
  


Record of Telephone Conversation, April 5, 2012 - Hyqvia




  

 
(System Info - 196112 SHIELDS MARK 04/09/2012 10:01:09 SHIELDSM)

RECORD OF TELEPHONE CONVERSATION

Submission Type: BLA Submission ID: 125402/0 Office: OBRR

Product:
 Immune Globulin Infusion (Human), 10% with Recombinant Human Hyaluronidase

Applicant:
 Baxter Healthcare Corporation

Telecon Date/Time: 05-Apr-2012 1:38 PM Initiated by FDA? Yes

Telephone Number:

Communication Categorie(s):
 1. Advice

 Author: MARK SHIELDS

Telecon Summary:
 Concerns with Immunogenicity

FDA Participants:

Basil Golding, Nisha Jain, Dorothy Scott, Jenifer Reed, Eva Struble, Laurence 
Landow, Mark Shields

Non-FDA Participants:

Baxter:
 Angela Blackshere, Sr. Director, Regulatory Affairs
 Hartmut Ehrlich, M.D., VP, Research and Development
 David Gelmont, M.D., Head, BioTherapeutics Clinical Research 
 Douglas Hunt, VP, Regulatory Affairs
 Julie Kim, MS, General Manager, BioTherapeutics
 Richard Schiff, M.D., Ph.D., BioTherapeutics
 Hans-Peter Schwarz, M.D., VP, BioTherapeutics Research and Development
 Don Baker, Ph.D., Baxter Contractor, Industry BPAC Alternate Member

Halozyme
 Gregory I. Frost, Ph.D., President and CEO
 Don A. Kennard, VP, Regulatory Affairs and Quality Assurance
 Barry J. Sugarman, Ph.D., Executive Director, Translational Technology
 Douglas B. Muchmore, M.D., Vice President, Endocrinology Clinical Development
 Daniel C. Maneval, Ph.D., VP, Pharmacology and Safety Assessment 
 
--------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------

Trans-BLA Group: No

Related STNs: None

Related PMCs: None

Telecon Body:
  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. Enteric 
    plexus 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.
      The impact of transplacental maternal high-titer antibodies on neuronal 
      development in the fetus is unknown
      The impact of high-titer antibodies in childhood on neuronal development 
      and plasticity, as well as the effect of chronic exposure to high titer 
      antibodies is unknown

    Male reproductive tissue The developmental impact of transplacental 
      maternal high-titer antibodies on the fetus is unknown
      The developmental impact of high-titer antibodies in childhood development 
      is unknown


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

FDA noted that there could be labeling restrictions if the product goes to 
approval including labeling restrictions for use in adults of reproductive age 
and pediatric use.

FDA noted that these are pre-marketing concerns that can't be satisfied with 
post marketing studies.

Baxter briefly presented additional comments regarding assay details, 
sensitivity and comparison of results between different assays, and stated that 
the ECL assay for antibodies is up to -----(b)(4)-------------- than 
conventional -----(b)(4)--- tests. Baxter commented that they have had no 
spontaneous reporting of clinical problems in patients who have received 
repeated doses of PH20. Baxter made reference to analysis of anti-PH20 
antibodies in serum samples from other, ongoing clinical studies in which 
repeated doses of Hylenex were administered either paired with 
---------(b)(4)-------------------------------------------------------, or 
administered to aid subcutaneous hydration. In these other studies, using a less 
sensitive immunogenicity assay, Baxter stated that the highest responses to PH20 
were only -(b)(4)- over background. [For comparison, note that in study 160603, 
boosted responses up to --(b)(4)-- over background were shown using Baxter's 
improved immunogenicity assay. Note also that these data have not yet been 
provided to FDA.]

FDA stated that if Baxter believes that anti-PH20 antibody levels are similarly 
low among patient groups receiving Hylenex, there is a need for side-by-side 
comparisons using the same immunogenicity assay. FDA suggested that there may be 
unique issues with this particular combination product. The presentation of 
recombinant PH20 with anti-PH20 antibodies in IGSC could elicit unique immune 
and/or inflammatory responses. FDA commented that the length of time required 
for adverse event monitoring is unknown. Neonates and children may require years 
of followup to monitor effects of anti-PH20 on reproductive or GI function.

Baxter stated that additional followup data in the extension study [for HyQvia] 
is available, and that anti-PH20 titers decreased in some patients over time, 
this data can be submitted. Baxter emphasized that in no trials have 
neutralizing antibodies been detected, and that research suggests anti-PH20 
antibodies target the C-terminal region of PH20, not the catalytic site. Epitope 
spreading is under study.

FDA enquired if any clinical studies have been preformed in pediatric 
populations or with pregnant women. Baxter replied that they have some pediatric 
data from a pediatric -----------------------(b)(4)----------------------. Some 
pregnant woman have been exposed in the –(b)(4)---- studies, which were protocol 
violations. In those cases successful pregnancies ensued. In one ---(b)(4) + 
PH20 study, some patients have received PH20 for as much as 2 years.

FDA plans to send Baxter a formal Information Request letter regarding these 
issues within one week of this telecon.

End
 

    
 


