T C I L N I D I P I N E

®

The 4th Generation calcium channel blocker

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 2

TOp DUal Action =

Essential Hypertension

INDICATION

Once a day (QD) as 10mg

DOSAGE & PACKAGE

MARKETED COUNTRIES

New Ca2+ Channel Blocker Cilnidipine (IHS) - C27H28N2O7

Manufacturer: Boryung Pharmaceutical Co., ltd. Shelf-life: 36months CTD dossier format

10mg Tablet(FCT) X 10 tablets in alu-alu blister

FORMULATION & PACKING

MISCELLANEOUS

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 3

MECHANISM OF DUAL L/N TYPE OF CILNIDIPINE

<Fig#1. Machanism of Dual type CCB Cilnidipine1)>

Cilnidipine is a unique Ca2+ channel blocker with an inhibitory action on the sympathetic N-type Ca2+ 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 Ca2+ channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations.

<Fig#2. Hypertension Guideline Management Algorithm1)>

1) Cilnidipine a new generation CCB with inhibitory action on sympathetic neurotransmitter release

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 4

RENO-PROTECTIVE EFFECT

REDUCING

REFLEX TACHYCARDIA

& ANKLE EDEMA

“≒”Amlodipine “>” Amlodipine

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 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)

1) Hypertens Res. 2005;28:1003-8

<Fig#3. Changes in blood pressure after amlodipine and cilnidipine treatment. (n=110) 1)

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 6

COMPARABLE BP LOWERING EFFECT vs AMLODIPINE

<Fig. #8. Changes in systolic and diastolic BP2)>

*P<0.05

<Fig. #7. Changes in systolic and diastolic BP1) >

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

1) Int J Med Sci. 2013;10(9):1209-16 2) Kidney International. 2007;72:1543-9

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)

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 7

Reducing ankle edema

Reno-protective effect

Reducing reflex tachycardia

advantages

C I L N I D I P I N E

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 8

REDUCING REFLEX TACHYCARDIA

1) Hypertens Res. 2005;28:1003-8 2) Dual LN-Type CCB Cilnidipine as a New Type of Antihypertensive Drug

<Fig. #9. Changes in pulse rate1)>

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)

<Fig. #10. Changes in pulse rate2)>

Comparison of effects of Ca2+ channel blockers on hypotension-induced 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)

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 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%

PMS in Korea: 0.00% (n=545) – Not dedected 3)

Observational study in Japan : 0.14% (n=2,920)

1) N Am J Med Sci. 2013;5(1):47-50 / 2. Local MA / 3. Hypertens Res. 2007;30(9):815-22 2) J Adv Pharm Technol Res 2015:6[2]:81-5 3) JPERM 2008;1:53-59

Cilnidipine 0.07% ~ 0.14%

<Fig. #11-1. Incidence of ankle edema with various CCB1)> <Fig. #11-2. Incidence of pedal edema in both the group 2)>

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

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 10 1) N Am J Med Sci. 2013;5(1):47-50

<L-type Ca2+ channel blocker> <L/N-type Ca2+ channel blocker>

Ankle circumference (cm)

Baseline After treatment Change p value

Right 26.0±1.94 23.7±2.10 -2.3±0.76 <0.001

Left 26.3±1.95 23.9±1.97 -2.4±0.75 <0.001

Comparison of anthropometric parameters at the start and end of the study

<Fig. #12. Incidence of ankle edema with various CCB2)>

REDUCING ANKLE EDEMA

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 11

RENOPROTECTIVE ACTION

1) J Hypertens. 2002;20:993-1000 / Int Heart J. 2008;49(6):723-32

Dilation of afferent arteriole only

Glomerular pressure↑

AER(albumin excretion rate) ↑

Dilation of both afferent and efferent arteriole

Glomerular pressure ↓

AER(albumin excretion rate) ↓

MECHANISAM

<Fig. #13. Mechanism of renoprotective action1)>

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 12

RENOPROTECTIVE ACTION

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

REDUCING PROTEINURIA

<Fig. #15. Changes in urinary protein/Cr ratio1)> <Fig. #14. Comparison for proteinuria rate vs Amlodipine>

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

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

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 13

Region: CIS Partner: P---- (MNC) Progress: Business proposal

Region: 6 countries in APAC Partner: Sandoz (Novartis) Progress: License contract completed

Region: 25 countries in Africa Partner: A----- (MNC) Progress: Business proposal

Region: Brazil Partner: E----- Progress: Business proposal

Region: Mexico Partner: P------ Progress: Business proposal

Region: 19 countries in MENA Partner: RAM Pharma Progress: License contract completed

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. 201602 l Page 14

N= Incidence rate Reference

S-amlodipine (Levamlodipine)

1,859 0.22% SESA Study group (August 2003). "Safety and Efficacy of S-Amlodipine – SESA study". JAMA-India 2 (8): 87–92.

Cilnidipine

2,920 0.14% Observation study in Japan

545 0.00% PMS Study; JPERM 2008;1:53-59

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 Ca2+ channels along with L-type Ca2+ 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.

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 16

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 May 2016 (12m) May 2018 (36m)

Completed Under testing

Shelf life 36months

Zone II Long term May 2016 (12m) May 2018 (36m)

Completed Under testing

Shelf life 36months

Accelerated Nov 2015 (6m) Completed

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 17

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: https://bricwallblog.wordpress.com/2015/12/30/current-state-of-data-protection-and-exclusivity-in-russia/ - Mexico: https://drive.google.com/file/d/0B3hpt_j_5grCdGhzZ0IwbWtlc1U/view?usp=sharing

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 1st 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. 201602 l Page 18

Original 95%

Gx 5%

Original 66%

Gx 34%

Original 27%

Gx 73%

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 20151) and the market

Original 35%

Gx 65%

JAPAN KOREA

AMLODIPINE NOV., 1993 MAR., 1991

CILNIDIPINE SEP., 1995 APR., 1998

<MA APPROVAL>

Todula l Boryung Pharmaceutical Co., Ltd. l Ver. 201602 l Page 19

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. 201602 l Page 20

2w CDA

3w Business proposal -Sales forecast -Retail price or NHI price (reimbursement) -Market share -Supply price, License fee, Running royalty

3w Term sheet

1w Due-diligence (On-line due diligence / Q&A)

4w Contract review and signing

Ceremony

THANK YOU