ASH Clinical News ACN_5.3_web | Page 47

FEATURE
designations, suggesting that the Orphan
Drug Act has not been a significant driver
of health-care spending in the U.S. 17
There are no concrete plans for lower-
ing the costs of orphan drugs, but not for
lack of trying. Dr. Fajgenbaum pointed
to several bills attempting to control
pharmaceutical pricing that have failed
to or are unlikely to pass. For example,
the Open Act, which has been under
review for about two years, seeks to
lower prices by incentivizing off-label
studies of approved drugs by offering
market exclusivity, but only for six
months. 18
Still, parents are unlikely to refuse
a drug that could save their child’s life
because the price tag is too high. “It’ll
be important to see what pediatric pa-
tients choose to do as they grow up,”
Dr. Regier remarked. Pharmaceutical
companies occasionally offer copay
assistance, though, so patients them-
selves may not struggle to cover the
cost of the drug. Instead, only insur-
ance companies shoulder the burden
of the astronomical price.
Nonetheless, Dr. Regier said
she was “impressed that the FDA is
thinking about rare diseases as well
as they are.” To her, the most effec-
tive strategy will be to continue to
decrease the cost of getting a drug to
market. “That’s going to help us have
more justification for saying this drug
shouldn’t be this expensive.”
—By Emma Yasinski ●
REFERENCES
1. Kaiser Health News. Government investigation finds flaws
in the FDA’s orphan drug program.” November 30, 2018.
Accessed January 14, 2019, from https://khn.org/news/
government-investigation-finds-flaws-in-the-fdas-orphan-
drug-program/.
2. National Organization for Rare Disorders. “Rare
Disease Information.” Accessed January 14, 2019, from
https://rarediseases.org/for-patients-and-families/
information-resources/rare-disease-information/.
3. U.S. Food and Drug Administration. “Office of
Orphan Products Development.” Accessed January
14, 2019, from https://www.fda.gov/aboutfda/
centersoffices/officeofmedicalproductsandtobacco/
officeofscienceandhealthcoordination/ucm2018190.htm.
4. Tufts Center for the Study of Drug Development. “Tufts
CSDD Impact Report May/June 2018.” May 29, 2018.
Accessed January 14, 2019, from https://csdd.tufts.edu/
csddnews/2018/3/8/marchapril-2018-volume-20-no-2-
impact-report-dz89z-2bbsa.
5. Cystic Fibrosis Foundation. “CF Foundation
Venture Philanthropy Model.” Accessed January
14, 2019, from https://www.cff.org/About-
Us/About-the-Cystic-Fibrosis-Foundation/
CF-Foundation-Venture-Philanthropy-Model/.
10. U.S. Food and Drug Administration. “Orphan Drug Act - Relevant
Excerpts.” Accessed January 14, 2019, from https://www.fda.
gov/forindustry/developingproductsforrarediseasesconditions/
howtoapplyfororphanproductdesignation/ucm364750.htm.
11. National Organization for Rare Disorders. “Trends in Orphan Drug
Costs and Expenditures Do Not Support Revisions in the Orphan
Drug Act: Background and History.” Accessed January 14, 2019,
from https://rarediseases.org/wp-content/uploads/2018/05/
NORD-IMS-Report_FNL.pdf.
12. U.S. Food and Drug Administration. “FDA unveils plan to
eliminate orphan designation backlog.” June 29, 2017. Accessed
January 14, 2019, from https://www.fda.gov/newsevents/
newsroom/pressannouncements/ucm565148.htm.
13. U.S. Food and Drug Administration. “FDA In Brief: FDA takes step
to close orphan drug loophole that let drug developers sidestep
pediatric studies.” December 19, 2017. Accessed January 14, 2019,
from https://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/
ucm589736.htm. 16. U.S. Department of Health and Human Services. “Prescription
Drugs: Innovation, Spending, and Patient Access.” December
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house.gov/sites/delauro.house.gov/files/Prescription-Drugs-
Innovation-Spending-and-Patient-Access-12-07-16.pdf.
14. Kaiser Health News. Drugmakers manipulate orphan drug rules
to create prized monopolies. January 17, 2017. Accessed January
14, 2019, from https://khn.org/news/drugmakers-manipulate-
orphan-drug-rules-to-create-prized-monopolies/. 17. National Organization for Rare Disorders. “New Study
Examines Use and Cost of Orphan Drugs.” October 17, 2017.
Accessed January 14, 2019, from https://rarediseases.org/
new-study-examines-use-and-cost-of-orphan-drugs/.
