TIDMGSK
RNS Number : 2974V
GlaxoSmithKline PLC
06 August 2020
Issued: 6 August 2020, London UK
FDA approves GSK's BLENREP (belantamab mafodotin-blmf) for the
treatment of patients with relapsed or refractory multiple
myeloma
-- BLENREP is a first-in-class anti-BCMA (B-cell maturation
antigen) therapy for patients whose disease has progressed despite
prior treatment with an immunomodulatory agent, proteasome
inhibitor and anti-CD38 antibody
-- BLENREP is the fifth major medicine approval for GSK in 2020
GlaxoSmithKline plc (LSE/NYSE: GSK) announced the US Food and
Drug Administration (FDA) has approved BLENREP (belantamab
mafodotin-blmf) as a monotherapy treatment for adult patients with
relapsed or refractory multiple myeloma who have received at least
four prior therapies including an anti-CD38 monoclonal antibody, a
proteasome inhibitor and an immunomodulatory agent. This indication
is approved under accelerated approval based on response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials. BLENREP is the first anti-BCMA (B-cell maturation antigen)
therapy approved anywhere in the world. ([i])
Dr Hal Barron, Chief Scientific Officer and President R&D,
GSK, said: "As the second most common form of blood cancer in the
US, multiple myeloma is an incurable and devastating disease.
BLENREP is the first approved anti-BCMA therapy and has the
potential to transform the treatment of patients with relapsed or
refractory myeloma who have limited treatment options today."
BLENREP is GSK's fifth major medicine approval in 2020 across
areas of significant unmet medical need such as cancer, HIV and
chronic kidney disease. This approval marks the second FDA approval
for GSK's oncology portfolio in four months.
BLENREP employs a multi-faceted mechanism of action and is
directed toward BCMA, a cell-surface protein that plays an
important role in the survival of plasma cells and is expressed on
multiple myeloma cells. ([ii]) The approval of BLENREP was based on
six-month primary results from the pivotal DREAMM-2 study, which
enrolled patients with relapsed or refractory multiple myeloma who
had actively progressing disease that had worsened despite current
standard of care.
Dr Sagar Lonial, MD, Chief Medical Officer, Winship Cancer
Institute of Emory University in Atlanta, Georgia, Chair of Emory
Department of Hematology and Medical Oncology and Principal
Investigator for DREAMM-2, said: "While treatable, refractory
multiple myeloma is a significant clinical challenge with poor
outcomes for patients whose disease has become resistant to the
current standard of care. Due to the limited options currently
available, these patients are often retreated with drugs from the
same classes after they relapse, which is why the approval of
BLENREP, the first anti-BCMA therapy, is significant for both
patients and physicians alike."
In the DREAMM-2 study, treatment with single-agent BLENREP 2.5
mg/kg every three weeks demonstrated a clinically meaningful
overall response rate (ORR) of 31% (97.5% CI; 21-43) in patients
who had received a median of seven prior lines of treatment (n=97).
The median duration of response (DoR) had not been reached at the
six-month analysis, but 73% of responders had a DoR equal to or
greater than six months. The most commonly reported adverse events
(>=20%) were keratopathy, decreased visual acuity, nausea,
blurred vision, pyrexia, infusion-related reactions, and fatigue.
Keratopathy is characterised as changes in the corneal epithelium
as seen on eye examination, which can manifest with or without
symptoms.
Ocular adverse reactions occurred in 77% of the 218 patients in
the pooled safety population and included keratopathy (76%),
changes in visual acuity (55%), blurred vision (27%) and dry eye
(19%). Corneal adverse events were monitored with eye exams prior
to each dose, allowing for dose reductions or interruptions as
appropriate. Patients also used preservative-free eye drops .
Keratopathy leading to treatment discontinuation affected 2.1% of
patients in the 2.5 mg/kg cohort.[iii]
BLENREP is available through participation in the BLENREP Risk
Evaluation and Mitigation Strategy (REMS), which was developed to
ensure appropriate use of the medicine. The programme requires
education for all physicians prescribing BLENREP and their patients
regarding the ocular risks associated with treatment as well as
monitoring. Additional information about the BLENREP REMS can be
found at www.blenreprems.com or 1-855-209-9188.
Paul Giusti, President and CEO of the Multiple Myeloma Research
Foundation (MMRF), said: "The approval of BLENREP is an important
advancement for patients with relapsed or refractory multiple
myeloma, as it brings a much-needed new treatment to patients who
face limited options due to their progressing disease. We are
grateful for GSK's continued commitment to myeloma patients and
their families."
In 2017, BLENREP was granted Breakthrough Therapy designation by
the FDA, which is intended to facilitate the development of
investigational medicines that have shown clinical promise for
conditions where there is significant unmet need.
