The Future of ImmunologyNew Therapy Options

William Blouin, MSN, ARNP, CPNPMiami Children’s Hospital

INGIDPrague

1 November 2014

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No disclosures relevant to this presentation.

Disclosure

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Provide an overview of new developments and future directions in immunologic therapy for Primary Immune Deficiencies.

Goal

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The Future of Immunology New Therapy Options

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IgG Replacement Therapy Transplantation

◦ Thymus Transplantation◦ Hematapoietic Stem Cell Transplantation & Gene Therapy

The Future of ImmunologyNew Therapy Options

Outline

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IgG Replacement Therapy

1890 - 1910 Animal Sera 1910 - 1930 Human Sera 1940 Cold Ethanol Fractionation 1950 First PID treated 1952 SC IM 1960 Pepsin Treated Late 60’s IVIG 1970 Other Chemical Methods 1980 IVIG Standard Therapy 1990’s SCIG Europe 2000 US SCIG Research 2006 First US SCIG Product 2010 - 2014 New Products IVIG & SCIG 2014 – Future ?

Immunoglobulin Therapy Timeline

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IgG TherapyDoes One Size Fit All?

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Dosing Flexibility

Immunoglobulin Therapy

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• Therapeutic IgG levels varies from patient to patient• Dosing should be individualized • Steady state IgG serum levels provide therapeutic

advantage

• Dosing regimens can be adjusted for optimal outcomes and mitigate wear-off• IVIG: weekly, q 3-4 weeks • SCIG: Frequent, weekly, biweekly• SCIG: Monthly with second compound hyaluronidase

IgG Therapy

1. Bonagura VR et al. J Allergy Clin Immunol 2008;122(1):210-2122. Lucas M et al. J Allergy Clin Immunol 2010;125:1354-1360

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Venous access required◦ Requires a healthcare provider to administer

Large volumes administered (every 3-4 weeks) Premedications commonly needed prior to IVIg administration Higher reports of systemic reactions: chills, fever, headache Less frequent dosing Peaks and troughs

IVIg Therapy

Berger M. Clin Immunol. 2004;112:1-7.

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SCIgWeekly, Biweekly, Monthly

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Venous access not required Gradual absorption (24-72 hours after the infusion) Consistent, steady IgG serum levels maintained with weekly and

biweekly infusions Small volumes administered frequently Pre-medications not required Facilitates self-infusion in home setting, allowing patients to

actively participate in therapy with provider oversight

SCIG Weekly or Biweekly Administration

Berger M. Clin Immunol. 2004;112:1-7.

SCIg Weekly/Biweekly dosing vs. IVIg Monthly

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• Dose should be individualized based on the patient’s clinical response to IgG therapy and serum IgG levels

1. Adapted with permission from Berger M. Clin Immunol 2004;112:1-7

Pharmacokinetic Serum Profile of IVIg and Weekly SCIg

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• Needle length can affect site reactions:− Too short results in increased irritation or leaking− Too long can result in discomfort/pain− Length range: 4 mm, 6 mm, 9 mm, 12 mm, 14 mm

• Gauge/brand can affect flow rate and impact local tolerability− 24, 26, or 27 gauge

• Flexible cannula can kink with excess subcutaneous tissue or movement

• Dry insertion technique is recommended• Rate of infusion may be slower in

pediatric patients, thinner patients and those with renal impairment/CV risk factors

Important Considerations

Younger ME, Aro L, Blouin W, et al. Nursing Guidelines for Administration of Immunoglobulin Replacement Therapy.

Journal of Infusion Nursing. 2013;36(1):58-68.

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◦ Venous access not required◦ Pharmacokinetic serum profile similar to IVIg (peaks and troughs)◦ Given once every 3-4 weeks after initial ramp-up schedule

(seven weeks)

◦ Large volume administered at infusion site(s), 300-600 mLs◦ 2-drug combination administered

Hyaluronidase first, 10% IgG after IgG gets into blood within 5 days

◦ Premedications not required◦ Not indicated for children

SCIg Monthly Administration

1. Wasserman RL et al. JACI. 2012.2. HyQvia Prescribing Information, 2014

SCIg Monthly Dosing vs IVIg Monthly

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Dose should be individualized based on the patient’s clinical response to IgG therapy and serum IgG levels

Serum IgG concentration for IGHy compared with IGIV and IGSC. Representative pharmacokineticcurves for one subject comparing a 4-week infusion of IGIV, a weekly infusion of IGSC, 10% at 143% of the IVdose with the same data points extended across the 4-week period to facilitate comparison with the othercurves, and a 4-week infusion of IGHy at 104% of the IV dose.

