Information Request Email, April 11, 2012 - Hyqvia




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From: Reed, Jennifer
Sent: Wednesday, April 11, 2012 4:57 PM
To: 'Blackshere, Angela L'; Scott, Dorothy
Cc: Shields, Mark
Subject: Information request: Immunogenicity Issues

Dear Angela,
As we discussed at the most recent tcon, below please find an information 
request pertaining to immunogenicity of rHuPH20.

Best regards, 
Jen

________________________________________________
 

I. We have outstanding concerns about immunogenicity of rHuPH20, specifically 
the toxicology data provided is not sufficient to address our concerns about the 
effect of anti-rHuPH20 antibodies on developing male reproductive tissue and on 
enteric plexus.  We note that rHuPH20 if licensed could be administered for 
extended periods of time to patients, including women who are or may become 
pregnant and pediatric populations.  Our concerns are enhanced by the potential 
for long-term chronic use, particularly in pediatric populations.

a. Enteric plexus 
i. There is insufficient evidence that the PH20 expressed in the enteric 
neuronal plexus is cytoplasmic or that the neuronal plexus is an immune 
privileged site.  Recent evidence suggests the importance of hyaluronan in 
migration and differentiation of neuronal cells (Sherman and Preston, Front. 
Biosci. 3:1165-79, 2012), increasing concerns about possible clinical effects of 
antibody development. 

ii. The impact of elevated levels of transplacental maternal PH20 directed 
antibodies on neuronal development in the fetus is unknown.

iii. The impact of elevated levels of PH20 directed antibodies in childhood on 
neuronal development and plasticity, as well as the effect of chronic exposure 
to elevated levels of PH20 directed antibodies is unknown. 

b. Male reproductive tissue 
i. The developmental impact of elevated levels of transplacental maternal PH20 
directed antibodies on the fetus is unknown

ii. The developmental impact of elevated levels of PH20 directed antibodies in 
childhood development is unknown

II. Baxter should propose preclinical studies in relevant animal species and/or 
clinical studies to address these issues.

III. FDA plans to seek advice concerning what data could reasonably address our 
immunogenicity concerns, from the Blood Products Advisory Committee, and would 
welcome Baxter’s participation.

Jennifer L. Reed, Ph.D.
Biologist / Team Leader
US Food and Drug Administration
29 Lincoln Drive, HFM-345 Room 302
Bethesda, MD  20892
301.496.0625 phone
301.402.2780 fax
jennifer.reed@fda.hhs.gov
 

    