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Hyqvia




  

 
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
MEMORANDUM

Date: 4.30.2014

From: Jennifer L. Reed, Ph.D.; CBER/OBRR/DH/LPD
HFM-345; 301-496-0625

To: File for BLA 125402/35

Reference: IND 13840; STN BL 125105 (Immune Globulin Intravenous (Human), 10% 
Solution; Gammagard Liquid); NDA 21-859 (hyaluronidase human injection, Hylenex)

Through: Dorothy Scott, M.D.; CBER/OBRR/DH/LPD; HFM-345; 301-827-3016

Cc: Cherie Ward-Paralta; CBER/OBRR/DBA; HFM-380; 301-827-9180

Subject: Major Information Amendment: Safety, Preclinical, Labeling
Product: Immune Globulin Infusion (Human), 10% with Recombinant Human 
Hyaluronidase, HYQVIA
Submission Date: April 29, 2014
Manufacturer: Baxter Healthcare Corporation

Recommendation:

The combination product HyQvia consists of Immune Globulin Infusion, 10% with a 
dispersion enhancer, recombinant human hyaluronidase (rHuPH20). During clinical 
trial, an unexpectedly high incidence of PH20-directed antibodies was observed 
in PID patients receiving HyQvia. No specific adverse event profile was 
associated with anti-PH20 antibody formation during the clinical study. However, 
CBER requested additional information to help understand the potential clinical 
significance of chronic exposure to PH20-directed antibodies.

In the current electronic submission, the Sponsor has provided additional new 
information relevant to potential risks associated with the anti-PH20 
antibodies. The new information includes:

1) Final reports for two preclinical studies in mice. The Sponsor evaluated 
neurological development and behavior in PH20 knockout mice. The Sponsor also 
evaluated PH20 expression in a mouse model of EAE, using reagents that are 
different from those used by the ---(b)(4)------. The Sponsor reports no PH20 
expression in the brain and no impact of PH20 deficiency on neurobehavioral 
development in the mouse.

2) The Sponsor evaluated the effect of hyaluronidase from tissue extract (not 
recombinant human PH20) on oligodendrocyte progenitor cell myelination. The 
Sponsor indicates that impurities in the preparation are responsible for the 
observed inhibition of myelination activity. Both items (1) and (2) are 
different from the observations of the ---(b)(4)------.

3) An interim summary of non-GLP assessment of PH20 transcripts in various 
normal tissues from mouse, human, and rabbit using -----(b)(4)------------ RNA 
sequencing.

4) An opinion written by Joy Cavagnaro, PhD, a biotechnology consultant 
specializing in preclinical data but not in hyaluronidase particularly. Dr. 
Cavagnaro' writes that Halozyme's extensive data refute the 
------(b)(4)------------------- findings re: PH20 expression and function in 
nerve tissue, and the in vivo preclinical studies together suggest that there is 
no risk associated with PH20 antibodies.

5) A safety update for study 160902, for patients receiving HyQvia out to 36 
months.

4) A poster regarding prevalence of preexisting low titer anti-PH20 antibodies 
in the general population. Incidence is listed as 5%.

5) A new package insert, which has several sentences regarding immunogenicity

The new information package is contains a substantial amount of new data not 
previously submitted to the Agency, and new analysis of studies not previously 
submitted to the pending supplement, and thus meets the definition of a Major 
Amendment in accordance with CBER SOPP 8402.

The new information spans several review disciplines. The review team will also 
need additional time to seek more input from SGEs, and to decide whether review 
by BPAC is warranted in the current review period. For these reasons it is 
recommended that 125402/35 should be classified as a Major Information 
Amendment.
 

    
 