About multiple myeloma
Multiple myeloma is the second most common blood cancer in the
US and is generally considered treatable, but not curable. ([iv])
In the US, more than 32,000 people are estimated to be diagnosed
with multiple myeloma this year and nearly 13,000 people will die
from the disease.[v] Research into new therapies is needed as
multiple myeloma commonly becomes refractory to available
treatments.[vi]
About B-cell maturation antigen (BCMA)
The normal function of BCMA is to promote plasma cell survival
by transduction of signals from two known ligands, BAFF (B-cell
activating factor) and APRIL (a proliferation-inducing ligand).
This pathway has been shown to be important for myeloma cell growth
and survival. BCMA expression is limited to B cells at later stages
of development. BCMA is expressed at varying levels in myeloma
patients and BCMA membrane expression is universally detected in
myeloma cell lines. (ii)
About BLENREP (belantamab mafodotin-blmf)
BLENREP is an antibody drug conjugate comprising a humanised
anti-B cell maturation antigen (BCMA) monoclonal antibody
conjugated to the cytotoxic agent auristatin F via non-cleavable
linker. The drug linker technology is licensed from Seattle
Genetics; monoclonal antibody is produced using POTELLIGENT
Technology licensed from BioWa.
IMPORTANT SAFETY INFORMATION FOR BLENREP
WARNING: OCULAR Toxicity
BLENREP caused changes in the corneal epithelium resulting in
changes in vision, including severe vision loss and corneal ulcer,
and symptoms such as blurred vision and dry eyes.
Conduct ophthalmic exams at baseline, prior to each dose, and
promptly for worsening symptoms. Withhold BLENREP until improvement
and resume, or permanently discontinue, based on severity.
Because of the risk of ocular toxicity, BLENREP is available
only through a restricted program under a Risk Evaluation and
Mitigation Strategy (REMS) called the BLENREP REMS.
WARNINGS AND PRECAUTIONS
Ocular Toxicity: Ocular adverse reactions occurred in 77% of the
218 patients in the pooled safety population. Ocular adverse
reactions included keratopathy (76%), changes in visual acuity
(55%), blurred vision (27%), and dry eye (19%). Among patients with
keratopathy (n = 165), 49% had ocular symptoms, 65% had clinically
relevant visual acuity changes (decline of 2 or more lines on
Snellen Visual Acuity in any eye), and 34% had both ocular symptoms
and visual acuity changes.
Keratopathy : Keratopathy was reported as Grade 1 in 7% of
patients, Grade 2 in 22%, Grade 3 in 45%, and Grade 4 in 0.5% per
the KVA scale. Cases of corneal ulcer (ulcerative and infective
keratitis) have been reported. Most keratopathy events developed
within the first 2 treatment cycles (cumulative incidence of 65% by
Cycle 2). Of the patients with Grade 2 to 4 keratopathy (n = 149),
39% recovered to Grade 1 or lower after median follow-up of 6.2
months. Of the 61% who had ongoing keratopathy, 28% were still on
treatment, 9% were in follow-up, and in 24% the follow-up ended due
to death, study withdrawal, or lost to follow-up. For patients in
whom events resolved, the median time to resolution was 2 months
(range: 11 days to 8.3 months).
Visual Acuity Changes : A clinically significant decrease in
visual acuity of worse than 20/40 in the better-seeing eye was
observed in 19% of the 218 patients and of 20/200 or worse in the
better-seeing eye in 1.4%. Of the patients with decreased visual
acuity of worse than 20/40, 88% resolved and the median time to
resolution was 22 days (range: 7 days to 4.2 months). Of the
patients with decreased visual acuity of 20/200 or worse, all
resolved and the median duration was 22 days (range: 15 to 22
days).
Monitoring and Patient Instruction : Conduct ophthalmic
examinations (visual acuity and slit lamp) at baseline, prior to
each dose, and promptly for worsening symptoms . Perform baseline
examinations within 3 weeks prior to the first dose. Perform each
follow-up examination at least 1 week after the previous dose and
within 2 weeks prior to the next dose. Withhold BLENREP until
improvement and resume at same or reduced dose, or consider
permanently discontinuing based on severity . Advise patients to
use preservative-free lubricant eye drops at least 4 times a day
starting with the first infusion and continuing until end of
treatment. Avoid use of contact lenses unless directed by an
ophthalmologist. Changes in visual acuity may be associated with
difficulty for driving and reading. Advise patients to use caution
when driving or operating machinery. BLENREP is only available
through a restricted program under a REMS.
BLENREP REMS: BLENREP is available only through a restricted
program under a REMS called the BLENREP REMS because of the risks
of ocular toxicity. Notable requirements of the BLENREP REMS
include the following:
-- Prescribers must be certified with the program by enrolling
and completing training in the BLENREP REMS.