Study Day 0 7 14 21 28

1. Wasserman RL et al. JACI. 2012.2. HyQvia Prescribing Information, 2014 17

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Feature SCIg IVIg SCIg MonthlyPharmacokinetics Stable serum trough IgG

levelVariability in serum IgG level between peak and trough

Pharmacokineticallyequivalent to IGIV

Efficacy Clinical efficacy demonstrated in PIDD (noninferior when compared with IVIg)

Clinical efficacy demonstrated in PIDD and other autoimmune disorders

Clinical efficacy demonstrated in PIDD (noninferior when compared with IVIg)

Systemic side effects

Infrequent Frequent More frequent than SCIg

Local site reactions Common Infrequent Common

Administration Self-administration; patient autonomy

Infusion center/ home setting with nursing support for venous access

Predominantly self administration; 7 week ramp up for initiation

Average length of infusion

1 to 2 hours 2 to 4 hours 2-3 hours

Dosing interval Weekly or every 2 weeks Variable – every 2 to 4 weeks Variable- every 3-4 weeks

Warnings Ig Class Ig Class • Ig Class• EU Risk Management Plan • US warnings:

• Antibodies to PH20• Infusion into or

around an infected area can spread a localized infection

Features of Ig Therapies

1. Berger M. Immunol Allergy Clin North Am. 2008;28:413-437.2. Wasserman et al. Journal Allergy Clin Immunol20123.. Bonilla FA, et al. Ann Allergy Asthma Immunol, 2005;94(5)(Suppl1):S1-S634.. Skoda-Smith S, Torgerson TR, Ochs HD. Ther Clin Risk Manag. 2010;6:1-10.5. HyQvia US Prescribing Information, Sept 2014

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Thymus Transplantation

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Complete DiGeorge Anomaly

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Thymus hypoplasia or aplasia

Congenital heart defects

Hypoparathyoidism

DiGeorge Anomaly

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Complete (Athymic) DiGeorge Anomaly

Fatal condition ~1% of all DiGeorge anomaly Diagnosis of athymia is based on blood test

◦ Usually < 50/mm3 T cells (normal 2500 – 5500/mm3)◦ Always < 50/mm3 naïve (CD45RA+CD62L+) T cells ◦Normal naïve number 1580 – 4900/mm3

Diagnosis based on athymia plus one of the following: ◦ Congenital heart disease◦ Hypoparathyroidism◦ CHARGE syndrome◦ 22q11.2 deletion syndrome

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Thymus Transplantation Methods

Harvest & Slice Postnatal Unmatched Thymus

Culture 2 – 3 weeks

Transplant into quadriceps

Biopsy graft at 2 – 3 months

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69 infants with complete DiGeorge 50 of 69 (73%) are alive (median survival rate 8.4

years) 49 of 51 (96%) who survived 1 year have naïve T-

Cells

Thymus Transplantation 2014

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Hematopoietic Stem Cell Transplant & Gene Therapy

Transplant of normal HSC from an allogeneic donor

PIDD Indications• SCID• HIGM• WAS

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Improved diagnosis◦ Newborn screening for SCIDs◦ Best outcomes reported in infants treated with HSCT before 3.5

months Novel therapy approaches

◦ SCID Optimal HSCT pre transplant conditioning Limit toxicity and long term adverse effects Anti-infective measures

◦ Non SCID HSCT – Other PIDs WAS HIGM CGD

HSCT Ongoing Research and Initiatives

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Research goals for the near future include• Identify optimal treatment using HSCT for newborns with SCID• Enroll as many children as possible diagnosed with SCID as

newborns into studies • Characterize all children with low T-cell receptor excision circle

numbers at birth • Determine which children with CGD should receive a transplant • Determine whether full donor chimerism is essential to prevent

post transplantation (e.g. autoimmunity in patients with WAS) • Develop joint studies• Initiate retrospective, prospective, and cross-sectional studies of

other rare non-SCID PIDs• Answer questions raised by the research studies in SCID

HSCT Goals for the Future

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Hematopoietic Stem Cell Transplant & Gene Therapy

Autologous transplant ofgene corrected HSC GENE THERAPY

“personalized therapy”

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Gene therapy conceptualized in 1972. The first FDA-approved gene therapy experiment

in the United States was 1990 for ADA-SCID.

