CLINICAL NEWS
Latest & Greatest
FDA Alerts Patients
About Blood Clot and
Mortality Risk With
Tofacitinib
The U.S. Food and Drug Administration
(FDA) has issued a Safety Announce-
ment for the Janus kinase (JAK) inhibitor
tofacitinib after a required postmarketing
trial of the drug revealed an increased
risk of pulmonary embolism and death
in patients who were taking tofacitinib
10 mg twice-daily for the treatment of
rheumatoid arthritis (RA).
The ongoing trial began in 2012,
when the FDA approved tofacitinib
for the treatment of adults with RA.
Sponsors enrolled patients with RA who
were at least 50 years old and had at
least one cardiovascular risk factor, then
compared the risks of cardiac-related
events, cancer, and opportunistic infec-
tions in patients treated with tofaci-
tinib (5 mg or 10 mg twice daily) plus
methotrexate versus those treated with a
tumor necrosis factor inhibitor.
According to the FDA’s announce-
ment, the agency’s Data Safety Monitoring
Board identified a safety signal of pul-
monary embolism and increased overall
mortality in patients who were receiving
tofacitinib at the higher 10-mg dose.
Pfizer, which manufactures and mar-
kets tofacitinib as Xeljanz and Xeljanz
XR, is transitioning patients on the trial
to the lower, currently approved dose of
5 mg twice daily. The higher 10-mg dose
was approved for patients with ulcer-
ative colitis in 2018, but not for patients
with RA.
“The FDA is actively examining the
data from the trial and working directly
with Pfizer to better understand the
safety signal, its impact on patients, and
how tofacitinib should be used,” said
Janet Woodcock, MD, director of the
FDA’s Center for Drug Evaluation and
Research, in a statement. “The FDA still
believes the benefits of taking tofaci-
tinib for its approved uses continue to
outweigh the risks.”
Source: FDA Safety Announcement, February 25, 2019.
FDA’s ODAC Rejects
Selinexor for Myeloma
In an 8-to-5 vote, the FDA’s Oncologic
Drug Advisory Committee (ODAC)
decided against recommending acceler-
ated approval of selinexor for treatment of
patients with relapsed/refractory multiple
24
ASH Clinical News
myeloma (MM), citing the difficulty of de-
termining whether the benefits outweigh
the risks.
Selinexor is a first-in-class, oral selec-
tive inhibitor of nuclear export (SINE)
compound manufactured by Karyopharm
Therapeutics. ODAC’s decision is based
on a review of data from the phase IIb
STORM (Selinexor Treatment of Re-
fractory Myeloma) Part 2 study, which
evaluated the drug in combination with
low-dose dexamethasone in patients with
penta-refractory MM.
STORM Part 2 enrolled 122 patients.
The overall response rate (the study’s
primary objective) was 26.2 percent, and
patients experienced a median response
duration of 4.4 months. However, 95.1
percent of participants experienced at
least one grade 3/4 adverse event, the
most common of which were thrombo-
cytopenia, anemia, neutropenia, hypona-
tremia, and fatigue. Nearly 30 percent of
patients discontinued treatment due to
toxicity.
ODAC recommended that the FDA
await results from the randomized,
open-label phase III BOSTON study,
which is evaluating bortezomib and
dexamethasone with or without selinexor
in relapsed and refractory MM, before
deciding on approval. Results of the
BOSTON study are expected in the first
half of 2020.
The FDA is not required to follow the
advisory committee’s recommendations, but
the agency often adheres to its decisions.
On March 14, the FDA extended the review
period of selinexor’s new drug application,
setting a new action date of July 6.
Source: Karyopharm Therapeutics press releases, February 26, 2019,
and March 14, 2019.
removes $750 million in funding for
the Centers for Disease Control and
Prevention (CDC).
However, the proposed budget out-
lines funding increases for several HHS
programs, including efforts to rein in
rising prescription drug costs and curb
the opioid epidemic. The administration
also proposes a $50-million increase for
pediatric cancer research for the next
fiscal year.
While cancer researchers and health-
care associations welcomed an increase in
funding for pediatric cancer research, they
argued that any potential benefit would
not offset the harms caused by decreases
in the overall funding. The overall fund-
ing for the National Cancer Institute,
they noted, would drop by almost $900
million, or 14.5 percent, in the proposed
budget.
