

Record of Telephone Conversation, November 23, 2011 - Hyqvia




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(System Info - 186971 SHIELDS MARK 01/10/2012 09:05:30 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: 23-Nov-2011 10:00 AM        Initiated by FDA? No
 Telephone Number: 
 Communication Categorie(s):
 1. Other - Study Design

 Author: MARK SHIELDS
 Telecon Summary:
 To discuss the study synopsis developed to evaluate the binding of anti-rHuPH20 
antibodies in a normal tissue panel (tissue cross rectivity study) and discuss 
the proposed study design.
 FDA Participants: 
 Basil Golding
 Bhanu Kannan
 Michael Kennedy
 Alpita Popat
 Jennifer Reed
 Dorothy Scott
 Mark Shields

Baxter Attendees:
 Angela Blackshere
 Maurus de la Rosa
 Barbara Dietrich
 Aiko Maruya
 Richard Schiff
 Hans Peter Schwarz

Halozyme Attendees:
 Don Kennard
 Mike LaBarre
 Dan Maneval
 Barry Sugarman
 Mary Wilhelm
 Trans-BLA Group: No

 Related STNs: None
 Related PMCs: None

Telecon Body:
 Ms. Blackshere started the meeting by thanking FDA for the opportunity to meet. 
Introductions of the FDA attendees on the line were followed by Baxter and 
Halozyme’s introduction of their attendees. Ms. Blackshere handed the discussion 
over to Mr. Kennard to address FDA’s 22 November 2011 comments regarding the 
proposed study with--(b)(4)--, “Immunohistochemical analysis of the 
cross-reactivity of a ---(b)(4)------ anti-rHuPH20 antibody in human tissues.”

Mr. Kennard thanked the division for their comments regarding the study 
synopsis. He indicated that as some of the proposed modifications to the methods 
for characterization of PH20 reactive antibodies would require methods 
development with technical challenges and uncertain timelines, Halozyme wanted 
to discuss several of the technical points and propose some alternative 
solutions.

 Dr. LaBarre acknowledged FDA’s agreement with the proposed human tissue array 
study synopsis. He went on to address the additional comments that were provided 
in FDA’s email dated 22 November 2011. Inclusion of pooled plasma samples from 
patients treated with rHuPH20 in the --(b)(4)-- tissue cross-reactivity study 
presents a number of technical challenges. The primary concern for using pooled 
human plasma on human tissue arrays is the high background expected due to 
cross-reactivity of endogenous human IgG and IgG epitopes. Preliminary 
discussions with ---(b)(4)-- indicated there are ways that this experiment could 
be approached, but that these options will require extensive method development 
and large pooled plasma sample volumes, which may not be timely or feasible. 
Another method that could be attempted is to use various cross-species 
-------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------.o
He noted that the PH20 reactive antibodies present in the control population 
would make development of this analytic approach very difficult, and results 
would be confounded by false positives caused by the background PH20 reactive 
antibodies inherent to IgG replacement therapy. Due to these considerations, he 
proposed performing the tissue cross reactivity study using the previously 
described polyclonal rabbit anti-PH20 antibody, 
-----------------------------(b)(4)-------------------------------------------------------------------------------------------------.o
Halozyme has already demonstrated that the rabbit polyclonal antibody contains 
high-affinity antibodies and as such is a suitable reagent for this study.

 Dr. Reed thanked Baxter and Halozyme for the thought that went into the 
agency’s questions within a short period of time. She acknowledged that the 
proposed tissue cross reactivity study accomplishes the intent of pinpointing 
which tissues express endogenous PH20.  Dr. Reed indicated interest in the 
number of PID patients’ antibody titer’s that boosted during the 160603 study 
over the background 1:160 titer that may result from passive transfer. The 
agency is encouraged that none of the antibodies generated are neutralizing, but 
inquired if there were any new epitopes that were generated that were also cross 
reactive. As she was uncertain as to whether the rabbit anti-rHuPH20 polyclonal 
or mouse anti-rHuPH20 the monoclonal would address this issue, Dr. Reed asked if 
the technical issues could be overcome by pooling only the plasma samples with 
the highest titers and asked about the amount of patient plasma samples that are 
remaining. 

 Dr. Schiff stated that there was approximately two milliliters of sample per 
subject available, which isn’t sufficient for affinity purification. In 
addition, Dr. Schiff said titers on some patients have begun to recover (i.e., 
come down over time) despite continued treatment.

 Dr. Reed indicated that the bridging assay might be used to differentiate 
between the cross-reactivity of the higher titer patient samples from the low or 
no titer patient samples. Dr. LaBarre responded that it may be possible to 
address cross-reactivity of rHuPH20 reactive antibodies to other hyaluronidases 
using a competitive bridging format.  Dr. Reed said she would also think about 
alternative approaches and provide feedback.

 Dr. Reed asked about the status of the development of assays for antibody 
isotypes. Dr. Sugarman stated that the approach has been an event-driven mode 
for tiered testing and thus we have developed an assay for human (b)(4) specific 
for rHuPH20. However, Dr. Sugarman said that Halozyme has worked on the assays 
for IgM and IgG but wasn’t satisfied with the degree of sensitivity or 
robustness. Dr. Reed would also be interested to know the distribution of IgG 
and IgM isotypes to understand potential sequalae of what types of inflammatory 
processes could be engaged if there was deposition of these antibodies in 
various tissues. Dr. LaBarre indicated that there’s information available that 
will be helpful relative to the mechanism and pathway of the isotypes 
--------------------------------------------------------(b)(4)-------------------------------------------.s
Dr. Reed said this was promising information and that the --(b)(4)-- study was a 
good start. She asked if Halozyme could provide a summary of what parameters 
they are looking at and what are the technical challenges.



