Final Journal Club Presentation

ANNA SLUPECKICOMMUNITY I I APPE

AUGUST 2016

NATHWANI AC, TUDD ENHAM EG, RANGARAJAN S, ROSALES C, MCI NTOSH J, ET AL . ( 2011 ) ADENOVI RUS -ASSOC IATED V IRUS

VECTOR-MED IATED GENE TRANSFER I N HEMOPHI LI A B . N ENGL J MED 365 : 2357–

2365 . D OI : 10 .1056 /NEJMOA1108046 . PMID :22149959

Gene Therapy & Hemophilia Journal Club

Background Information


Currently there are 7 different pharmaceutical companies conducting clinical trials for gene therapy use in hemophilia A or B Baxter International, Uniqure, Dimensions Therapeutics,

Spark Therapeutics, BioMarin Pharmaceutical, Sangama Biosciences/Shire, Biogen Idec

Uniqure is using the theraputic IX gene used in the following study by a research team at St. Jude’s/UCL

BioMarin is using a hemophilia A program licensed from the same research facilities

http://www.xconomy.com/national/2015/03/23/stop-the-bleeding-can-gene-therapy-finally-cure-hemophilia/?single_page=true

http://www.pharmacypracticenews.com/Clinical/Article/08-16/Gene-Therapy-for-Hemophilia-Gains-Ground/37554


Company: UniqurePhase I/II Study of AMT-060-01 for

Hemophilia B 30 minute IV infusion, locally prepared in pharmacy 24 hour observation in hospital Adenovirus-Associated Virus (AAV5) Vector–Mediated

Gene Transfer of Human Factor VIXGoal: Dose-Escalation, safety, and efficacyStatus: On going

Access date: 8/17/16 http://learningcenter.ehaweb.org/eha/2016/21st/135223/frank.leebeek.first.results.from.a.dose-escalating.study.with.aav5.vector.html?f=p14m3s92207Acess Date: 8/8/16 htps://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8&ved=0ahUKEwinp9fI5cjOAhWBcCYKHX1SBvIQFgglMAE&url=http%3A%2F%2Fwww.uniqure.com%2Fuploads%2Fpresentations%2FAMT-060%2520Presentation%2520at%2520WFH%2C%25202016.pdf&usg=AFQjCNFmZDA3Ll0fm4-83wN56FQplevP-w


Company: BioMarinPhase I/II Gene Therapy Study of BMN 270

for Hemophilia A BMN 270 is administered as a single IV infusion Adenovirus-Associated Virus (AAV8) Vector–Mediated

Gene Transfer of Human Factor VIIIGoal: Dose-Escalation, Safety, Tolerability,

and EfficacyStatus: Ongoing

http://www.biomarin.com/hemophilia-a Access date: 8/8/16

http://www.biomarin.com/hemophilia-a

Vance et al. In Gene Therapy -Principles and Challenges (2015).

Approved Gene Therapies (EU only)

Alipogene Tiparvovec (Glybera) Treatment of lipoprotein lipase deficiency w/ severe or

multiple attacks of pancreatitis despite low fat diet Derived from a virus modified to carry lipoprotein

lipase gene October 2012: First gene therapy approved EVER in a

Western countryStrimvelis

Treatment of ADA-SCID for whom no suitable HLA-matched stem cell donor is available

Stem cell gene therapy – autologous CD34+ cells express ADA

May 2016: First gene therapy approved for children Access date: 8/17/16 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/uman/medicines/002145/human med_001480.jsp&mid=WC0b01ac058001d124 Access date: 8/17/16 http//www.gsk.com/en-gb/media/press-releases/2016/strimvelistm-receives-european-marketing-authorisation-to-treat-very-rare-disease-ada-scid/

ADENOVIRUS-ASSOCIATED VIRUS VECTOR-MEDIATED

GENE TRANSFER IN HEMOPHILIA B

Study Overview

Relevance of Study

Prophylactic treatment with factor is not curative, is expensive, and is associated with inhibitor formation

Gene therapy offers the potential cure after a single administration assuming continuous endogenous production of FIX

A small rise in endogenous FIX (>1%) can decrease bleeding

Treatment Regimens

Peripheral vein administration of vector particles (220mL total, 1 hour infusion) No FIX administration during procedure

Dosing regimen: 2 × 1010 vg/kg 6 × 1010 vg/kg 2 × 1011 vg/kg A minimum of 2 subjects to start at each dose

Study Design

Phase I/II Clinical TrialOpen LabelDose Escalation

Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, et al. (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365: 2357–2365. doi: 10.1056/NEJMoa1108046. pmid:22149959

Methods

Inclusion Criteria

Males ≥ 18 years of age with established severe HB (FIX:C<1u/dl) resulting from a missense mutation in the hFIX gene which has not been associated with an inhibitor with detectable FIX in serum.

Individuals with a stop codon mutation, a promoter mutation, a small insertion or deletion causing a frame shift, a small in frame insertion or deletion or a splice junction mutation could be enrolled if their mutation had not been associated with an inhibitor.

