Increasing  Clinical  Use  of  IVIG  –  Threats  and  Opportunities  

Travis  A.  Miller,  MD,  FACAAI,  FAAAAI,  FAAP,  D-­‐ABIM  Medical  Director,  The  Allergy  Station  at  SACENT  

Board  of  Director,  BloodSource  Sacramento,  CA  

•  Alcon  •  AstraZeneca  •  Genentech-­‐Roche  •  MEDA  •  Merck  •  Mylan  •  Novartis  •  Sunovion  •  TEVA  

•  Board  of  Directors  of:  •  BloodSource  •  California  Society  of  Allergy,              Asthma  &  Immunology  •  Sacramento  Valley  Allergy                Society  •  Western  Society  of  Allergy,                Asthma  &  Immunology  

Disclosures  

1.  Review  History  of  Immunoglobulin  Treatment  2.  Understand  how  Primary  Immune  Deficiency  

diagnosis  is  made  3.  Patient  Case  Review  –  2  Zebras  4.  PID  Guidelines  –  Framework  for  Identifying  5.  Explosion  of  Molecular  Genetics  6.  Patient  Advocacy  Groups  Impact  on  PID  7.  Threats  8.  Opportunities  

Learning  Objectives  

described  use  of  “serum”  for  

specific  diseases.  

Mid  1800’s  

Horse  and  other  animal  

preparations  derived  as  “antitoxin”  

Late  1800’s  

Cohn  devises  a  purification  for  enriched  IgG/  

immunoglobulin.  1  

Early  1900’s  

History  of  IVIG  

Trivia  Question:  Who  won  the  Nobel  Prize  for  Medicine  in  1901?  For  what?      

*  1952  –  Colonel  Ogden  Bruton  describes  IgG  (IMIg)    as  a  “therapeutic  agent”  for  primary  immune  deficiency  (XLA)  in  2  y.o.  boy  w  recurrent  pneumonia  and  bacterial  sino-­‐pulmonary  infections.  1  

*     

2  

*  Mapped  to  chromosome  Xq21.3,  37.5kb  w/  19  exons  

Bruton’s  Agammaglobulinemia  

*  September  22nd,  2014  Office  Schedule    *  815  am:    Wilson,  B    Runny  Nose  *  830  am:    Nedder,F    Cough      *  845  am:    Adamek,J  Hives  *  900  am:    Smith,T    Peanut  Allergy  *  915  am:      Nelson,W  Skin  abscesses,  pneumonia  *  930  am:    Patel,C    Acute  Sinus  Infxn  follow  up    *  945  am:      Fisher,  L    Asthma  

 (catch  my  breath)  *  10  am:          Tampano,  L  Migraines  ?  Allergies  *  1015  am:    Mellish,    J  Watery  eyes    

The  Life  of  an  Immunologist    

* Marty  *  10  years  old  *  Lived  at  Central  Park  Zoo  *  Best  friends:    *  Alex,  Melman  and  Gloria  

*  Travels  to  Madagascar  *  Now  stranded  in  Europe  *  Relatively  easy  to  spot  

*   http://www.youtube.com/watch?v=NQ3A7P3k8mI  

A  Tale  of  Two  Zebras  -­‐  Marty  

vs      ?  A  Tale  of  Two  Zebras  –    

Not  all  are  that  easy  to  Spot  

•  19  y.o.  male  •  Mr.  California  -­‐  3  times  before  age  

23  •  Healthy  eating  habits  •  Earns  degree  in  Diagnostic  Medical  

Ultrasound  •  Continued  work  as  full  time  

sonographer  •  Exercises  daily  •  Continues  to  eat  well,  hikes,  

practices  Yoga  

But  …  

•  Numerous  sinus,  ear,  bronchial  infections  as  child  •  19  y.o.  -­‐    has  5  Staph  Infections  •  First  sinus  surgery  at  26  •  26  y.o.  Diagnosed  with  CVID  (by  a  Pulmonologist)    •  Has  1st  of  4  ICU  hospital  stays  •  Age  38  –  develops  

•   Hypothyroidism,  Hypogonadism,  Hyposomatism,    

•  Develops  Hepatosplenomegaly,  Diffuse  Lymphadenopathy,  Mild  Bronchiectasis,  Auto  Immune  Hepatitis    

•  Developed  Idiopathic  Dilated  4  Chamber  Cardiomyopathy  with  resulting  CHF  (EF  22%)    -­‐  •  Considering  listing  for  heart  transplant  

•  Takes  14  medications,  cost  $11K  monthly  •  Has  team  of  6  specialists  

A  Tale  of  Two  Zebras  –  F.M.    

