Han Wook Yoo M.D., Ph.D. Medical Genetics Center, Department of Pediatrics, Asan Medical Center Children’s Hospital

1. Phase 2 multicenter, open label, switch over trial to evaluate the safety and efficacy of Abcertin®(Imiglucerase) in patients with type 1 Gaucher disease previously treated with Cerezyme Han Wook Yoo M.D., Ph.D. Medical Genetics Center, Department of Pediatrics, Asan Medical Center Children’s Hospital University of Ulsan College of Medicine, Seoul, Korea

2. Disclosure statement • Principal investigator of clinical studies using recombinant enzyme products from ISU ABXIS in Korean Gaucher and Fabry disease patients

3. Introduction • Abcertin® • CHO cell derived, human macrophage-targeted recombinant human β-glucocerebrosidase (Imiglucerase) • Structural, physicochemical, biological, and immunological properties are well characterized in pre-clinical studies, and comparable to the reference product. • Reference product: Cerezyme® (Genzyme) • Appearance: Lyophilized vial • Developer: ISU ABXIS Co., Ltd. (S. Korea)

4. Korean Gaucher Patient Registry (April 1997∼ Dec 2011) Introduction * Discontinued ERT

5. Spectrum of GBA mutations in Korean Gaucher patients Introduction Neuronopathic Non-neuronopathic

6. Phase 1 (Stand-alone in Korea) Double-Blind, Placebo-controlled, Single Ascending Dose (SAD) phase 1 clinical trial in Healthy Subjects Day 0 Day 5 Abcertin: 60 Units/ kg Day 0 Day 5 Abcertin: 30 Units/ kg Abcertin: 6 subjects Placebo: 2 subjects Day 0 Day 5 Abcertin: 15 Units/ kg Abcertin : 6 subjects Placebo: 2 subjects Abcertin: 6 subjects Placebo: 2 subjects • Primary objective: To determine the safety and tolerability of single ascending dose of Abcertin in healthy subjects • Secondary objective: To evaluate pharmacokinetics of single ascending doses of Abcertinin healthy subjects

7. Phase 1 – Results (1/2) Safety; No clinically significant change was observed in vital signs, local tolerability test, laboratory test and ECG monitoring following the administration of Abcertin in each dose level.

8. Phase 1 – Results (2/2) Pharmacokinetics; Pharmacokinetic linearity was observed

9. Phase 1 - Conclusion • Phase I study showed favorable safety, tolerability and pharmacokinetic linearity within the dose range with single dose Abcertin infusion in healthy adults. • No clinically significant change was observed in vital signs, local tolerability test, laboratory test and ECG within the dose range. • No serious adverse event was reported. • No antibody formation was observed within the dose range .

10. Phase 2: Switch-over study A multicenter, open label phase 2 study of Abcertin® in patients with Type 1 Gaucher disease previously treated with Imiglucerase 0 6 months Pts pretreated with Imiglucerase Abcertin*, every two weeks Type I Gaucher patients stably treated with Cerezyme during at least past 6 months The dose of Abcertin will be equal to each patient’s previous Cerezyme dose. Primary objective: To evaluate the safety of every other week dosing of Abcertin in patients previously treated with Imiglucerase Secondary objective: To evaluate the efficacy

11. Assessment criteria Safety √ Laboratory evaluation, Vital sign, ECG, Adverse event, Anti-drug antibody Efficacy • Primary endpoint • √ Changes in hemoglobin concentration • √ Changes in platelet counts • Secondary endpoint • √ Changes in liver and spleen volume and liver function • √ Changes in biomarkers: acid phosphatase, angiotensin converting enzyme, • and chitotriosidase • √ Changes in skeletal status and bone mineral density

12. Inclusion criteria • Type 1 Gaucher disease • Patient who was stably treated with Cerezyme® and who was maintaining the consistent dosage of Cerezyme® for at least 6 months prior to study drug administration • Patient aged 2 years or older • Female patient with contraception during the study period (oral or injectable contraceptive hormones, intrauterine device, physical devices using condom, sponge form, jelly, and femidom) • Patient who signed the informed consent form

13. Exclusion criteria • Patient who participated in other clinical studies within 90 days before study drug administration • Unstable hemoglobin concentration and platelet counts for at least 6 months before study drug administration • Hypersensitivity to Cerezyme • Positive to HIV antibody, hepatitis B antigen, and hepatitis C antibody • Fe, folic acid, or vitamin B12-deficient anemia • Patient who received Miglustat within 6 months before study drug administration • Patient who received erythrocyte growth factor or chronic systemic corticosteroids within 6 months before study drug administration • Patient who had clinically significant splenic infarction within 12 months before study drug administration or were splenectomized. • Pregnant or lactating patient

14. Study Flow Chart

15. Results - Study subjects A total of six patients underwent screening, of whom one patient was withdrawn due to ineligibility of inclusion/exclusion criteria, and the remaining five patients were enrolled in this study, and then received the study drug. Among enrolled five subjects, no subject was withdrawn due to adverse events, absence of efficacy, and subject’s withdrawal from the study participation.

16. Results-Safety(1) • (1) Lab tests(Hematology, Serum chemistry, Urinalysis, Coagulation) • : There was no clinically significant change • (2) Vital signs (Systolic/Diastolic blood pressure, Heart rate, Body temperature) • : There was no clinically significant change • (3) Adverse events: • 10 cases, but no relevance to study drug • No SAE • (4) Anti-drug antibody: No antibody formation

17. Results- Safety(2) “Adverse events” One or more adverse events occurred in all of five subjects. Thus, a total of 10 adverse events were reported. No serious adverse event occurred, and no relevance to the study drug was found. In addition, neither withdrawal nor death caused by adverse events was found. [Adverse Events] [Summary of AE]

18. Results- Efficacy(1) Primary endpoint “the mean percentage changes in hemoglobin concentration and platelet count between at the baseline and 24 weeks ” →The mean percent change in hemoglobin concentration and platelet count were increased to be 0.30% and 6.86%, respectively, but no statistically significant change was found (p-value=0.9332, p-value=0.6217).

19. Results- Efficacy(2) Hemoglobin concentration and Platelet count were ranged within ±1g/dL and ±20%, respectively, at all measurement points. ▶ Abcertin® maintained the efficacy of Cerezyme®throughout the administration period.

20. Results- Efficacy(3) Secondary endpoint 1. Changes in liver and spleen volume: No significant changes 2. Changes in liver function (ALT, AST): No significant changes 3. Changes in skeletal status: No significant changes 4. Changes in bone mineral density: No significant changes 4. Changes in biomarkers (ACE, Acid phosphatase, and Chitotriosidase): No significant changes

21. Safety Efficacy No changes in hemoglobin concentration, platelet count, liver and spleen size, skeletal status and bone mineral density No clinically significant adverse events Conclusion • Abcertin® maintained the efficacy of Cerezyme® and showed no clinically significant AE • Abcertin® could be used as an alternative therapeutic agent in patients who are treated with Cerezyme® • Further study is needed in treatment-naïve Gaucher patients from a larger cohort to further verify its clinical efficacy.

22. Acknowledgement Son YB, Department of Clinical Genetics, Ajou University School of Medicine Koh JM, Department of Pediatrics, Seoul National University College of Medicine Lee JS, Department of Clinical Genetics, Severance Children’s Hospital Lee BH, Medical Genetics Center, University of Ulsan College of Medicine