CLINICAL NEWS
On Location Progress in Transplant and Cellular Therapy
Bangkok, Thailand presented the results at
the 2019 Transplantation & Cellular Therapy
Meetings of the ASBMT and CIBMTR.
The LentiGlobin gene-therapy product
is designed to overcome a key limitation of
allogeneic hematopoietic cell transplanta-
tion – lack of a compatible donor – for pa-
tients who require long-term red blood cell
(RBC) transfusions, Dr. Anurathapan ex-
plained. To manufacture this gene therapy,
investigators obtained mobilized autologous
CD34-positive cells from patients, then
transduced the cells ex vivo with the Lenti-
Globin BB305 vector, which encodes adult
hemoglobin (HbA) with a T87Q amino-
acid substitution (HbAT87Q). Patients
underwent conditioning with busulfan prior
to the modified cells being re-infused.
Earlier results from 22 patients en-
rolled in the two companion trials were
published in the New England Journal of
Medicine, and data from the HGB trials
FEIBA (anti-inhibitor coagulant complex)
for intravenous use, lyophilized powder for solution
Brief Summary of Prescribing Information: Please see package
insert for Full Prescribing Information
WARNING: EMBOLIC AND THROMBOTIC EVENTS
• Thromboembolic events have been reported during post-marketing
surveillance following infusion of FEIBA, particularly following the
administration of high doses and/or in patients with thrombotic risk
factors.
• Monitor patients receiving FEIBA for signs and symptoms of
thromboembolic events.
INDICATIONS AND USAGE
FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B
patients with inhibitors for:
• Control and prevention of bleeding episodes
• Perioperative management
• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation
factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation
factor IX.
CONTRAINDICATIONS
• Known anaphylactic or severe hypersensitivity reactions to FEIBA or any if its
components, including factors of the kinin generating system.
• Disseminated intravascular coagulation (DIC).
• Acute thrombosis or embolism (including myocardial infarction).
WARNINGS AND PRECAUTIONS
Embolic and Thrombotic Events
Thromboembolic events (including venous thrombosis, pulmonary embolism, myocardial
infarction, and stroke) can occur with FEIBA, particularly following the administration of
high doses (above 200 units per kg per day) and/or in patients with thrombotic risk
factors [see Adverse Reactions].
Patients with DIC, advanced atherosclerotic disease, crush injury, septicemia, or
concomitant treatment with recombinant factor VIIa have an increased risk of developing
thrombotic events due to circulating tissue factor or predisposing coagulopathy.
Potential benefit of treatment with FEIBA should be weighed against the potential risk of
these thromboembolic events.
Monitor patients receiving more than 100 units per kg of body weight of FEIBA for the
development of DIC, acute coronary ischemia and signs and symptoms of other
thromboembolic events. If clinical signs or symptoms occur, such as chest pain or
pressure, shortness of breath, altered consciousness, vision, or speech, limb or
abdomen swelling and/or pain, discontinue the infusion and initiate appropriate
diagnostic and therapeutic measures.
The safety and efficacy of FEIBA for breakthrough bleeding in patients receiving
emicizumab has not been established. Cases of thrombotic microangiopathy (TMA)
were reported in a clinical trial where subjects received FEIBA as part of a treatment
regimen for breakthrough bleeding following treatment with emicizumab. Consider the
benefits and risks with FEIBA if considered required for patients receiving emicizumab
prophylaxis. If treatment with FEIBA is required for patients receiving emicizumab, the
hemophilia treating physician should closely monitor for signs and symptoms of TMA.
In FEIBA clinical studies thrombotic microangiopathy (TMA) has not been reported.
Hypersensitivity Reactions
Hypersensitivity and allergic reactions, including severe anaphylactoid reactions, can
occur following the infusion of FEIBA. The symptoms include urticaria, angioedema,
gastrointestinal manifestations, bronchospasm, and hypotension. These reactions can be
severe and systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm,
and circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension
have also been reported. If signs and symptoms of severe allergic reactions occur,
immediately discontinue administration of FEIBA and provide appropriate supportive care.
Transmission of Infectious Agents
Because FEIBA is made from human plasma it may carry a risk of transmitting
infectious agents, e.g., viruses, and the variant Creutzfeldt-Jakob disease (vCJD)
agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk has been
minimized by screening plasma donors for prior exposure to certain viruses, by
testing for the presence of certain current virus infections and by inactivating and
removing certain viruses during the manufacturing process [see Description in full
prescribing information]. Despite these measures, the product may still potentially
transmit human pathogenic agents. There is also the possibility that unknown
infectious agents may still be present.
