N-ACETYLCYSTEINE (NAC): A PHASE 1/2 TRIAL IN FANCONI ANEMIA. Rabindra Tirouvanziam, PhD Department of Pediatrics, Emory University Atlanta, GA, USA

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1 N-ACETYLCYSTEINE (NAC): A PHASE 1/2 TRIAL IN FANCONI ANEMIA Rabindra Tirouvanziam, PhD Department of Pediatrics, Emory University Atlanta, GA, USA 22 nd Annual FA Family Meeting - July 2, 2013

2 Investigative Team Yigal Dror - PI Sick Kids - Toronto David Chitayat - Co-PI Sick Kids - Toronto Sharon Moalem - Fellow Sick Kids - Toronto Lilian Sung - Statistician Sick Kids - Toronto Jakub Tolar - Site PI U Minnesota - Minneapolis Helmut Hanenberg - Site PI Indiana U - Indianapolis Eva Guinan - Site PI Dana Farber - Boston Ray Monnat - Site PI U Washington - Seattle Carlo Dufour - Site PI Gaslini Institute - Genoa, Italy Johanna Svahn - Clinician Gaslini Institute - Genoa, Italy Rabindra Tirouvanziam - Site PI Emory U - Atlanta

3 Outline 1. Background What is NAC? Safety and efficacy profiles How does it work? 2. FA NAC Trial Rationale Target population Experimental schedule Endpoints

4 Background - What is NAC?

5 Background - Safety and efficacy profiles NAC is safe when given orally, in high doses In humans, no evidence for leakage into plasma (issue in mice) In our own prior phase 2 trials (cystic fibrosis: NCT , autism: NCT ), only significant side effect was mild digestive upset in some patients (same for placebo and NAC groups; likely due to excipient in tablets, which is absent from the new formulation to be used in FA trial) NAC is efficacious in inhibiting various pathological processes Oxidative damage: liver (acetaminophen), kidney (contrast agent) Inflammation: cystic fibrosis, chronic obstructive pulmonary disease Excitability: autism, obsessive compulsive disorders

6 Background - How does NAC work? N-acetylcysteine (NAC) Oral intake Cysteine Cysteine Glutathione (tripeptide: γglutamyl-cysteinyl-glycine) Entry into cells / Deacetylation Transfer Enzymatic synthesis Transfer GUT LIVER Glutathione Inihibits oxidative stress, inflammation and excitotoxicity Systemic distribution Systemic effects BLOOD & OTHER ORGANS

7 FA NAC Trial - Rationale Oxidative damage is a hallmark of FA FA mutations lead to DNA instability, hematological function FA causes oxidant / aldehyde levels NAC as a systemic treatment in FA: a low-hanging fruit Advantages: safe, cheap, repurposed (fast path to FDA approval) Expected outcomes: DNA instability, hematological function, oxidant levels Proposed phase 1/2 trial Safety of NAC (high-dose: 2.4 g per day, duration: 6- to 12-month) Efficacy of NAC (DNA stability, hematological function, other outcomes)

8 FA NAC Trial - Target population Inclusion criteria Diagnosis of Fanconi Anemia: all complementation groups* Cytopenia (mild to severe, single or bi or trilineage) as defined by Hb 12 and/or WBC 3.5 x10 9 /l and/or Platelets 150 x10 9 /l Bone marrow analysis demonstrating normal karyotype Age 2 and 45 years at the time of enrolment Subject and/or guardian able to give informed consent *modified in July 2013 after FA Family Meeting Exclusion criteria Other investigational drugs or change in treatments within 90 d prior to screening or during trial Antioxidants and GSH prodrugs within 30 days prior to trial Known allergy to any constituent of the investigational drug History or evidence of malignancy / myelodysplasia History of hepatitis B or C or HIV Patients post- or anticipated to undergo stem cell transplantation Pregnant females

9 FA NAC Trial - Experimental schedule Timepoints Clinical tests Research samples / tests MAIN: - Pre-treatment (within 1 week) - 6 month (end of trial) - 12 month (optional extension) INTERMEDIATE: - 6, 12, 18 weeks - History, physical examination - Complete blood count with reticulocyte hemoglobin F - Blood chemistry (Alb., Alk Phos, ALT, AST, Bil., Ca, Cl, Creat., Na, K, P, Prot., Urea) - Bone marrow testing (aspirate, trephine biopsy for cytology, morphology, iron stain, cytogenetics) - History, physical examination - Complete blood count - Blood: DNA damage and chromosome fragility - Blood and plasma: Oxidative stress (Cys / Cys-Cys, GSH / GSSG, Glu, Aldehydes) - Bone marrow aspirate: DNA damage, Clonogenic assay, Response to NAC - Mouth wash and urine: Banking - N/A

10 FA NAC Trial - Endpoints Primary endpoint: safety Evaluate the safety of high dose oral NAC in patients with FA group A or C taken over 6 to 12-month, including the incidence of adverse effects. Even though safety and tolerability on NAC has been excellent in a number of clinical trials, mild gastrointestinal symptoms are possible Secondary endpoints: efficacy Evaluate the effect of high-dose oral NAC on genome stability in FA Evaluate the effect of high-dose oral NAC on oxidative markers in blood Evaluate the effect of high-dose oral NAC on hematological parameters Correlate clinical response with hematopoietic colony formation in vitro >> Multicenter trial will give definitive answer on NAC s benefits in FA >> Integrated clinical / research approach will form template for future trials