-- Prescribers must counsel patients receiving BLENREP about the
risk of ocular toxicity and the need for ophthalmic examinations
prior to each dose.
-- Patients must be enrolled in the BLENREP REMS and comply with monitoring.
-- Healthcare facilities must be certified with the program and
verify that patients are authorized to receive BLENREP .
-- Wholesalers and distributers must only distribute BLENREP to
certified healthcare facilities.
Further information is available at www.BLENREPREMS.com and
1-855-209-9188.
Thrombocytopenia: Thrombocytopenia occurred in 69% of 218
patients in the pooled safety population, including Grade 2 in 13%,
Grade 3 in 10%, and Grade 4 in 17%. The median time to onset of the
first thrombocytopenic event was 26.5 days. Thrombocytopenia
resulted in dose reduction, dose interruption, or discontinuation
in 9%, 2.8%, and 0.5% of patients, respectively. Grade 3 to 4
bleeding events occurred in 6% of patients, including Grade 4 in 1
patient. Fatal adverse reactions included cerebral hemorrhage in 2
patients. Perform complete blood cell counts at baseline and during
treatment as clinically indicated. Consider withholding and/or
reducing the dose based on severity.
Infusion-Related Reactions: Infusion-related reactions occurred
in 18% of 218 patients in the pooled safety population, including
Grade 3 in 1.8%. Monitor patients for infusion-related reactions.
For Grade 2 or 3 reactions, interrupt the infusion and provide
supportive treatment. Once symptoms resolve, resume at a lower
infusion rate. Administer premedication for all subsequent
infusions. Discontinue BLENREP for life-threatening
infusion-related reactions and provide appropriate emergency
care.
Embryo-Fetal Toxicity: Based on its mechanism of action, BLENREP
can cause fetal harm when administered to a pregnant woman because
it contains a genotoxic compound (the microtubule inhibitor,
monomethyl auristatin F [MMAF]) and it targets actively dividing
cells. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective
contraception during treatment with BLENREP and for 4 months after
the last dose. Advise males with female partners of reproductive
potential to use effective contraception during treatment with
BLENREP and for 6 months after the last dose.
ADVERSE REACTIONS
The pooled safety population described in Warnings and
Precautions reflects exposure to BLENREP at a dosage of 2.5 mg/kg
or 3.4 mg/kg (1.4 times the recommended dose) administered
intravenously once every 3 weeks in 218 patients in DREAMM-2. Of
these patients, 194 received a liquid formulation (not the approved
dosage form) rather than the lyophilized powder. Among the 218
patients, 24% were exposed for 6 months or longer.
The safety of BLENREP as a single agent was evaluated in
DREAMM-2. Patients received BLENREP at the recommended dosage of
2.5 mg/kg administered intravenously once every 3 weeks (n = 95).
Among these patients, 22% were exposed for 6 months or longer.
Serious adverse reactions occurred in 40% of patients who
received BLENREP. Serious adverse reactions in >3% of patients
included pneumonia (7%), pyrexia (6%), renal impairment (4.2%),
sepsis (4.2%), hypercalcemia (4.2%), and infusion-related reactions
(3.2%). Fatal adverse reactions occurred in 3.2% of patients,
including sepsis (1%), cardiac arrest (1%), and lung infection
(1%).
Permanent discontinuation due to an adverse reaction occurred in
8% of patients who received BLENREP; keratopathy (2.1%) was the
most frequent adverse reaction resulting in permanent
discontinuation.
Dosage interruptions due to an adverse reaction occurred in 54%
of patients who received BLENREP. Adverse reactions which required
a dosage interruption in >3% of patients included keratopathy
(47%), blurred vision (5%), dry eye (3.2%), and pneumonia
(3.2%).
Dose reductions due to an adverse reaction occurred in 29% of
patients. Adverse reactions which required a dose reduction in
>3% of patients included keratopathy (23%) and thrombocytopenia
(5%).
The most common adverse reactions (>=20%) were keratopathy
(71%), decreased visual acuity (53%), nausea (24%), blurred vision
(22%), pyrexia (22%), infusion-related reactions (21%), and fatigue
(20%). The most common Grade 3 or 4 (>=5%) laboratory
abnormalities were lymphocytes decreased (22%), platelets decreased
(21%), hemoglobin decreased (18%), neutrophils decreased (9%),
creatinine increased (5%), and gamma-glutamyl transferase increased
(5%).
USE IN SPECIFIC POPULATIONS
Lactation: There is no data on the presence of belantamab
mafodotin-blmf in human milk or the effects on the breastfed child
or milk production. Because of the potential for serious adverse
reactions in the breastfed child, advise women not to breastfeed
during treatment with BLENREP and for 3 months after the last
dose.