All infections thought by a physician to have been possibly transmitted by this product
should be reported by the physician or other healthcare providers to Baxalta US Inc.,
at 1-800-423-2090 (in the U.S.) and /or to FDA Med Watch (1-800-FDA-1088 or
www.fda.gov/medwatch).
Presence of Isohemagglutinins and Interference with Laboratory Tests
FEIBA contains blood group isohemagglutinins (anti-A and anti-B). Passive transmission
of antibodies to erythrocyte antigens, e.g., A, B, D, may interfere with some serological
tests for red cell antibodies, such as antiglobulin test (Coombs test).
were recently used to support the E.U.
regulatory review of LentiGlobin for
transfusion-dependent thalassemia.
During his presentation, Dr. Anuratha-
pan shared longer-term follow-up from each
study. As of September 14, 2018, 18 patients
(median age = 20 years; range = 12-35 years)
had been treated in the HGB-204 trial and
16 patients (median age = 19 years; range =
8-34 years) had been treated in HGB-207.
HGB-204 included patients with either
ADVERSE REACTIONS
The most frequently reported adverse reactions observed in >5% of subjects in the
prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody
positive, nausea, and vomiting.
The serious adverse reactions seen with FEIBA are hypersensitivity reactions and
thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety assessment of FEIBA is based on the review of the data from two prospective
clinical trials in which FEIBA was used for the treatment of acute bleeding episodes and
a prospective trial that compared the use of FEIBA prophylactically versus on-demand
treatment.
The adverse reactions reported from two prospective clinical trials in which FEIBA was used
for the treatment of acute bleeding episodes were chills, chest pain, chest discomfort,
dizziness, dysgeusia, dyspnea, hypoesthesia, increase of inhibitor titer (anamnestic
response), nausea, pyrexia, and somnolence. Specifically, the first trial was a multicenter
randomized, double-blind trial in 15 hemophilia A subjects with inhibitors to factors VIII. The
second trial was a multicenter FEIBA study conducted in 44 hemophilia A subjects with
inhibitors, 3 hemophilia B subjects with inhibitors and 2 acquired factor VIII inhibitor
subjects. Of the 489 infusions used to treat acute bleeds during the second trial, 18 (3.7%)
caused minor transient reactions of chills, fever, nausea, dizziness and dysgeusia. Out of
49 subjects, 10 (20%) had a rise in their inhibitor titers after treatment with FEIBA. Five of
these subjects (50%) had increases that were, tenfold or more, and 3 (30%) of these
subjects received factor VIII or IX concentrates within 2 weeks prior to treatment with FEIBA.
These anamnestic rises were not associated with decreased efficacy of FEIBA.
Table 1 lists the adverse reactions in >5% of subject reported in the randomized,
prospective prophylaxis trial comparing FEIBA prophylaxis with on-demand treatment in
36 hemophilia A and B subjects with inhibitors to factors VIII or IX. The trial population
included 33 (92%) subjects with hemophilia A and 3 (8.3%) subjects with hemophilia B.
Four (11%) subjects were ≥7 to <12 years of age, 5 (14%) were ≥12 to <16 years of
age, and 27 (75%) were ≥16 years of age. A total of 29 (80.6%) subjects were Caucasian,
3 (8.3%) Asian, 2 (5.6%) Black/African American, and 2 (5.6%) other. The subjects
received a total of 4,513 infusions (3,131 for prophylaxis and 1,382 for on-demand).
Table 1 Prophylaxis Study Adverse Reactions (ARs) in >5% of Subjects
MedDRA System
Organ Class Adverse Reaction
Blood And Lymphatic
System Disorders
Gastrointestinal Disorders Anemia
Investigations
Musculoskeletal And
Connective Tissue Disorders
Diarrhea
Nausea
Vomiting
Hepatitis B Surface
Antibody Positive
Hemarthrosis
Number Number of Percent of
of ARs Subjects Subjects
(N=36)
2
2
5.6
2
2
2 2
2
2 5.6
5.6
5.6
4 4 11.1
5 3 8.3
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
FEIBA. Because post-marketing reporting of adverse reactions is voluntarily and from a
population of uncertain size, it is not always possible to reliably estimate the frequency
of these reactions or establish a causal relationship to product exposure.