       Classification  ARTICLE  *  Front. Immunol., 22 April 2014 doi:  10.3389/fimmu.2014.00162    

*  Primary  immunodeficiency  diseases:  an  update  on  the  classification  from  the  International  Union  of  Immunological  Societies  Expert  Committee  for  Primary  Immunodeficiency  3  

*  Waleed  Al-­‐Herz1,2,  Aziz  Bousfiha3,  Jean-­‐Laurent  Casanova4,5,  Talal  Chatila6,  Mary  Ellen  Conley4,  Charlotte  Cunningham-­‐Rundles7,  Amos  Etzioni8,  Jose  Luis  Franco9,  H.  Bobby  Gaspar10*,  Steven  M.  Holland11,  Christoph  Klein12,  Shigeaki  Nonoyama13,  Hans  D.  Ochs14,  Erik  Oksenhendler15,16,  Capucine  Picard5,17,  Jennifer  M.  Puck18,  Kate  Sullivan19  and  Mimi  L.  K.  Tang20,21,22  

*  #  of  PID’s        269  *  #  of  PID  Genes      248  *  #  of  Unique  Mutations    5012  4,5  

Currently  Defined    Immune  Deficiencies  -­‐  IUIS  

*  Immunodeficiency  Update  6    *  Chair:  Dr.  Francisco  Bonilla  *  JTF  Liaison:  Dr.  David  Khan  *  Workgroup  Members:  *  Zuhair  K,  Ballas,  MD      Robert  P.  Nelson,  Jr.,  MD  *  Javier  Chinen,  MD,  PhD      Jordan  S.  Orange,  MD,  PhD  *  Michael  M  Frank,  MD      John  M.  Routes,  MD  *  Michael  Keller,  MD      William  T.  Shearer,  MD,  PhD  *  Lisa  J  Kobrynski,  MD      Ricardo  U.  Sorensen,  MD  *  Hirsh  Komarow,  MD      James  Verbsky,  MD,  PhD  *  Bruce  Mazer,  MD  *  Status:  JTF  and  Workgroup  review  of  comments  

*  Anticipated  revision  date:    Late  2014                            Journal  for  Publication:  Journal  of  Allergy,  Asthma,  &  Clinical  Immunology  

Guidelines  Help  

* CVID  •  IgG  <  2  SD  below  the  mean  for  age  •   Marked  decrease  in  at  least  one  of  IgM  or  IgA,  and  fulfills        

 all  of  the  following  criteria:  1)  Onset  of  immunodeficiency  at  greater  than  2  years  of  age  2)  Absent  isohemagglutinins  and/or  poor  response  to  vaccines  3)  Defined  causes  of  hypogammaglobulinemia  have  been  excluded    

US  Prevalence:  1:2400  Most  common  PID  requiring  immunodeficiency  8  

Guidelines  Help  

*  http://www.immunodeficiencysearch.com/algorithm#!__algorithm  

Molecular  Genetics  –    An  explosion  of  Information  

*  States  currently  screening  for    Severe  Combined  Immune  Deficiency:    *  California  *  Colorado  *  Connecticut  *  Delaware  *  Florida  *  Illinois  *  Iowa  *  Maine  *  Massachusetts  *  Michigan  *  Minnesota  *  Mississippi  *  New  Jersey  *  New  York  *  Ohio  *  Oregon  *  Pennsylvania  *  Rhode  Island  *  Texas  *  Utah  *  Washington  *  West  Virginia  *  Wisconsin  *  Wyoming  

States  and  territories  currently  planning  to  begin  screening  in  2014  or  2015:  *  Alaska  *  Arkansas  *  Georgia  *  Hawaii  *  Idaho  *  Kentucky  *  Maryland  *  Missouri  *  Nebraska  *  New  Mexico  *  North  Carolina  *  North  Dakota  *  Oklahoma  *  Puerto  Rico  *  South  Carolina  *  South  Dakota  *  Tennessee  *  Virginia  *  States  where  Advisory  Committees  have  approved  

adding  SCID,  but  have  a  longer  timetable  for  implementation:  