Organizations are calling for
Con-gress to reject the budget. 2019
American Society of Hematology (ASH)
President Roy Silverstein, MD, ex-
pressed disappointment in the proposed
budget: “ASH is deeply concerned that
the president’s proposal to cut public
health funding will jeopardize exist-
ing research programs, potentially halt
exploration into new and promising
avenues of study, and negatively affect
our nation’s health.”
He urged Congress to pass an NIH
budget of at least $41.6 billion, which
represents a $2.5-billion increase over its
2019 funding. With a higher budget, he
said, the agency could “continue to sup-
port existing research, including projects
included in the Innovation Account es-
tablished by the 21st Century Cures Act,
such as the Precision Medicine Initiative,
and also support new programs in
promising fields.” ASH also encouraged
Congress to provide the CDC with at
least $7.8 billion in fiscal year 2020.
Biomedical Research
Community Concerned
About Cuts in
Proposed 2020
Scott Gottlieb Resigns
Budget
as FDA Commissioner
Sources: The Washington Post, March 11, 2019; American Society of
Hematology press release, March 12, 2019.
On March 11, President Donald Trump
released his proposed fiscal year 2020
budget, called “A Budget for a Better
America,” that includes a substantial
12-percent cut to funding for the U.S.
Department of Health and Human
Services (HHS). This amounts to a
$4.7-billion decrease in funding for the
National Institutes of Health (NIH) – the
U.S.’s largest provider of funding for bio-
medical research.
The administration’s budget also
On March 5, FDA Commissioner Scott
Gottlieb, MD, announced his resignation,
citing a desire to spend more time with
family.
“I get home late Friday, work on
weekends, and come back to Washington
on Sunday. I did the job 100 percent,” Dr.
Gottlieb said in an interview with The
Washington Post. “It was a very hard deci-
sion. This is the best job I will ever have.”
The resignation came as a surprise to
many officials. Dr. Gottlieb, a physician
and venture capitalist, has held the posi-
tion of FDA commissioner since 2017 and
has prioritized the approval of generic
drugs to lower drug prices and tackling
public health issues like opioid addiction
and youth vaping during his tenure.
Norman “Ned” Sharpless, MD, the
current director of the National Cancer
Institute, will serve as acting commission-
er of the FDA as the agency searchers for a
permanent replacement for Dr. Gottlieb.
Sources: The Washington Post, March 5, 2019 and March 7, 2019.
FDA Halts Trials
of Venetoclax for
Myeloma
The FDA has issued a warning to health-
care professionals and clinical investigators
about the risks associated with the investi-
gational use of venetoclax in patients with
MM, following a review of clinical trials
data that showed an increased risk of death
among venetoclax-treated patients.
The FDA reviewed interim results
from the phase III BELLINI trial, which
is evaluating the efficacy of venetoclax
in combination with bortezomib and
dexamethasone in patients with pre-
viously treated MM, compared with
placebo. According to a safety and ef-
ficacy analysis conducted on November
26, 2018 (the prespecified data cutoff
date), there were 41 deaths among the
194 patients in the venetoclax-containing
arm (21.1%), compared with 11 deaths
among the 97 patients in the placebo arm
(11.3%), translating to a two-fold higher
risk of death with venetoclax (hazard
ratio = 2.03; 95% CI 1.04-3.94; p value
not reported).
Based on these findings, the FDA
suspended enrollment in BELLINI and
other ongoing clinical trials of venetoclax
in MM. Currently enrolled patients who
are receiving clinical benefit with veneto-
clax are permitted to continue treatment
in these trials after they reconsent. This
action does not apply to patients taking
venetoclax for an approved indication,
including acute myeloid leukemia and
chronic lymphocytic leukemia or small
lymphocytic lymphoma.
The FDA said it is working with
AbbVie, the trial’s sponsor, to determine
the extent of the safety issue. The agency
also encouraged health-care profession-
als and patients to report any adverse
events related to the use of venetoclax to
the agency’s MedWatch Adverse Event
Reporting program. ●
Source: FDA announcement, March 21, 2019.
May 2019