Information Request Email, April 16, 2013 - Hyqvia



 
From: Blackshere, Angela L [Angela_Blackshere@baxter.com]
Sent: Tuesday, April 16, 2013 8:52 PM
To: Shields, Mark
Cc: Shah, Alpa; Reed, Jennifer
Subject: RE: 125402/0/26 CRMTS 8779 Immune Globulin Infusion( Human), 10% 
(rHuPH20)

Dear Mark:

I confirm receipt of FDA’s below comments and request for additional 
information.

Thank you and best regards,

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: Tuesday, April 16, 2013 12:19 PM
To: Blackshere, Angela L
Cc: Shah, Alpa; Reed, Jennifer
Subject: 125402/0/26 CRMTS 8779 Immune Globulin Infusion( Human), 10% (rHuPH20)

Hi Angela,

Please acknowledge receipt.

Please see the comments and request for additional information regarding our 
telecon scheduled for May 1, 2013.  Kindly respond at your earliest convenience.

1)  Please provide an update on clinical trial experience of rHuPH20 used as a 
permeation enhancer for chronic subcutaneous biologics treatments in other 
ongoing clinical trials.  Specifically, is immunogenicity of rHuPH20 a 
consistent finding?  What adverse events if any have been associated with the 
development of PH20-directed antibodies in other trials?

2)  You stated that based on additional studies, you have concluded that PH20 is 
not expressed in enteric plexus or in CNS.  Please submit additional information 
regarding the IHC, RT-PCR and in situ procedures you used to reach this 
conclusion.  What positive controls were used to demonstrate sensitivity of 
these assays for detecting progenitor cell antigens and transcripts?

3)  Your conclusion that PH20 is not expressed in CNS or enteric plexus appears 
to be based on assessments made in baseline, normal tissues obtained from 
adults.  Since PH20 expression may be enhanced in progenitor cell types (Preston 
2013), use of gut tissues that have enhanced numbers of progenitors such as 
post-natal tissues (Metzger et al Gastroenterology 2009) may increase the 
sensitivity of your detection approach and help to increase confidence in your 
conclusion.  We note that Preston and coworkers (2013) successfully documented 
PH20 expression in active CNS lesions of MS patients and in mice with EAE.  In 
both instances oligodendrocyte precursors were more numerous than in baseline 
tissues.  Please comment.

4)  Please provide additional information on the studies you performed in SPAM1 
knockout mice. Since expression of Hyal1 and Hyal2 has been reported in corpus 
callosum and purified OPCs (Preston 2013), it seems possible that these might be 
able to compensate for constitutive deletion of SPAM1 during neurological 
development.  Please comment.  Has an EAE model been performed using mice with 
constitutive SPAM1 deletion?  Have you investigated whether an inducible SPAM1 
knockout mouse is available for study?

5) Have you evaluated PH20 expression in enteric plexus and/or CNS of monkeys or 
rabbits, either at baseline or in models featuring injury and damage?

6) For your CR letter response, please submit:
  Details of Halozyme’s studies on enteric plexus samples, including details of 
  antibody preparations used (commercial sources, how patient plasma was 
  selected for IgG purification), and more details about the “specific 
  laboratory reagent” believed to be responsible for positive staining.
  Results of GLP pregnancy studies, in utero antibody exposure in rabbits study, 
  and male rabbit fertility study.
  Sensitivity testing and positive controls for tissue staining and PCR 
  detection of rHuPH20.

END

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 301-827-2405 
email: mark.shields@fda.hhs.gov 
1401 Rockville Pike 
Rockville, MD 20852-1448

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