By 2014, approximately 2,000 clinical trials

Gene Therapy

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Gene therapy is the use of DNA to treat disease by delivering therapeutic DNA into a patient's cells. • DNA can replace a mutated or dysfunctional gene with

one that encodes a functional, therapeutic one directly correcting a mutation.

Gene Therapy

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• DNA that encodes a therapeutic protein drug (rather than a natural gene) to provide treatment. DNA is packaged within a vector to get the DNA inside cells. DNA expressed by the cell produces the therapeutic protein

and treats the disease.

Gene Therapy

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Gene Therapy

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Gene Therapy for Primary Immunodeficiencies

In the clinic:SCIDX1 (retro+ SIN retro), ADA (retro +lenti), CGD (retro + lenti), WAS (retro+ lenti)

B T NK

CD4 CD8

nTreg

WAS

CGD CGD

SCID

ADA

IL2RG

HSC

CLP

N MPLT

RBC

PERFORIN

Artemis

RAG-1/-2

FOXP3CD18

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Gene modified HSCT for treatment of Primary Immunodeficiency Disease

Gene transfervector

Autologous gene modifed

HSCT

+/- conditioning

Benefits:Autologous procedure (No rejection/ GVHD)Potential reduced toxicity vs ChemotherapyPotential lower morbidity and mortality vs ChemotherapyExploit natural selective advantage (primary immunodeficiency)Ability to deliver supranormal levels of protein or enzymes by design

Challenges:Efficient and stable gene transferAdequate dose of gene corrected HSCTEngraftment and expansion of gene corrected cellsEfficient regulated expression of therapeutic geneReduce the risk of insertional oncogenesis

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Stem cell isolation

Gene Therapy for PID

Cell growth

Reduced intensitychemotherapy

Infusion

Bone marrow harvest

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Current Trials for PID◦ ADA SCID◦ X-Linked SCID◦ Chronic Granulomatous Disease◦ Wiskott Aldrich Syndrome◦ Leukocyte Adhesion Defect

Gene Therapy

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Clinical Results

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Gene Therapy for Primary Immunodeficiencies

ADA-SCIDRecent/Completed trials

From: Stiehm’s Immune Deficiencies, 2014

Ongoing trials

DU3

EF1a Hu ADA

DU3ψWPRE

EFS-ADA Lentiviral Vector

University College LondonBobby GasparAdrian Thrasher

UCLA-NIHDonald B. KohnFabio Candotti

Centers

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ADA-SCID◦ Survival rate from ADA-SCID gene therapy has been 100% with

efficacy when comparing favorably with HCT with fully matched donor.

◦ Children's growth and bone age improved following treatment although were not normalized in all patients (Cavazzana-Calvo et al., 2012).

◦ Will soon be considered standard of care for patients without matched sibling donors.

ADA SCID

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Gene Therapy for Primary Immunodeficiencies

Lentiviral vector: CL20-I4-EF1a-hgc-OPTDU3+Ins

EF1a hgc-OPT

DU3+Ins

g-Retroviral vector: SRS11 SFgc

EF1a hgc

SIN-MPSV SIN-MPSV

WPRE

X-linked SCID

Completed trials

Ongoing trials

St. Jude Inclusion criteria • Age 3-12 mos• “Classic” SCID phenotype • No HLA-id sib donor• No conditioning

NIH

• Age >1 yr• Failed transplant • Atypical presentation• No HLA-id sib donor• 6 mg/kg Busulfan

London, ParisBoston, Cincinnati, Los Angeles

Inclusion criteria

• Age >3 mos• No HLA-id donor, no MUD• No conditioning

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SCID-X Linked ◦ Results from initial trials demonstrated clinical benefit but

supported recommendations for changes of insertion vectors and prognostic indicators Occurrence of leukemia due to insertional transactivation of

proto-oncogenes (MDS/EVI1 and LMO2) by elements present within the viral LTR

◦ Preliminary results rom an on-going 2010 multi-center (EU & US) trial involving 8 patients indicates similar clinical benefits and no adverse events although follow up is short.