*  North  Carolina  

*  Also  screening:  District  of  Columbia,  Navajo  Nation  

Patient  Advocacy  Groups  Help  

Patient  Advocacy  Groups  Help  

Patient  Advocacy  Groups  Help  

Translated  in  28  Languages  •  From  Arabic  –  Turkish  

•  Travel  Grants  –  MD,  RN’s  •  Research  Grants  

•  Patient  Education,  Outreach  

•  Expert  Immunologist  Locator  

•  http://www.info4pi.org  

*  Infectious    +  *  Immunodeficiency    

“In  immune  deficient  patients,  IVIG  is  administered  to  maintain  adequate  antibody  levels  to  prevent  infections  and  confers  a  passive  immunity”  

*  Immuno-­‐modulatory  ***  Despite  over  40  years  of  use,  the  precise  mechanism  by  which  IVIG  suppresses  harmful  inflammation  has  not  been  definitively  established  but  is  believed  to  involve  the  inhibitory  Fc  receptor.  

Mechanism  of  Action  –    Much  Still  to  Be  Learned  

Figure 3 A schematic representation of the proposed mechanisms of action of intravenous immunoglobulin in rheumatic diseases

*  FDA-­‐approved  indications  for  IVIG  10  

*  Allogeneic  bone  marrow  transplant  *  Chronic  lymphocytic  leukemia  *  Common  variable  immunodeficiency  

(CVID)  a  group  of  approximately  150  primary  immunodeficiencies  (PIDs),  which  have  a  common  set  of  features  (including  hypogammaglobulinemia)  but  which  have  different  underlying  causes  

*  Idiopathic  thrombocytopenic  purpura  *  Pediatric  HIV  *  Primary  immunodeficiencies  *  Kawasaki  disease  *  Chronic  inflammatory  demyelinating  

polyneuropathy  (CIDP).    *  Only  the  "Gamunex"  brand  

manufactured  by  Talecris  is  approved  for  CIDP  (in  2008),  under  the  U.S.  Orphan  Drug  law  provisions  

*  Kidney  transplant  with  a  high  antibody  recipient  or  with  an  ABO  incompatible  donor  

*  Off-­‐label  uses  *  Adult  HIV  *  Alzheimer's  disease[17]  *  Autism  *  Behçet's  disease[18][19][20]  *  Capillary  leak  syndrome  *  Chronic  fatigue  syndrome  *  Clostridium  difficile  colitis  *  Dermatomyositis  and  polymyositis  *  Graves'  ophthalmopathy  *  Guillain-­‐Barré  syndrome  *  Kimura  disease  [21]  *  Muscular  dystrophy  *  Inclusion  body  myositis  *  Infertility  *  Lambert-­‐Eaton  syndrome  *  Lennox-­‐Gastaut  *  Lupus  erythematosus  *  Multifocal  motor  neuropathy  *  Multiple  sclerosis  *  Myasthenia  gravis  *  Neonatal  alloimmune  

thrombocytopenia  *  Parvovirus  B19  

*  Pemphigus  *  Post-­‐transfusion  purpura  *  Renal  transplant  rejection  *  Spontaneous  abortion/miscarriage  *  Sjogren's  Syndrome  *  Stiff  person  syndrome  *  Susac's  syndrome  *  Opsoclonus  myoclonus  *  Severe  sepsis  and  septic  shock  in  

critically  ill  adults[22]  *  Toxic  epidermal  necrolysis  *  In  chronic  lymphocytic  leukemia  and  

multiple  myeloma  

*  Phase  III  testing  in  the  US*  *  Alzheimer's  Disease  

*  35    Million  Worldwide  *  5    Million  in  U.S.  

Indications  and  Uses  of  IVIg/SQIg  

*  Supply  Shortage  –  ?  Inadequate  Donor  Recruitment  *  Production  Shortage  –  Catastrophic  Loss/QC  *  *  New/Emerging  Infectious  Agents  

*  Retroviruses,  Lentiviruses  *  Arboviruses  and  Enteroviruses  *  Prion  and  other  small  particle  based  disorders  *  Babesial  disease  

*  http://www.hhs.gov/ash/bloodsafety/advisorycommittee/acbtsa-­‐2014-­‐11-­‐meeting-­‐agenda.html  

*  Inappropriate  Use  of  IVIG  *  Open  Med.  2012;  6(1):  e28–e34.        Published  online  Mar  13,  2012.            PMCID:  PMC3329117  *  Appropriateness  of  the  use  of  intravenous  immune  globulin  before  and  after  the  introduction  of  a  utilization  control  

program;  Thomas  E  Feasby,  Hude  Quan,  Michelle  Tubman,  David  Pi,  Alan  Tinmouth,  Lawrence  So,  and  William  A  Ghali  

