A Phase 1/2 Clinical Trial of Intra- Arterial Gene Transfer of raavrh74.mck.galgt2 for DMD: Initial Safety Profile

Transcription

1 A Phase 1/2 Clinical Trial of Intra- Arterial Gene Transfer of raavrh74.mck.galgt2 for DMD: Initial Safety Profile Kevin Flanigan, MD Center for Gene Therapy Nationwide Children s Hospital June 29, 2018

2 Disclosures Site principal investigator for PTC Therapeutics, Prosensa, Abeona Therapeutics, Akashi, and the NIH FOR-DMD study; site coinvestigator for Sarepta Advisory boards for Sarepta, PTC, Audentes, Eli Lilly, 4D Therapeutics, and Dynacure

3 The dystrophin-associated glycoprotein (DAG) complex

4 Dystroglycan complexes in skeletal muscle B4GALNT2 (GALGT2) Neu5Ac/Gca2,3[GalNAcb1,4]Galb1,4GlcNAcb1,2Man(PO 4 )a-o-ser/thr

5 Dystrophin-deficient mdx mice

6 Galgt2 transgenic muscles overexpress synaptic dystroglycan binding partners Nguyen, Jayasinha, Xia, Hoyte, and Martin PT (2002) Proc. Natl. Acad. Sci. USA 99,

7 Galgt2 overexpression results in upregulation of multiple membrane-associated proteins

8 Lack of muscle damage in Galgt2 transgenic (CT) mdx mice Nguyen et al., Proc Natl Acad Sci U S A. 99(8): (2002)

9 Absent muscle pathology in Galgt2 transgenic (CT) mdx mice for almost the lifespan of the animal Xu et al., Neuromuscular Disorders 17 (2007)

10 raavrh74.mck.galgt2 shows comparable improvement to raavrh74.mck.microdystrophin (12 wks p.i.) Martin et al, Am J Physiol Cell Physiol 296:C476-C488 (2009)

11 Galgt2 shows broad therapeutic potential in the muscular dystrophies MDC1A dy W LGMD2D Sgca -/- DMD mdx Nguyen et al (2002) Proc. Natl. Acad. Sci. USA 99, Hoyte et al. (2004) Am. J. Pathol. 164, Xu et al. (2007) Neuromusc. Disord. 17, Xu et al. (2007) Am. J. Pathol. 171, Xu et al. (2009) Am. J. Pathol., 175, Martin et al. (2009) Am. J. Physiol. 296,C May be therapeutic in multiple animal models of muscular dystrophy 2. Should be no issues with transgene auto-immunity (endogenous protein) 3. Would be able to treat all DMD mutations

12 Phase I/IIa gene transfer clinical trial for Duchenne Muscular Dystrophy using raavrh74.mck.galgt2 IND# Intravascular limb infusion for gene transfer delivered bilaterally via a femoral artery lower limbs The femoral vein and artery on each side are cannulated, and catheter localization confirmed via angiography. In one leg, blood flow is interrupted via inflation of the venous and arterial balloons, and the vector dose (of approximately 300 ml) is delivered over approx. 1 min 30 secs Blood flow remains interrupted for a 10 minute dwell time The arterial and then the venous balloons are then deflated, and blood flow re-established. The procedure was then repeated on the left leg.

13 ILI delivery to non-human primates results in widespread expression of the CT antigen

14 Open label, dose escalation, phase I/II trial Dose escalation planned Low Dose (N=3): 2.5 x vg/kg/leg (Total: 5 x vg/kg) High Dose (N=3): 5 x vg/kg/leg (Total: 1 x vg/kg) The primary objective is assessment of safety Primary efficacy outcome is expression of the CT antigen by immunofluorescent analysis Secondary outcomes include 100 MWT and NSAA

15 Subject GAL-DMD-01 Enrolled at 8.4 years old Mutation: Duplication of exons On prednisone 10 mg/day Baseline Clinical Assessments

16 GAL-DMD-01 Baseline MRI

17 RFA Run-Off Angio With Balloon Occlusion

18 Monitoring Legs During ILI

19 S c r e e n i n g D o s i n g B e g a n t a p e r B A C K T O B S L S T E R O I D S Adverse events G A L - D M D W B C ( K / c u m m ) 1. Bruising at catheterization site (resolved by day 30) 2. Decreased absolute lymphocyte count (ALC) t h o u s a n d p e r m m p e r m m 3 C a l c u l a t e d A N C ( / c u m m ) C a l c u l a t e d A L C ( / c u m m ) D a y

20 S c r e e n i n g D o s i n g B e g i n T a p e r B A C K T O B S L S T E R O I D S U / L Serum transaminases and CK Visit CK ( U/L) ,583 7,803 (-64%) 12,296 (-43%) * A L T ( U / L ) A S T ( U / L ) C K ( U / L ) Screening Day Day Day Day Day Day Day Day *Specimen hemolyzed D a y

21 S F C / 1 e 6 P B M C s S c r e e n i n g D o s i n g ELISPOT B e g i n T a p e r B A C K T O B S L S T E R O I D S G A L - D M D P o s i t i v e 0 A A V r h 7 4 C a p s i d P e p t i d e P o o l 1 A A V r h 7 4 C a p s i d P e p t i d e P o o l 2 A A V r h 7 4 C a p s i d P e p t i d e P o o l 3 G A L G T 2 P e p t i d e P o o l 1 G A L G T 2 P e p t i d e P o o l 2 D a y

22 Functional and isolated muscle strength testing shows no convincing evidence of decline, indicating safety

23 Preliminary (unblinded) analysis of CT antigen shows widespread expression

24 Conclusions raavrh74.mck.galgt2 delivery at a total of 5 x vg/kg via bilateral isolated limb-infusion is well-tolerated No convincing evidence for functional decline at 4 months post-injection Anticipate approval to dose a single, second patient at the higher intra-arterial dose Dose finding studies for systemic delivery supporting an intravenous trial are complete

25 Acknowledgments NIH/NIAMS: 1R21AR Paul Martin, PhD Louis G. Chicoine, MD John P. Cheatham, MD Sharon L. Cheatham, CNP Linda P. Lowes, PhD Megan Iammarino, DPT Megan A. Waldrop, MD Rachel A. Schrader, APN, BSN Federica Rinaldi, PhD Rui Xu Deborah Zygmunt Jerry Mendell, MD Louise Rodino-Klapac, PhD Tabatha R. Simmons, PhD

26 Questions?

27 Thank you!