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Additional Immunogenicity Comments for Sponsor Memo, December 2, 2011 - Hyqvia




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MEMORANDUM

Date: 12.2.2011

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

To: File for BLA 125402/0

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: Additional Immunogenicity Comments for Sponsor Post-tcon
Product: Immune Globulin Infusion (Human), 10% with Recombinant Human 
Hyaluronidase: HYQVIA
Submission Date: November 29, 2011
Manufacturer: Baxter Healthcare Corporation

Product Information:
The proposed product is Immune Globulin Infusion (Human), 10% (IGI, 10%) with 
recombinant human hyaluronidase (rHuPH20), intended for the treatment of 
patients with primary immunodeficiency (PI) with defects in humoral immunity.

The combination product contains one vial of rHuPH20 and one vial of IGI, 10% 
for sequential administration. Hyaluronidase pretreatment of the injection site 
is intended to allow patients to receive a monthly dose of IGI, 10%, in a single 
subcutaneous injection. The proposed combination product, if approved, would be 
the first FDA-licensed chronic use of a hyaluronidase permeation enhancer in 
combination with a biologic product.

An issue of potential concern is the apparently high percentage of combination 
product recipients who have elevated anti-rHuPH20 antibody levels. A tcon with 
the Sponsor was conducted on November 29, 2011 to discuss a GLP tissue 
cross-reactivity study. The planned study is intended to clarify tissue 
expression of endogenous PH20 in human males and females. During discussion of 
the tissue cross reactivity study parameters, the Sponsor requested a summary of 
the Division’s concerns regarding immmunogenicity risk posed by rHuPH20. The 
letter-ready summary of our immunogenicity concerns appears below.

Recommendation

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

In our teleconference on November 29, 2011, you asked for a summary of our 
thoughts and concerns regarding immunogenicity of rHuPH20, in order to clarify 
the context and rationale for additional studies. In this regard, the following 
comments and possible issues have been raised during the ongoing review of your 
BLA submission125402.

Study report 10059:

Immunogenicity Assessment and Risk Management Recommendation for Recombinant 
Human Hyaluronidase PH20 (rHuPH20)

Page 11, paragraph 1-2: You stated that safety concerns associated with 
hyaluronidase preparations from animal extracts were due to animal origin and 
lack of purity of the preparations. You also suggested the possibility that 
rHuPH20 would be less immunogenic than animal-derived hyaluronidases based on 
increased purity and human rather than animal protein sequence. We noted that a 
systematic comparison of immunogenic responses to recombinant human 
hyaluronidase versus an animal-derived preparation hasn’t been done to 
substantiate this hypothesis more completely.

Page 12, paragraph 2 and Table 2, and page 21: You emphasize that human 
hyaluronidases are between 33 and 42% identical overall, and that risk of 
anti-PH20 antibodies reacting with “distally related” tissue hyaluronidases is 
low. However, we analyzed the human hyaluronidases based on peptide regions 
proposed by Chan and coworkers working in the guinea pig model (Life Science 64: 
1989-2000). The highly immunogenic peptide 3 identified by Chan and coworkers 
appears 63-80% identical among human hyaluronidases. Thus the risk of anti-PH20 
antibodies binding to more highly conserved regions of other human 
hyaluronidases may be worth investigating further.

Page 21, Safety Risk Categories: We are not entirely convinced of your assertion 
on page 12 regarding the redundancy of tissue hyaluronidases, since disease in 
humans has been associated with Hyal1 deficiency (Imundo and coworkers, J Inheri 
Metab Dis 24: 1013-22), and at there is at least proof-of-concept data 
suggesting a unique role for Hyal2 in a genetically defined mouse model (Jadin 
and coworkers, FASEB J 22: 4316-26).

Page 24, in -----(b)(4)----: You show that PH20 is not particularly immunogenic 
based on ----(b)(4)------- modeling. How does this information comport with your 
finding of rHuP20 reactive antibodies in IGI, 10%, manufactured from normal 
human plasma?

Pages 26-28: You acknowledge that the rHuPh20 product contains host cell 
proteins 
------------(b)(4)-------------------------------------------------------------------------------.
forms which increase as rHuPH20 degrades. This section of your immunogenicity 
assessment should include a discussion of how your manufacturing process and 
recommended storage conditions were designed to limit patient exposure to 
potentially immunogenic process- and product-related contaminants.

Page 32, Role of endogenous PH20 and consequences of loss of function: You 
listed three references as evidence that PH20 is expressed in females. The first 
(Beech et al 2002) is an mRNA study that did not confirm PH20 protein expression 
in breast tissue. The second study (El Hajjaji et al, 2005) does not clarify how 
many samples of ex vivo expanded synoviocyte samples were evaluated for PH20 
mRNA. It isn’t clear whether rabbit antibodies raised against a PH20 peptide 
could possibly be reactive with Hyal1 or Hyal2, thus positive identification of 
PH20 in these samples is incomplete. The third reference (Zhang et al 2003) 
demonstrates PH20 expression in the female reproductive tract of mice. While 
similar expression of PH20 may occur in reproductive tissue of humans, this 
hasn’t been shown to our knowledge. Later you supplied to us some online IHC 
information from --------------------------(b)(4)------------ suggesting PH20 
may be expressed to some degree in non-reproductive tissue including 
gastrointestinal tissue and bronchial epithelium. Our own experience with data 
provided by the ---(b)(4)----- website is that the information is provided 
primarily for advertising purposes and there is no particular assurance of 
quality. We feel that additional information is required particularly to clarify 
PH20 antigen experience in women, and to help understand which tissues would be 
theoretically targeted by PH20-directed antibodies.

Page 37, Role of PH20 in fertility:

1) We feel that the clinical data to date point to the potential for a role of 
PH20 in human fertility. We are not entirely convinced by your statement that 
“the preponderance of preclinical data suggests that administration of rHuPH20 
and de novo generation of anti-rHuPH20 antibodies is unlikely to impair 
fertility.” It is unclear which of the animal models studied is most predictive 
of the role of PH20 in human fertility.

Page 38, paragraph 1: We are not convinced that joint abnormalities in Hyal1 
deficient patients constitute a mild condition. This section would be improved 
by a discussion of the potential for deposition in tissue of PH20-directed 
antibodies which are cross-reactive with other human hyaluronidases, and the 
possibility of enhanced inflammation.
 

    
 


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