*  Rapidly  Developed  New  Indication(s)  *  Waning/Variant  Vaccine  &  Natural  Immunity  Patterns  

IVIg/SQIg  -­‐  Threats  

*  New  Routes  *  IMIG,  IVIG,  SQIG,  ?  TCIG  

*  New  Formulations  *  FDA  Approves  Baxter's  HYQVIA  for  Treatment  of  Adults  with  Primary  Immunodeficiency    

*  DEERFIELD,  Ill.  and  SAN  DIEGO,  Calif.,  September  12,  2014  -­‐  Baxter  International  Inc.  (NYSE:BAX)  and  Halozyme  Therapeutics,  Inc.,  (NASDAQ:HALO)  today  announced  that  the  United  States  Food  and  Drug  Administration  (FDA)  approved  Baxter's  subcutaneous  treatment  for  adult  patients  with        primary  immunodeficiency  (PI),  HYQVIA  

[Immune  Globulin  Infusion  10%  (Human)  with  Recombinant  Human  Hyaluronidase].    *  HYQVIA  is  a  product  consisting  of  Immune  Globulin  Infusion  10%  (Human)  (IG  10%)  and  Recombinant  Human  Hyaluronidase  (developed  by  Halozyme  Therapeutics).  The  IG  

component,  a  10%  solution  that  is  prepared  from  large  pools  of  human  plasma  consisting  of  at  least  98%  IgG,  contains  a  broad  spectrum  of  antibodies  and  provides  the  therapeutic  effect.  The  Recombinant  Human  Hyaluronidase  of  HYQVIA  increases  dispersion  and  absorption  of  the  Immune  Globulin  Infusion  10%  (Human).  

*  Safer  Products  *  New  Diseases  

*  Neuro-­‐inflammatory  (ALZ,  PD,  MS,  etc)  *  Emerging  Infectious  Agents  *  Ebola-­‐Virus  

*  Experts  at  the  WHO’s  Geneva  meeting  were  most  optimistic  about  two  related  methods  of  treatment:  whole  blood  transfusion  and  purified  blood  plasma,  known  as  convalescent  serum  

*  Fast-­‐tracking  treatments:  The  hunt  for  Ebola  medicines  is  being  accelerated  Sep  13th  2014  |  The  Economist  

*  Convergence  of  Immune-­‐regulation  *  Non  specific  (herd  immunity)  and  immunomodulation  

IVIg/SQIg  -­‐  Opportunities  

*  James  R.  Baker,  Jr.  MD  *  Mark  Ballow,  MD  *  Jordan  S.  Orange,  MD  PhD  *  Marcia  Boyle  *  Janet  Gandy  

*  My  Wife  and  Kids  

Thank  You  

*  1.  Weiler,  CS.  Int.  Journ  of  Derm.  2004:  43(3);163-­‐6.  *  2.http://misc.medscape.com/pi/iphone/medscapeapp/

html/A1050956-­‐business.html  *   3.  Front.  Immunol.,  22  April  2014  doi:  10.3389/fimmu.

2014.00162    *  4.    http://www.ims.riken.jp/english/databases/  *  5.    http://web16.kazusa.or.jp/rapid/  *  6.  http://www.allergyparameters.org/parameters-­‐

undergoing-­‐review/  *  7.  http://www.jacionline.org/article/S0091-­‐6749(12)

01103-­‐7/pdf  

References  

*  8.  http://esid.org/Working-­‐Parties/Clinical/Resources/Diagnostic-­‐criteria-­‐for-­‐PID2  

*  9.http://www.nejm.org/doi/pdf/10.1056/NEJMoa1102140  *  10.http://en.wikipedia.org/wiki/Intravenous_immunoglobulin  *  11.  

http://primaryimmune.org/idf-­‐advocacy-­‐center/idf-­‐scid-­‐newborn-­‐screening-­‐campaign/  

*  12.   Bayry J et al. (2007) Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action Nat Clin Pract Rheumatol 3: 262–272 doi:10.1038/ncprheum0481

*  13. http://www.cdc.gov/vhf/ebola/outbreaks/guinea/qa-experimental-treatments.html

*  14. http://www.economist.com/news/science-and-technology/21616888-hunt-ebola-medicines-being-accelerated-fast-tracking-treatments

References