The vector used in this trial was different (based on a SIN γ-

retrovirus in which the IL2RG gene is driven from an internal EF1α promoter)

Advances in Gene Therapy

http://dx.doi.org/10.1016/j.gene.2013.03.098

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Gene Therapy for Primary ImmunodeficienciesChronic Granulomatous Disease

Completed Trials

Ongoing trials

France, Germany, Switzerland, UKBoston, Los Angeles, NIH

DU3

Chim Hu GP91

DU3ψWPRE

Lentiviral vector: G1XCGD

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CGD ◦ Research ongoing since 1995◦ Variable clinical results◦ Newer viral vectors undergoing trials

Chronic Granulomatous Disease

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Wiskott-Aldrich Syndrome

Gene Therapy for Primary Immunodeficiencies

Completed Trials

Ongoing trials Lentiviral vector: W1.6wDU3

WASp WAS

DU3

WPRE

MilanParisLondonBoston

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Current Gene Therapy Trials for WAS

Lentiviral vector: W1.6w

Paris

London

Boston

Milan

• Severe phenotype• No HLA-id donor• No MUD (if <5 yo)• BU (12 mg/kg) + FLU conditioning• Rituximab ± ATG

DU3

WASp WAS

DU3

WPRE

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WAS◦ Similar issues with vector insertion

Occurrence of leukemia due to insertional transactivation of proto-oncogenes MDS/EVI1 and LMO2 by elements present within the viral LTR

Newer viral vectors undergoing trials

Wiskott-Aldrich Syndrome

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◦ Current multi-center trial in the UK, the US, France and Italy. Different vector for insertion Multicenter approach for gathering data on safety,

multi-lineage reconstitution, & clinical efficacy Uniform parameters of pre-conditioning and vector

quality

Further Research in WAS Gene Therapy

http://dx.doi.org/10.1016/j.gene.2013.03.098

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Promising results in animal models Potential human clinical trials

Leukocyte Adhesion Defect

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HSCT Gene Therapy

• HSCT gene therapy is efficacious in restoring immune functions in PID patients

• Pre-treatment conditioning is required for long-term engraftment of stem cells

• Adequate dose of transduced CD34+ cells is important

• Safety needs to be carefully balanced with vector design, nature of transgene and disease background

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• Progress with ADA SCID, X Linked SCID

• Preclinical studies and novel clinical trials using are very promising (XHIM, XLA, XLP)

• Safety and efficacy balance in comparison to allogeneic BMT

• When will gene therapy become a medicinal drug/standard of care?

Current Status of Gene Therapy

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The Future of Immunology?

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Sheridan C (2011). "Gene therapy finds its niche". Nature Biotechnology 29 (2): 121–128.Ferrua F, Brigida I, Aiuti A (2010). "Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency". Current Opinion in Allergy and Clinical Immunology 10 (6): 551–556.Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH (2014). "Gene Editing ofCCR5in Autologous CD4 T Cells of Persons Infected with HIV". New England Journal of Medicine 370 (10): 901–10

Bonagura VR et al. J Allergy Clin Immunol 2008;122(1):210-212Lucas M et al. J Allergy Clin Immunol 2010;125:1354-1360Berger M. Clin Immunol. 2004;112:1-7

Wasserman RL et al. JACI. 2012. HyQvia Prescribing Information, 2014 Berger M. Immunol Allergy Clin North Am. 2008;28:413-437. Bonilla FA, et al. Ann Allergy Asthma Immunol, 2005;94(5)(Suppl1):S1-S63 Skoda-Smith S, Torgerson TR, Ochs HD. Ther Clin Risk Manag. 2010;6:1-10. Younger ME, Aro L, Blouin W, et al. Nursing Guidelines for Administration of Immunoglobulin

Replacement Therapy. Journal of Infusion Nursing. 2013;36(1):58-68.

References

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Alessandro Aiuti MD, PhDHSR TigetMilan, IT

Elizabeth K. Garabedian, RN, MSLSNational Institutes of HealthNHGRI

M. Louise Markert, M.D., Ph.D.Professor of Pediatrics and ImmunologyDuke University Medical Center

Elyse Murphy BSN RNMedical Science Liaison Leader, Immunology Medical Affairs, CSL Behring

M. Elizabeth M. Younger CRNP, PhDAssistant Professor, PediatricsJohns Hopkins University School of Medicine Division of Pediatric Allergy and Immunology

Richard I Schiff, MD, PhD(Posthumous), Baxter

Thank You