The 4 th Generation calcium channel blocker C I L N I D I P I N E

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1 T The 4 th Generation calcium channel blocker C I L N I D I P I N E

2 = TOp DUal Action New Ca 2+ Channel Blocker Cilnidipine (IHS) - C 27 H 28 N 2 O 7 INDICATION Essential Hypertension DOSAGE & PACKAGE Once a day (QD) as 10mg MARKETED COUNTRIES FORMULATION & PACKING 10mg Tablet(FCT) X 10 tablets in alu-alu blister MISCELLANEOUS Manufacturer: Boryung Pharmaceutical Co., ltd. Shelf-life: 36months CTD dossier format Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 2

3 MECHANISM OF DUAL L/N TYPE OF CILNIDIPINE Cilnidipine is a unique Ca 2+ channel blocker with an inhibitory action on the sympathetic N-type Ca 2+ channels, which is used for patients with hypertension. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca 2+ channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. <Fig#1. Machanism of Dual type CCB Cilnidipine 1) > <Fig#2. Hypertension Guideline Management Algorithm 1) > 1) Cilnidipine a new generation CCB with inhibitory action on sympathetic neurotransmitter release Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 3

4 Amlodipine > Amlodipine REDUCING REFLEX TACHYCARDIA & ANKLE EDEMA RENO-PROTECTIVE EFFECT Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 4

5 COMPARABLE BP LOWERING EFFECT vs AMLODIPINE The Fig.#3. shows the characteristics of the 110 hypertensive patients on whom this study was conducted. There were no significant differences between the amlodipine and cilnidipine groups in any clinical characteristic or in the baseline clinic, 24-h, daytime or nighttime BP (Cilnidipine: mean 12.2±4.5mg/d, Amlodipine: mean 5.7±1.8mg/d) <Fig#3. Changes in blood pressure after amlodipine and cilnidipine treatment. (n=110) 1) 1) Hypertens Res. 2005;28: Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 5

6 COMPARABLE BP LOWERING EFFECT vs AMLODIPINE <Fig. #7. Changes in systolic and diastolic BP 1) > <Fig. #8. Changes in systolic and diastolic BP 2) > No changes were observed in the serum Cr level or egfr level with treatment. Changes in these two parameters were not different between the two groups (n=330) *P = 0.31 and P = 0.13, respectively Diastolic BP did not differ between the two groups during the treatment. In the last month of treatment, systolic and diastolic BP did not differ either (n=239) *P<0.05 1) Int J Med Sci. 2013;10(9): ) Kidney International. 2007;72: Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 6

7 Reducing reflex tachycardia Reducing ankle edema advantages C I L N I D I P I N E Reno-protective effect Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 7

8 REDUCING REFLEX TACHYCARDIA <Fig. #9. Changes in pulse rate 1) > <Fig. #10. Changes in pulse rate 2) > Cilnidipine treatment achieved a significantly greater decrease in PR than amlodipine treatment in hypertensive patients. Sympathetic inhibitory action of Cilnidipine(L/N channel) may not caused increasing the PR. (n=110) 1) Hypertens Res. 2005;28: ) Dual LN-Type CCB Cilnidipine as a New Type of Antihypertensive Drug Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 8 Comparison of effects of Ca2+ channel blockers on hypotensioninduced sympathetic activation. Nifedipine, amlodipine, azelnidipine or cilnidipine was intravenously administered to halothane-anesthetized dogs, and changes in mean blood pressure, heart rate and cardiac contractility were observed.. (n=110)

9 REDUCING ANKLE EDEMA Nifedipine 6% Amlodipine 6-15% Nicardipine 3% Nifedipine (extended release) 10-30% Diltiazem 6-10% Nisoldipine 6-19% Isradipine 6% Diltiazem (ER) 2-3% Manidipine 4.9-6% Lacidipine 4-4.4% Lercandipine 1.2-9% Mibefradil 7% Cilnidipine 0.07% ~ 0.14% <Fig. #11-1. Incidence of ankle edema with various CCB 1) > <Fig. #11-2. Incidence of pedal edema in both the group 2) > PMS in Korea: 0.00% (n=545) Not dedected 3) Observational study in Japan : 0.14% (n=2,920) Patients: BP>40/90 adult ages 35~75 (n=60) Method: Cilnidipine 10~20mg/d(n=30), amlodipine 5~10mg/d (n=30) for 3months 1) N Am J Med Sci. 2013;5(1):47-50 / 2. Local MA / 3. Hypertens Res. 2007;30(9): ) J Adv Pharm Technol Res 2015:6[2]:81-5 3) JPERM 2008;1:53-59 Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 9

10 REDUCING ANKLE EDEMA <L-type Ca 2+ channel blocker> <L/N-type Ca 2+ channel blocker> Comparison of anthropometric parameters at the start and end of the study Ankle circumference (cm) Baseline After treatment Change p value Right 26.0± ± ±0.76 <0.001 Left 26.3± ± ±0.75 <0.001 <Fig. #12. Incidence of ankle edema with various CCB 2) > 1) N Am J Med Sci. 2013;5(1):47-50 Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 10