15. U.S. Government Accountability Office. “Orphan Drugs: FDA Could
Improve Designation Review Consistency; Rare Disease Drug
Development Challenges Continue.” Accessed January 14, 2019,
from https://www.gao.gov/assets/700/695765.pdf. 18. Congress.gov. “H.R.1223 - OPEN Act.” Accessed January 14,
2019, from https://www.congress.gov/bill/115th-congress/
house-bill/1223.
CDK9 regulation of MCL-1
inhibits apoptosis, enabling
1-5
AML BLAST
SURVIVAL
CDK9
MCL-1 mRNA
MCL-1 dependence may
drive progression of AML
3,6
CDK9 is a key regulator of
MCL-1 function
1,2,5
Disease progression and
treatment resistance in a subset
of acute myeloid leukemia (AML)
have been associated with a key
anti-apoptotic protein, myeloid
cell leukemia 1 (MCL-1). 3,6 MCL-1
is a member of the apoptosis-
regulating BCL-2 family of proteins. 7 MCL-1 mRNA transcription in
AML blasts is regulated by cyclin-
dependent kinase 9 (CDK9), 1,2 a
protein that plays a critical role in
transcription regulation without
directly affecting cell-cycle control. 5,10
In MCL-1–dependent AML,* the
AML blasts depend primarily
on the function of MCL-1 for the
anti-apoptotic mechanism of
survival. 8,9 MCL-1 inhibits apoptosis
and sustains the survival of AML
blasts, allowing them to proliferate,
which may lead to relapse. 3 MCL-1
dependence is also associated
with resistance to agents that
otherwise have activity against
leukemic blasts. 7 CDK9-mediated transcriptional
regulation of anti-apoptotic
proteins, including MCL-1,
is critical for the survival of
MCL-1–dependent AML blasts. 5
Inhibition of CDK9 as a
rational therapeutic strategy
in MCL-1–dependent AML
1,5,7
Because MCL-1 has a short half-
life of 2-4 hours, the effects of
targeting its upstream regulators
are expected to reduce MCL-1
levels rapidly. 11 CDK9 inhibition
has been shown to block MCL-1
transcription, resulting in rapid
depletion of MCL-1 protein, which
may restore apoptosis in MCL-1–
dependent AML blasts. 1,5,7
Understanding the role of CDK9
in regulating MCL-1 may inform
therapeutic targeting strategies
in AML.
*The prevalence of MCL-1–dependent
AML is under investigation.
6. Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative,
idiopathic multicentric Castleman disease: novel
insights into biology, pathogenesis, and therapy. Blood.
2014;123:2924-33.
7. American Society of Hematology. “American Society of
Hematology to Launch Sickle Cell Disease Clinical Trials
Network.” September 29, 2018. Accessed January 14, 2019,
from http://www.hematology.org/Newsroom/Press-
Releases/2018/8952.aspx.
8. Rare Disease Clinical Research Network. “Rare Disease
Research Training Program.” Accessed January 14, 2019,
from https://www.rarediseasesnetwork.org/spotlight/
spring2016/training.
9. American Society of Hematology. “FDA-ASH Sickle Cell
Disease (SCD) Clinical Endpoints Workshop.” Accessed
January 14, 2019, from http://www.hematology.org/
Meetings/8840.aspx.
A matter of cell life
and cell death
Learn more at www.toleropharma.com
Tolero Pharmaceuticals, Inc. is a leading developer of novel therapeutics to inhibit
biological drivers of hematologic and oncologic diseases.
References: 1. Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by fl avopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519. 2. Ocana A, Pandiella A.
Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234. 3. Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1
is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125. 4. Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer
biology. Trends Cell Biol. 2013;23(1):22-29. 5. Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A. Cyclin dependent kinase 9 inhibitors for cancer therapy. J Med Chem. 2016;59(19):8667-
8684. 6. Xiang Z, Luo H, Payton JE, et al. Mcl1 haploinsuffi ciency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest. 2010;120(6):2109-2118. 7. Thomas D, Powell JA, Vergez F, et al. Targeting
acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748. 8. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, et al. FLT3-ITD up-regulates
MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specifi c STAT5 activation. Blood. 2009;114(24):5034-5043. 9. Butterworth M, Pettitt A, Varadarajan S, Cohen GM. BH3 profi ling
and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. Br J Cancer. 2016;114(6):638-641. 10. Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle.
2016;15(4):519-527. 11. Gores GJ, Kaufmann SH. Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors. Genes Dev. 2012;26(4):305-311.
Tolero Pharmaceuticals is a registered trademark of Sumitomo Dainippon Pharma Co., Ltd. ©2018 Boston Biomedical, Inc. All rights reserved. PM-NPS-0008 4/2018
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