnormal blood
counts.7
About Lilly Oncology
For more than four decades, Lilly Oncology, a division of Eli Lilly and
Company, has been dedicated to delivering innovative solutions that improve the
care of people living with cancer. Because no two cancer patients are alike,
Lilly Oncology is committed to developing novel treatment approaches. To learn
more about Lilly's commitment to cancer, please visit www.LillyOncology.com.
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing
portfolio of pharmaceutical products by applying the latest research from its
own worldwide laboratories and from collaborations with eminent scientific
organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -
through medicines and information - for some of the world's most urgent medical
needs.
P-LLY
# # #
This press release contains forward-looking statements about the potential of
LY2784544 for the treatment of myeloproliferative neoplasms and reflects
Lilly's current beliefs. However, as with any pharmaceutical compound, there
are substantial risks and uncertainties in the process of development and
commercialization. There is no guarantee that this compound will be approved by
the relevant regulatory authorities or prove to be commercially successful. For
further discussion of these and other risks and uncertainties, see Lilly's
filings with the United States Securities and Exchange Commission. Lilly
undertakes no duty to update forward-looking statements.
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, Indiana 46285
U.S.A.
National Cancer Institute. What Are Myeloproliferative Disorders?,
www.cancer.gov/cancertopics/types/what-are-myeloproliferative-disorders
(Accessed: November 8, 2011).
Garber, Ken. JAK2 Inhibitors: Not the Next Imatainib But Researchers See Other
Possibilities." J of the National Cancer Institute, vol. 101, pgs. 980-982
(Issue 14, July 15, 2009).
A. Tefferi and A. Pardanani. JAK inhibitors in myeloproliferative neoplasms:
Rationale, current data and perspective. Blood Reviews vol. 25, pgs. 229-237
(2011).
F.P.S. Santos and S. Verstovsek. JAK2 inhibitors: What's the true therapeutic
potential? Blood Reviews vol. 25, pgs. 53-63 (2011).
Passamonti and E. Rumi. Clinical relevance of JAK2 (V617F) mutant allele
burden. Haematologica. Vol. 94, No. 1, pgs. 7-10 (2009).
The National Cancer Institute, "General Information About Chronic
Myeloproliferative Disorders," Updated: September 27, 2011.
http://www.cancer.gov/cancertopics/pdq/treatment/myeloproliferative/Patient#Keypoint1 ,
(Accessed: November 7, 2011).
The University of California San Francisco Medical Center, "Myeloproliferative
Disorders," Updated: September 15, 2011.
http://www.ucsfhealth.org/conditions/myeloproliferative_disorders/ ,
(Accessed: November 7, 2011).
University of Maryland Medical Center, "Myeloproliferative Disorders."
http://www.umm.edu/altmed/articles/myeloproliferative-disorders-000114.htm ,
(Accessed:November 7, 2011).
END
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