Treated/exposed to FIX concentrates for at least 10 years. A minimum of an average of 3 bleeding episodes per year requiring

FIX infusions or prophylactic FIX infusions because of frequent prior bleeding

episodes. Able to give informed consent and comply with requirements of the

trial. Currently free of inhibitor and have no history of inhibitors to FIX

protein and A negative family history for the development of an inhibitor. Willing to practice a reliable barrier method of contraception.Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, et al. (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med

365: 2357–2365. doi: 10.1056/NEJMoa1108046. pmid:22149959

Exclusion Criteria

Evidence of active infection with Hepatitis B or C virus Exposure to Hepatitis B or C and on antiviral therapy Serological evidence of HIV or HTLV infection Significant liver dysfunction as defined by an abnormal ALT, bilirubin, alkaline

phosphatase or INR. Potential participants who have had a liver biopsy in the past 3 years were excluded if they

had significant fibrosis of 3 or 4 as rated on a scale of 0-4 Coronary artery disease as a co-morbid condition Platelet count of <150 x 109/l Creatinine ≥ 1.5 mg/dl Hypertension with systolic BP consistently ≥ 130mmHg or diastolic BP

consistently ≥ 90mmHg History of active tuberculosis, fungal disease, or other chronic infection History of chronic disease adversely affecting performance Detectable antibodies reactive with AAV8 Subjects who were unwilling to provide the required semen samples Poor performance status (WHO performance status score >1) or Received an AAV vector previously or any other gene transfer agent in the

previous 6 monthsNathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, et al. (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365: 2357–2365. doi: 10.1056/NEJMoa1108046. pmid:22149959

Endpoints

Primary endpoint: Safety Emphasis on:

Vector induced hepatitis Germline transmission Formation of neutralizing antibodies against FIX

Efficacy was a secondary endpoint Persistence of biologically active FIX at ≥ 3% of

normal levels Expression of FIX was assessed frequently during the

study period but only after a minimum of 72 hours had elapsed since the last infusion of FIX protein concentrates


Statistical Methods

No sample size justificationDescriptive analysis of dataCollected in a longitudinal manner Analyzed using a mixed effect modelPer protocol analysis


Results

Primary Outcome: Safety Germline Transmission


Semen

Plasma

Primary Outcome: Safety Vector Induced Hepatitis


Primary Outcome: Safety Formation of neutralizing antibodies against

FIX

Neutralizing antibodies to FIX were not detected at any time point in any participant


Secondary Outcomes: Efficacy

4 of 6 participants were able to stop using prophylaxis with FIX concentrate without having spontaneous hemorrhage


Increasing Dose of AAV vector

Clinical Significance

Therapeutic expression of a transferred factor IX gene can be achieved in humans


Author’s Primary Conclusion

FIX level increases are dose dependentIndividual variations in immunity & exposure to AAV

influence the type and magnitude of immune responses to this gene therapy

To determine the frequency & clinical significance of ALT elevations a larger number of participants needs to be treated at the high dose level Routine use of corticosteroids is not indicated since the incidence

and timing of immune mediated ALT elevations is uncertainThis gene therapy approach has the potential to

convert severe bleeding hemophilia to a mild form or reverse it entirely


Study Analysis & Critique

Internal Strengths Internal Weaknesses

2 times per week observations

Restart prophylactic FIX if levels fall below 1%

Small cohort (N=6)Open label

Study Validity

External Strengths External Weaknesses

Only male participants

Only severe hemophilia patients (FIX:C < 1U/dL)

Exclusion of: Patients with inhibitor Patients with active or

treatment for Hep B/C Patients with HIV

Age range: 27-64 y.o.

Treatment with FIX for at least 10 years

Study Validity

Conclusion & Role in Clinical Practice

Hemophilia gene therapy has the potential to be an effective way to reduce the need for factor replacement

Larger trials are necessary to determine liver safetyClinical trials are set to finish Phase I/II as early as 2020The cost of gene therapy may be prohibitive to how

many people it actually treats Average factor replacement cost = $250,000 per year Current gene therapy cost in the EU: $650,000 - $1 million once

Durability of effect ~ 5 years (mean follow up of 3.2) No data available if a dose of vector may need to be repeated

Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, et al. (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 371: 1994–2004. doi: 10.1056/NEJMoa1407309. pmid:25409372

References


Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, et al. (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 371: 1994–2004. doi: 10.1056/NEJMoa1407309. pmid:25409372

http://www.pharmacypracticenews.com/Clinical/Article/08-16/Gene-Therapy-for-Hemophilia-Gains-Ground/37554

http://www.xconomy.com/national/2015/03/23/stop-the-bleeding-can-gene-therapy-finally-cure-hemophilia/?single_page=true

Access date: 8/17/16 http://learningcenter.ehaweb.org/eha/2016/21st/135223/frank.leebeek.first.results.from.a.dose-escalating.study.with.aav5.vector.html?f=p14m3s92207

Acess Date: 8/8/16 https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8&ved=0ahUKEwinp9fI5cjOAhWBcCYKHX1SBvIQFgglMAE&url=http%3A%2F%2Fwww.uniqure.com%2Fuploads%2Fpresentations%2FAMT-060%2520Presentation%2520at%2520WFH%2C%25202016.pdf&usg=AFQjCNFmZDA3Ll0fm4-83wN56FQplevP-w

http://www.biomarin.com/hemophilia-a Access date: 8/8/16 Vance et al. In Gene Therapy -Principles and Challenges (2015). 8/17/16 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002145/

human_med_001480.jsp&mid=WC0b01ac058001d124 8/17/16 http://www.gsk.com/en-gb/media/press-releases/2016/strimvelistm-receives-european-

marketing-authorisation-to-treat-very-rare-disease-ada-scid/ http://www.pharmacypracticenews.com/Clinical/Article/08-16/Gene-Therapy-for-Hemophilia-Gains-

Ground/37554

Final Journal Club Presentation

Documents

Transcript of Final Journal Club Presentation