Blood and Lymphatic System Disorders: disseminated intravascular coagulation
Cardiac Disorders: tachycardia, flushing
Respiratory, Thoracic, and Mediastinal Disorders: bronchospasm, wheezing
Gastrointestinal Disorders: abdominal discomfort
Skin and Subcutaneous Tissue Disorders: pruritus
General Disorders and Administration Site Conditions: malaise, feeling hot, injection site pain
DRUG INTERACTIONS
Concomitant Medications
Consider the possibility of thrombotic events when systemic antifibrinolytics such as
tranexamic acid and aminocaproic acid are used during treatment with FEIBA. No
adequate and well-controlled studies of the combined or sequential use of FEIBA and
recombinant factor VIIa antifibrinolytics, or emicizumab have been conducted. Use of
antifibrinolytics within approximately 6 to 12 hours after the administration of FEIBA is
not recommended.
Clinical experience from an emicizumab clinical trial suggests that a potential drug
interaction may exist with emicizumab when FEIBA was used as part of a treatment
regimen for breakthrough bleeding (see Warnings and Precautions above; see also
Oldenburg et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J
Med 2017:377:809-818).
BAXALTA ® and FEIBA ® are trademarks of Baxalta Incorporated, a wholly-owned, indirect
subsidiary of Shire plc., a Takeda company. Takeda and the Takeda Logo are
trademarks or registered trademarks of Takeda Pharmaceutical Company Limited.
Baxalta US Inc., Lexington, MA 02421 USA
U.S. License No. 2020 Issued: 12/2018 S45732 02/19
non-β 0 /β 0 or β0/β 0 genotypes, while HGB-
207 included those with only non-β0/β 0
genotypes. All participants were transfu-
sion dependent at the time of enrollment
(defined as the receipt of ≥8 transfusions
or ≥100 mL/kg of packed RBCs per year
in the 2 years before enrollment).
In both studies, participants were
treated with a median of 8.0×10 6 cells/kg
(median = 5.0-19.4×10 6 cells/kg).
Two-thirds of patients (n=23/34) experi-
enced an any-grade bleeding-related adverse
event (AE) within two years of infusion.
“The safety profile was generally con-
sistent with a myeloablative conditioning
regimen,” Dr. Anurathapan noted. Most
treatment-related AEs were grade 1 (includ-
ing abdominal pain, dyspnea, and dyspla-
sia), but two patients in HGB-204 and one
patient in HGB-207 experienced serious
AEs (1 thrombosis and 2 instances of veno-
occlusive liver disease [VOD]).
After a median follow-up of 38.9 months
(range = 29.3-48.1 months), 16 of 18 patients
in HGB-204 (89%) achieved the study’s pri-
mary endpoint of Hb improvement (defined
as ≥2 g/dL of HbAT87Q between 18 and 24
months after infusion). Hb levels were stable
in all patients, ranging from 9.1 g/dL to 12.5
g/dL at the last study visit.
Eleven patients achieved transfusion
independence, which ranged from 22.8 to
46.3 months at last follow-up. A greater
proportion of patients with non-β0/β0
genotypes achieved transfusion indepen-
dence (n=8/10; 80%), compared with pa-
tients with β0/β0 genotype (n=3/8; 37.5%).
After a median follow-up of 9.3
months (range = 0.7-20.4 months), 11
patients in HGB-207 had at least three
months of follow-up and were evaluable.
Ten of these patients (91%) had stopped
RBC transfusions, with all achieving Hb
levels of at least 11 g/dL at last study visit.
Three patients had at least 12 months
of follow-up and were evaluable for the
primary endpoint analysis; two patients
met the criteria for the primary endpoint
(Hb ≥9 g/dL without RBC transfusions
for ≥12 months post-infusion).
These data suggest that patients can
achieve “near-normal” Hb levels without
transfusions or any additional safety signals
compared with myeloablative transplant
conditioning, Dr. Anurathapan concluded.
The patient population in each trial was
small, which limits the broad applicability of
the studies’ results. Dr. Anurathapan added
that the small number of enrolled patients
limits the investigators’ ability to identify
potential factors that caused delayed platelet
engraftment in some patients. ●
The authors report relationships with
Bluebird Bio, the manufacturer of Lenti-
Globin and the sponsor of this trial.
REFERENCES
Anurathapan U, Locatelli F, Kwiatkowski JL, et al. Lentiglobin gene
therapy for transfusion-dependent ß-thalassemia: outcomes from the
phase 1/2 Northstar and phase 3 Northstar-2 studies. Abstract #84.
Presented at the Transplantation & Cellular Therapy Meetings of ASTCT
and CIBMTR, February 23, 2019; Houston, TX.
May 2019