	  Fractionated Plasma Products > Major Amendment: Tissue Cross Reactivity 
Study Comments to Sponsor Memo, June 1, 2012 - Hyqvia                  
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Major Amendment: Tissue Cross Reactivity Study Comments to Sponsor Memo, June 1, 
2012 - Hyqvia




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MEMORANDUM

Date: 6.1.2012

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

To: File for BLA 125402/21

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: Mark Shields; CBER/OBRR/DBA; HFM-380; 301-827-6173

Subject: Major Amendment: Tissue Cross Reactivity Study
Product: Immune Globulin Infusion (Human), 10% with Recombinant Human 
Hyaluronidase: HYQVIA
Submission Date: March 1, 2012
Manufacturer: Baxter Healthcare Corporation

Recommendation:
The Sponsor has not provided a preclinical toxicology proposal to address PH20 
related immunogenicity issues, as had been requested. Instead the Sponsor has 
compiled some retrospective analysis of toxicology study plasma, some tissue 
analysis intended to counter the GLP immunohistochemical study previously 
submitted, and more literature review, in an attempt to call into question 
immunogenicity issues that have been raised. None of the information the Sponsor 
proposes to share with us this month addresses the specific safety issues we 
have raised regarding the impact of elevated PH20-directed antibodies on GI and 
reproductive tissue development in the fetus and during childhood. While the 
Sponsor is certainly free to collect this information, a face-to-face meeting to 
discuss the results is not warranted prior to the action due date. The results 
instead should be submitted along with the preclinical toxicology study 
proposals to address immunogenicity concerns.

The following letter-ready comments may be communicated to the Sponsor:

The Stage 1 studies you outline may provide useful information to support your 
proposed Stage 2 preclinical toxicology proposals. We have the following points:
  In your evaluation of relevant preclinical models, please examine whether 
  hyaluronidase expression occurs in enteric plexus in addition to male 
  reproductive tissue.
  In 6.1.1, please indicate which characteristics you intend to compare between 
  cross-reactive and treatment-emergent antibodies. Examples may include 
  subclass, determination of whether these two types of antibodies react with 
  the same epitopes on rHuPH20 and tissues, affinity for rHuPH20, and other 
  characteristics. Measures of antibody comparability and sources of antibody 
  preparations for study should be defined and justified in advance of the 
  study. Cross-reactive antibodies in IGIV given to pregnant women would be 
  present in substantially lower levels than are treatment-emergent antibodies, 
  limiting the value of current human safety data for IGIV in pregnant women. We 
  note that autoantibody levels correlate with disease severity in some 
  situations (such as anti-C1Q antibodies in lupus nephritis). Since 
  cross-reactive and treatment-emergent antibodies may have qualitative 
  differences as well, absence of fetal or developmental effects will not be 
  probative of treatment-emergent antibody safety. Your proposal is that tissue 
  binding by both types of antibodies, if these have comparable characteristics 
  would obviate concerns. We do not agree, not least because of the magnitude of 
  differences in levels of antibodies.
  In 6.1.2, we agree that these studies may be useful, but they do not address 
  the question of developmental toxicities.
  In 6.1.3, we note that in mice, little if any transplacental transfer of IgG 
  antibodies occurs, limiting the usefulness of this species for your proposed 
  studies if you intend to assess the impact on fetal development.

Review:
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. The additional 
information included an immunohistochemical analysis of anti-PH20 antibody 
binding to a panel of normal human tissues. Specific binding to both male 
reproductive tissue and enteric plexi of the male and female GI tract were 
observed. In April 2012, CBER requested that the Sponsor propose new preclinical 
studies to address potential safety issues associated with increased 
hyaluronidase antibody levels. Particular concerns included the impact of 
transplacental transfer of elevated anti-PH20 levels on enteric plexus and/or 
reproductive tissue development in the fetus; and the impact of elevated 
anti-PH20 levels on reproductive and GI development during childhood.

Review:
In the current, brief electronic submission, the Sponsor does not provide 
proposals for preclinical toxicology studies as requested. Instead, the Sponsor 
proposes a “staged approach” in addressing our immunogenicity concerns.

In Stage 1, which appears to have already been initiated, the Sponsor proposes 
the following activities:

A) The Sponsor will obtain or has already obtained human reproductive tissue and 
enteric plexus tissue for qPCR and monoclonal antibody staining, to confirm that 
PH20 is expressed. If the tissues were found to be negative, this would call 
into question the results of the Sponsor’s previous immunogenicity study. The 
Sponsor might claim that staining observed with the highly-specific, 
experimental PH20 directed antibody preparation could have been directed against 
some non-specific contaminant rather than PH20 itself. A negative result in qPCR 
or with mAb staining should not abrogate the positive staining with anti-PH20 
pAb that Baxter already submitted in a GLP study. Failure to detect PH20 message 
might reflect poor tissue preparation or other technical issue.

B) The Sponsor will do, or has already performed, new tissue cross reactivity 
study, to see if anti-PH20 antibodies from clinical study samples and Gammagard 
liquid bind to PH20 in reproductive tissue and enteric plexus. CBER had asked 
the Sponsor to perform this study previously, but the Sponsor declined citing 
technical issues. The Sponsor now states that if clinical samples and GGL fail 
to bind PH20 in tissue, this will suggest lower risk. A negative result with GGL 
and/or clinical study samples might reflect technical issues previously cited by 
the Sponsor. Of itself this data set would not set aside concerns about 
immunogenicity.

C) The Sponsor will retrospectively analyze (or has already analyzed) plasma 
samples from the developmental and reproductive toxicology study in mice, to 
determine if, and when, maternal anti-PH20 was transferred to the fetus. The 
Sponsor argues that if anti-PH20 transfer had occurred, the data from the 
existing study may provide evidence that PH20 binding antibodies do not 
adversely impact development. Ideally the Sponsor would have collected this 
information during the vetting of the model and submitted it to the BLA 
previously. The likelihood of useful data emerging from this retrospective 
analysis is low.

D) The Sponsor will assess whether anti-PH20 antibodies developed in different 
species will bind to endogenous PH20 in reproductive tissue and enteric plexus. 
The submission does not discuss whether human PH20 is being used to immunize the 
different species, or a recombinant version of endogenous PH20 for the species, 
or natural PH20 from tissue extract. This data set will be essential for 
justifying new preclinical toxicology studies, when the proposals are submitted.

E) The Sponsor will share interim safety data from ongoing clinical study 
160902. While such an update will be useful, the lack of a safety signal related 
to reproductive or GI health would not be definitive given the shortcomings of 
adverse event collection previously discussed with the Sponsor.

F) The Sponsor will perform, or has already performed, another literature review 
to discuss whether treatment of pregnant women with normal IGIV (which contains 
some amount of anti-PH20) has any effect on fetal development. The lack of 
record of safety signals for IGIV use during fetal development doesn't address 
the issue of elevated PH20-directed antibodies.

The Sponsor proposes to submit some amount of data gathered in activities A-F 
above within the next months. The Sponsor wants to discuss this information in a 
face-to-face meeting 3 weeks before the action-due date. The Sponsor 
specifically wants to know if the information collected is “adequate”, and 
states that new toxicology proposals will not be submitted until after the 
face-to-face meeting.

The Sponsor has not provided a preclinical toxicology proposal to address PH20 
related immunogenicity issues, as had been requested None of the information the 
Sponsor proposes to share with us this month addresses the specific safety 
issues we have raised regarding the impact of elevated PH20-directed antibodies 
on GI and reproductive tissue development in the fetus and during childhood.
 

    
 


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