IVACAFTOR THE ISRAELI EXPERIENCE ADI DAGAN MD THE ISRAELI CF CENTER SHEBA MEDICAL CENTER, TEL-HASHOMER

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1 IVACAFTOR THE ISRAELI EXPERIENCE ADI DAGAN MD THE ISRAELI CF CENTER SHEBA MEDICAL CENTER, TEL-HASHOMER

2 February 21, 2014 U.S. Food and Drug Administration Approves KALYDECO (ivacaftor) for Use in Eight Additional Mutations that Cause Cystic Fibrosis KALYDECO * The first medicine to treat the underlying cause of CF for people with specific mutations in the CFTR gene * Facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein * The eight additional mutations are present in approximately 150 people ages six and older in the United States- KALYDECO was first approved in January 2012 for people with CF ages 6 and older who have at least one copy of the G551D mutation KALYDECO is now approved for use in people with CF with the following nine mutations: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D.

3 IN ISRAEL 13 patients 4 centers 5 F, 8 M 9 per indication S549R 4 non indicated W1282X / Jewish, 2 Muslim N Ethnicity Sex Mutations age cf dx. age begin Pancrease W1282X S549R D192G S549R S549R S549R W1282X D1152H W1282X KB>T Kb del 8.6 Kb S549R W1282X S549R W1282X KB>T W1282X KB>T ΔF508 S549R ΔF508 S549R W1282X S549R W1282X S549R

4 Missense mutation (KEREM B et al) S549R MUTATION Rare gating mutation (61 described patients in CFTR2) Bedouin population of United Arab Emirates, Saudi Arabia and North Africa Guanine (G) to Thymine (T) transversion at CFTR nucleotide 1779, exon 11 Replacement of serine with arginine in the first nucleotide binding domain of the protein - severe clinical presentation Clinical phenotype - homozygous S549R severe, similar to homozygous deltaf508 Additional mild processing defect besides the defective channel gating - lower in vitro response to Ivacaftor than other gating mutations Information on clinical benefits in this mutation - scarce

5 CLINICAL DATA Body mass index (BMI) Lung function tests (FEV1, FVC, and FEF25-75) Pseudomonas colonization in sputum culture Sweat chloride test Glucose tolerance test and Hb-A1C Number of days on intravenous antibiotics one year before and after treatment

6 RESULTS Baseline Data (9 patients S549R; 4 patients no-s549r ) Age of diagnosis (yrs) Age of medication initiation (yrs) Sweat test (NaCl) FVC (%p) FEV1 (%p) FEF25-75 (%p) BMI Hb A1C (10 patients) PI Glucose metabolism Use of IV antibiotics the year prior (days) 5.1 ± ± ±31 84 ±23 69 ±24 (Mildly obstructed) 54 ± ±3.3 (poor nutritional status) 5.7 ±0.6 9 patients PI; 4 patients PS 4 patients CFRD, 3 IGT, 6 normal 37 ±41.3

7 - A YEAR ON IVACAFTOR

8 A YEAR ON IVACAFTOR 1 patient excluded no adherence / no follow up Glucose metabolism changed - 2 CFRD (of 4), 2 IGT (of 3), 8 normal (1 excluded) (of 6). QOL - not established Pseudomonas colonization in sputum no change (1 patient intermittent was eradicated) Other bacteria and fungi - not examined

9 IVACAFTOR EFFECT ON THE S549R MUTATION

10 CONCLUSIONS: Nine Cystic Fibrosis patients from Israel are indicated for treatment with Ivacaftor. All carry the S549R mutation gating mutation on one or both allelles of the CFTR gene and are pancreatic insufficient. Eight of them are currently being treated with Ivacaftor, and are showing excellent results of improvement in their disease status. Improvements included: Significant lowering of sweat test NaCl, indicating CFTR function. Elevation of all parameters of pulmonary functions. Improved nutritional status with better glucose tolerance. Four Israeli patients receiving the drug without clear indication, did not show significant changes in all mentioned parameters.

11 LIMITATIONS: Small number of patients Missing assessments: QOL (CFQR) Bacteria in sputum (other than Pseudomonas MRSA, Mycobacterium) ABPA Number of exacerbations per year No conclusions about the non indicated group

12 תודות למרכזים על שיתוף הפעולה בי"ח כרמל ד"ר גלית לבנת בי"ח שניידר ד"ר חגית לוין, פר' חנה בלאו בי"ח הדסה ד"ר מאלנה כהן, פר' איתן כרם