Females and Males of Reproductive Potential: BLENREP can cause
fetal harm when administered to pregnant women. There are no
available data on the use of BLENREP in pregnant women to evaluate
for drug-associated risk. No animal reproduction studies were
conducted with BLENREP.
Pregnancy Testing : Pregnancy testing is recommended for females
of reproductive potential prior to initiating BLENREP.
Infertility : Based on findings in animal studies, BLENREP may
impair fertility in females and males. The effects were not
reversible in male rats but were reversible in female rats.
Geriatric Use: Of the 218 patients who received BLENREP in
DREAMM-2, 43% were aged 65 to less than 75 years and 17% were aged
75 years and older. Keratopathy occurred in 80% of patients aged
less than 65 years and 73% of patients aged 65 years and older.
Among the patients who received BLENREP at the 2.5-mg/kg dose in
DREAMM-2 (n = 95), keratopathy occurred in 67% of patients aged
less than 65 years and 73% of patients aged 65 years and older.
Renal Impairment: No dose adjustment is recommended for patients
with mild or moderate renal impairment (estimated glomerular
filtration rate [eGFR] 30 to 89 mL/min/1.73m(2) as estimated by the
Modification of Diet in Renal Disease [MDRD] equation). The
recommended dosage has not been established in patients with severe
renal impairment (eGFR 15 to 29 mL/min/1.73 m(2) ) or end-stage
renal disease (ESRD) with eGFR <15 mL/min/1.73 m(2) not on
dialysis or requiring dialysis.
Hepatic Impairment: No dose adjustment is recommended for
patients with mild hepatic impairment (total bilirubin <=upper
limit of normal [ULN] and aspartate aminotransferase (AST) >ULN
or total bilirubin 1 to <=1.5 × ULN and any AST). The
recommended dosage of BLENREP has not been established in patients
with moderate or severe hepatic impairment (total bilirubin >1.5
× ULN and any AST).
INDICATION
BLENREP is indicated for the treatment of adults with relapsed
or refractory multiple myeloma who have received at least 4 prior
therapies, including an anti-CD38 monoclonal antibody, a proteasome
inhibitor, and an immunomodulatory agent.
This indication is approved under accelerated approval based on
response rate. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
a confirmatory trial(s).
The full Prescribing Information, including BOXED WARNING and
Medication Guide, will be available here .
GSK in Oncology
GSK is focused on maximising patient survival through
transformational medicines. GSK's pipeline is focused on
immuno-oncology, cell therapy, cancer epigenetics, and synthetic
lethality. Our goal is to achieve a sustainable flow of new
treatments based on a diversified portfolio of investigational
medicines utilising modalities such as small molecules, antibodies,
antibody drug conjugates and cells, either alone or in
combination.
About GSK
GSK is a science-led global healthcare company with a special
purpose: to help people do more, feel better, live longer. For
further information please visit www.gsk.com/about-us .
Editor's Note: In addition to the FDA's approval of BLENREP, GSK
has received four major medicine approvals to date in 2020 for
CABENUVA (cabotegravir and rilpivirine) in Canada, DUVROQ
(daprodustat) in Japan and ZEJULA (niraparib) and RUKOBIA
(fostemsavir) in the US.
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DC)
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enquiries: 5194
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projections made by GSK, including those made in this announcement,
are subject to risks and uncertainties that may cause actual
results to differ materially from those projected. Such factors
include, but are not limited to, those described under Item 3.D
"Risk Factors" in the company's Annual Report on Form 20-F for 2019
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of the Q2 Results and any impacts of the COVID-19 pandemic.
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References
[i] NCI Drug Dictionary - Anti-BCMA Antibody-Drug Conjugate
GSK2857916. National Cancer Institute.
https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-bcma-antibody-drug-conjugate-gsk2857916.
Accessed May 2020.
[ii] Trudel S, Lendvai N, Popat R, et al. Antibody-drug
conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an
update on safety and efficacy from dose expansion phase I study.
Blood Cancer Journal. 2019;9(4).
doi:10.1038/s41408-019-0196-6.
[iii] Lonial, S, et al. Belantamab mafodotin for relapsed or
refractory multiple myeloma (DREAMM-2): a two-arm, randomised,
open-label, phase 2 study. Lancet Oncol. 2020; 21(2):207-21.
[iv] Estimated number of incident cases worldwide, both sexes,
all ages. World Health Organization. https://gco.iarc.fr/ Published
2020. Accessed May 2020.
[v] SEER Cancer Facts & Figures 2019. Available at:
https://seer.cancer.gov/statfacts/html/mulmy.html . Accessed
December 19, 2019.
[vi] Nooka AK, Kastritis E, Dimopoulos MA. Treatment options for
relapsed and refractory multiple myeloma. Blood. 2015;125(20)
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END
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