 Ms. Blackshere asked if these questions were postmarketing concerns. Dr. Reed 
responded that the information from the --(b)(4)-- study is needed in the near 
term and wondered about the timing of the study. Ms. Blackshere indicated that 
the complete          ---(b)(4)-- study would be available mid to end of March. 
Dr. Golding replied that an additional 3 months could be added to the review 
cycle if data not received earlier. Dr. Sugarman clarified that Phase 1 of the 
study would be completed by the end of January and would include optimization of 
the methods and positive and negative control tissues with the rabbit 
polyclonal. Dr. Reed agreed this approach was reasonable, but even with the 
negative control panel in Phase 1, FDA would need time to look at the Phase 2 
study. Dr. LaBarre replied that the final report would be available the end of 
March, but that raw data could be provided earlier. It was agreed that the 
earlier the report could be available the better and that efforts will be made 
to advance the --(b)(4)-- report to February to give FDA adequate time to review 
before the April PDUFA date.  Dr. Scott agreed that an interim report would be 
good and asked about reproductive tissues. Baxter and Halozyme had very recently 
(November 18) received a set of specific questions from FDA related to this 
topic. Dr. Maneval indicated that a written response to the toxicology and 
nonclinical questions would be sent by 16 December 2011.

 Dr. Golding indicated that the question of tissue cross-reactivity was 
important; with a focus on gonads and that a full data set is needed. Dr. 
LaBarre said that the information to be provided in the December 16th response 
will address information related to gonads. Dr. Reed said the faster we can get 
a response to the recent toxicology questions and the interim data the better. 
Ms. Blackshere requested that once we submit the information that Baxter would 
like to have another teleconference to see if the information is meeting FDA’s 
needs. FDA agreed.

 Dr. Scott asked whether or not testing of human plasma is possible in a tissue 
cross reactivity format, considering the interference that could result from 
background levels of rHuPH20 reactive antibodies that would be in all patient 
plasma samples. There was a discussion of whether or not running an assay with 
background problems is feasible without a negative control (i.e., Dr. LaBarre 
indicated that approximately 5-10% normal healthy volunteers have background 
reactive binding antibodies to rHuPH20).

 Dr. Sugarman said that the rHuPH20-reactive binding antibodies in Gammagard 
were of the ----(b)(4)------- isotypes. Dr. Reed asked for Halozyme to provide a 
summary of assays for developing isotypes. She requested that we send responses 
to the toxicology and nonclinical questions and a summary of assay development 
regarding isotyping of PH20 antibodies in patient plasma.

 Dr. Reed continued that FDA reviewed the  immunogenicity risk assessment and 
references submitted in the BLA, but feels there is not sufficient clarity 
regarding expression in female tissues (e.g., breast) and chondrocytes.  
Furthermore, the likelihood of cross-reactivity of an anti-PH20 antibody may be 
higher than predicted and FDA still has questions regarding fertility, so 
additional information is needed. 

Dr. Reed was also interested in tissues that express PH20 because they could be 
where the deposition of rHuPH20-reactive antibodies occurs. She was especially 
interested in the results from the proposed --(b)(4)-- TCR study which will 
identify tissues in females that express PH20 as well as chondrocytes where 
other hyaluronidases are expressed. With data that may indicate patient antibody 
titer boosting during the clinical study we [FDA] began to question the 
possibility for epitope spreading and thus the potential for changes in tissue 
deposition of rHuPH20-reactive antibodies. Dr. LaBarre indicated that a review 
of the long term toxicology study will also address these concerns and will be 
part of the December response. Halozyme is also in collaboration with an 
investigator at -------(b)(4)- that is evaluating effects in ---(b)(4)---- 
monkeys. A summary of this information will also be provided in the December 
response. It was requested that Dr. Reed send a summary of her concerns on the 
anti-PH20 antibodies and Dr. Reed agreed. Ms. Blackshere ended the call by 
thanking FDA for their time and reviewing the action items.

Follow-up Action Items:
  Halozyme to provide a summary of isotyping assays for rHuPH20-specific 
  antibodies in the response to FDA’s nonclinical and toxicology questions due 
  to FDA by 16 December 2011.
  Halozyme to provide Phase I --(b)(4)-- study data by January 2012, rabbit 
  anti-rHuPH20 tables listing and figures from Phase II --(b)(4)-- study by 
  early February 2012 and final --(b)(4)-- study report no later than the end of 
  February 2012.
  Baxter to schedule a teleconference with FDA the week of 23 January 2012 after 
  submission of the response to FDA’s RFI (comprehensive toxicology review) by 
  16 December 2011 to get FDA feedback on the response as well as to discuss the 
  progress on the tissue cross-reactivity study.
  Dr. Reed to provide Baxter and Halozyme with a summary of FDA concerns 
  regarding rHuPH20 reactive antibodies, the potential for expanded epitope 
  involvement and tissue distribution. Dr. Reed also said she would provide 
  feedback on alternative approaches to address FDA’s request #1 in the 22 
  November 2011 email.  Although a timeline was not defined in the 
  teleconference, Baxter respectfully requests the written summary and feedback 
  by 21 December 2011.
  Halozyme to use a modification of the current bridging immunoassay used for 
  detecting rHuPH20-reactive antibodies in human plasma to assess 
  cross-reactivity of these antibodies with other recombinant human 
  hyaluronidases compared to naturally occurring PH20 reactive antibodies. The 
  competitive format of this assay will use ------------------(b)(4)).  These 
  data will be provided by mid-February and should address FDA’s requests #1 and 
  #2 in the 22 November 2011 email.
 

    