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From: Blackshere, Angela L [Angela_Blackshere@baxter.com]
Sent: Wednesday, December 21, 2011 11:48 AM
To: Shields, Mark
Cc: Maruya, Aiko
Subject: RE: 125402/0 Immunogenicity comments - Baxter Immune Globulin Infusion 
(Human), 10% with Recombinant Human Hyaluronidase

Dear Mark:

I acknowledge receipt of the below correspondence.

Happy Holidays,

Angela

*************************************

Angela Blackshere
Sr. Director, Global Regulatory Affairs
Baxter Healthcare Corporation, Baxter BioScience
One Baxter Way
Westlake Village, CA 91362
(805) 372-3050/Phone
(805) 372-3052/Fax
angela_blackshere@baxter.com

 

From: Shields, Mark [mailto:Mark.Shields@fda.hhs.gov]
Sent: Wednesday, December 21, 2011 8:09 AM
To: Maruya, Aiko
Cc: Blackshere, Angela L
Subject: 125402/0 Immunogenicity comments - Baxter Immune Globulin Infusion 
(Human), 10% with Recombinant Human Hyaluronidase

Dear Ms. Maruya:

Please acknowledge receipt.

In our teleconference on November 23, 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)--------------------------------------------------------------------------o
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.

Please address any comments as an amendment to this file, STN 125402/0 .

Best Regards,

Mark A. Shields RAC
Regulatory Project Manager
HFM-380 FDA/CBER
Office of Blood Research and Review
Division of Blood Applications
301-827-6173 fax 301-827-2857
email: mark.shields@fda.hhs.gov
1401 Rockville Pike
Rockville, MD 20852-1448

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