11 RENOPROTECTIVE ACTION MECHANISAM Dilation of afferent arteriole only Glomerular pressure AER(albumin excretion rate) <Fig. #13. Mechanism of renoprotective action 1) > Dilation of both afferent and efferent arteriole Glomerular pressure AER(albumin excretion rate) 1) J Hypertens. 2002;20: / Int Heart J. 2008;49(6): Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 11

12 RENOPROTECTIVE ACTION REDUCING PROTEINURIA <Fig. #14. Comparison for proteinuria rate vs Amlodipine> Changes in proteinuria at 12 months compared to the baseline levels. Left column, changes in mg/g creatinine; right column, percent changes. The amlodipine group showed significantly higher levels than the cilnidipine group (p<0.05):400-5 <Fig. #15. Changes in urinary protein/cr ratio 1) > Results are expressed as the mean ±s.e.m. The urinary protein/cr ratio was suppressed in the cilnidipine group but not in the amlodipine group. *P<0.05 1) Comparison between Cilnidipine and Amlodipine besilate with respect to proteinuria in hypertensive patients with renal diseases 2) Antiproteinuric effect of the CCB cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 12

13 Region: CIS Partner: P---- (MNC) Progress: Business proposal Region: Mexico Partner: P Progress: Business proposal Region: Brazil Partner: E----- Progress: Business proposal Region: 19 countries in MENA Partner: RAM Pharma Progress: License contract completed Region: 6 countries in APAC Partner: Sandoz (Novartis) Progress: License contract completed Region: 25 countries in Africa Partner: A----- (MNC) Progress: Business proposal 24 COUNTRIES ARE CAPTURED FOR THE LICENSE RIGHT BUT THE OTHER TERRITORIES ARE OPENED. S. KOREA, JAPAN, PHILIPPINES, THAILAND, SINGAPORE, HONG KONG, MALAYSIA, TAIWAN, UAE, LEBANON, JORDAN, KUWAIT, QATAR, OMAN, SUDAN, IRAQ, KSA, YEMEN, BAHRAIN, GUINEA, GHANA, MOROCCO, ALGERIA, EGYPT, LIBYA, TUNISIA, BENIN, BRAZIL, MEXICO, RUSSIA Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 13

14 1) There is no head to head study among those 2 molecules but cilnidipine is unique dula(n/l) type CCB and levamlodipine(s-amlodipine) is only L-type which reduce the safety of amlodipine. Since Cilnidipine shows inhibitory action on sympathetic N-type Ca 2+ channels along with L-type Ca 2+ channels, cardioprotective, renoprotective and neuroprotective effects of cilnidipine have been reported in clinical or animal studies 1) 2) Cilnidipine shows better edema incidence rate through the PMS study in Korea and Observation study in Japan. N= Incidence rate Reference S-amlodipine (Levamlodipine) 1, % SESA Study group (August 2003). "Safety and Efficacy of S-Amlodipine SESA st udy". JAMA-India 2 (8): Cilnidipine 2, % Observation study in Japan % PMS Study; JPERM 2008;1:53-59 Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 14

15 Cilnidipine is under 36months stability test for Zone II, and IVb climate condition and completed the 12months. Classification Contents Status Stability Storage condition Room temperature Zone IVb Long term Shelf life Zone II Long term May 2016 (12m) May 2018 (36m) 36months May 2016 (12m) May 2018 (36m) Completed Under testing Completed Under testing Shelf life 36months Accelerated Nov 2015 (6m) Completed Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 16

16 1. Data exclusivity: Many countries have Data protection exclusivity to protect the new data such as NCE drug and grants 6~10 years from MA approval. - Russia: - Mexico: 2. Todula is fomulated by granulation tableting process not the simple direct tableting in order to stable dissolution profile. It make difficult to generate the Bioequivalent test profile for the 1 st Gx player and creates uncertainty risk. Gx player will need 3~4 years along with BE test cost (not sure how many times they try) Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 17

17 Cilnidipine is one of popular CCBs in the Japan and Korea which is using granule tableting, and the Originator still selling with remarkable M/S until ) and the market Gx 34% Gx 5% Gx 65% Original 35% Original 66% Gx 73% Original 27% Original 95% <MA APPROVAL> Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 18 JAPAN KOREA AMLODIPINE NOV., 1993 MAR., 1991 CILNIDIPINE SEP., 1995 APR., 1998

18 TYPE: Licensing & Distribution Agreement COMMERCIAL TERMS (Mandatory) -Supply price: ±40% of local retail price -Licensing fee -Royalty: 3% -Currency: US$ -Target sales Quantity: over 10% of total CCB Market SUPPLIES -Packing: 10blister package bulk or 10tab unit FP -Territory -Contractual period: More than 10 years MA GRANT - Registration: Brand and MA is owned by Boryung basically but whole right for the MA and Brand during term belongs to MA holder - Cost for Registration: MA holder - Order unit: 800,000 tab. Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 19

19 2w 3w 3w CDA Business proposal -Sales forecast -Retail price or NHI price (reimbursement) -Market share -Supply price, License fee, Running royalty Term sheet 1w 4w Due-diligence (On-line due diligence / Q&A) Contract review and signing Ceremony Todula l Boryung Pharmaceutical Co., Ltd. l Ver l Page 20

20 THANK YOU