ASH Clinical News March 2017 | Page 22

7 UP FRONT 11 CLINICAL NEWS volume 03 | number 01 january 2017

Written in Blood

— DIAN WINKELHORST

ADYNOVATE ® [ Antihemophilic Factor ( Recombinant ), PEGylated ] Lyophilized Powder for Solution For Intravenous Injection Brief Summary of Prescribing Information : Please see package insert for full Prescribing Information .

INDICATIONS AND USAGE

ADYNOVATE , Antihemophilic Factor ( Recombinant ), PEGylated , is a human antihemophilic factor indicated in children and adults with hemophilia A ( congenital factor VIII deficiency ) for :

• On-demand treatment and control of bleeding episodes

• Perioperative management

• Routine prophylaxis to reduce the frequency of bleeding episodes

Limitation of Use ADYNOVATE is not indicated for the treatment of von Willebrand disease . CONTRAINDICATIONS

ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE , to the parent molecule ADVATE ® ( Antihemophilic Factor [ Recombinant ]), mouse or hamster protein , or excipients of ADYNOVATE ( e . g . Tris , mannitol , trehalose , glutathione , and / or polysorbate 80 ).

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions

Hypersensitivity reactions are possible with ADYNOVATE . Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with other recombinant antihemophilic factor VIII products , including the parent molecule , ADVATE . Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema , chest tightness , dyspnea , wheezing , urticaria , and pruritus . Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur .

Neutralizing Antibodies

Formation of neutralizing antibodies ( inhibitors ) to factor VIII can occur following administration of ADYNOVATE . Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests . Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected , or if bleeding is not controlled with expected dose .

Monitoring Laboratory Tests

• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained .

• Monitor for the development of factor VIII inhibitors . Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present . If expected factor VIII activity plasma levels are not attained , or if bleeding is not controlled with the expected dose of ADYNOVATE , use Bethesda Units ( BU ) to determine inhibitor levels .

ADVERSE REACTIONS The most common adverse reactions ( ≥1 % of subjects ) reported in the clinical studies were headache and nausea .

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 clinical trials of another drug and may not reflect the rates observed in practice .

The safety of ADYNOVATE was evaluated in 237 previously treated patients ( PTPs ) and 6 previously untreated patients ( PUPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 3 completed multicenter , prospective , open label clinical studies and 4 ongoing clinical studies . The median duration of participation per subject was 401 ( min-max : 3-1034 ) days and the median number of exposure days to ADYNOVATE per subject was 111 ( min-max : 1-322 ). Table 1 lists the adverse reactions reported during clinical studies .

There was no consistent evidence for the value of adding steroids to IVIg , and the rate of treatment-related complications appeared to be higher when IVIg was used with corticosteroids ( values not reported ). The most commonly reported side effect of corticosteroid treatment was oligohydramnios ; the most commonly reported side effects of IVIg were headache and rash , which led to IVIg discontinuation in one patient .

Table 1 : Adverse Reactions Reported for ADYNOVATE

MedDRA System Organ Class

Gastrointestinal Disorders Immune System Disorder Nervous System Disorders Skin and Subcutaneous Tissue Disorders Vascular Disorders

MedDRA Preferred Term

Number of Subjects n (%) ( N = 234 )

Rate of AEs per 100 Infusions ( N = 30865 )

Hypersensitivity a 1 ( 0.4 %) 0.003

Headache 5 ( 2.1 %) 0.026 Rash 1 ( 0.4 %) 0.003 Flushing 1 ( 0.4 %) 0.003 a

The event of hypersensitivity was a mild transient non-serious rash , occurring in one 2-year old patient who had developed a previous rash while on ADYNOVATE .

Two cases of acute pancreatitis , with no precipitating cause identified in one case , were reported in adults during an extension study of the clinical trial which evaluated 137 subjects . Administration of ADYNOVATE continued and both cases resolved .

Immunogenicity

The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3 completed and 4 ongoing clinical trials . Subjects consisted of adolescent and adult ( n = 148 with ≥150 prior EDs ) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs ( n = 32 ), ≥6 years of age with ≥150 prior EDs ( n = 57 )], and pediatric PUPs ( n = 6 ). In 191 adult and pediatric PTPs who were treated for at least 50 exposure days with ADYNOVATE , the factor VIII inhibitor frequency was 0 ( 95 % CI of 0 to 0.019 ). One PUP subject from an ongoing study , who received at least one infusion of ADYNOVATE , developed neutralizing antibodies to factor VIII .

Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII , PEGylated ( PEG ) -factor VIII , PEG and Chinese hamster ovary ( CHO ) protein using validated ELISA assays . The majority of subjects ( 238 / 243 ) with at least one infusion of ADYNOVATE did not develop a persistent binding antibody response to any of these antigens . Twenty-eight subjects in total showed pre-existing antibodies to factor VIII ( n = 3 ), PEG-factor VIII ( n = 25 ) and / or PEG ( n = 3 ) prior to the first exposure to ADYNOVATE . Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII ( n = 6 ), or PEG-FVIII ( n = 8 ) at one or two consecutive study visits . Antibodies were transient and not detectable at subsequent visits . Five subjects showed positive results for binding antibodies at study completion or at the time of data cutoff . Binding antibodies that were detected prior to exposure to ADYNOVATE , that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters . There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data . No subject had pre-existing or treatment-emergent antibodies to CHO protein .

The detection of antibodies that are reactive to factor VIII is highly dependent on many factors , including : the sensitivity and specificity of the assay , sample handling , timing of sample collection , concomitant medications and underlying disease . For these reasons , comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading .

Baxalta , Advate , Adynovate , and Baxject are trademarks of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc .

Baxalta US Inc . Westlake Village , CA 91362 USA U . S . License No . 2020 Issued 12 / 2016 16I045-ADY-US S24588 01 / 17

Comparatively , of the 24 studies in which patients were treated with FBS with or without IUPT , the rate of complications was relatively high ( 11 %, or 54 complications in 497 treated pregnancies ). The most frequently described complications were emergency cesarean section , mostly due to fetal distress ; approximately half of these procedures resulted in delivery prior to 34 weeks ’ gestation . Fourteen complications resulted in fetal or neonatal death ( 26 %).

“ Regarding the optimal dose and start of the treatment , there are insufficient data to recommend a specific gestational age or specific dose ,” Dr . Winkelhorst and co-authors wrote . However , the data supported the following treatment strategies :

• treatment of high-risk pregnancies ( i . e ., sibling suffered from ICH ): IVIg 1 g / kg per week , started between 12 and 20 weeks ’ gestation

• treatment of standard-risk pregnancies ( i . e ., no sibling suffered from ICH ): IVIg 1 g / kg per week with or without steroids , started between 20 and 24 weeks ’ gestation

The authors cautioned that the use of IVIg in pregnancies at risk for FNAIT is “ still off-label and the possible immunostimulative or immunosuppressive effect of exposing the maturing fetal immune system to IVIg has not been adequately addressed .” They added that the study was limited by the small number of randomized studies and lack of an adequate control group , as well as the heterogeneity of extracted data . ●

REFERENCE

Winkelhorst D , Murphy MF , Greinacher A , et al . Antenatal management in fetal and neonatal alloimmune thrombocytopenia : a systematic review . Blood . 2017 January 11 . [ Epub ahead of print ]

On Location : Highlights from the ASH Annual Meeting

CONTENTS

Editor ’ s Corner Alice Ma ’ s Hematology Wishlist

ASH Directions Announcing the 2017 Scholar Award Recipients

Written in Blood Cytomegalovirus Infection and the Risk of Acute Lymphocytic Leukemia

Literature Scan Can Overly Restrictive Exclusion Criteria Block Patients from Effective Therapy ?

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March 2017