Overview of

Acelex (Polmacoxib),
a Novel NSAID
for Osteoarthritis
January 2016

Corporate Overview
CrystalGenomics is a commercial stage biopharmaceutical company with
innovative platform technologies dedicated in the discovery and
development of novel pharmaceuticals in unmet medical need areas.
Vision
Vision

ToTobecome
becomeaafully
fullyintegrated
integratedbiopharmaceutical
biopharmaceuticalcompany
companyininKorea
Koreaand
andexpand
expand
internationally
internationallythrough
throughcollaborations
collaborationsand
andpartnerships
partnerships

History
History

2000.07
2000.07
2003.09
2003.09
2006.01
2006.01
2006.10
2006.10
2012.06
2012.06
2014.07
2014.07
2015.02
2015.02
2015.09
2015.09

Key
KeyPrograms
Programs

Founded
Founded
Publication
PublicationininNature
Nature(article
(articleand
andcover
coverbased
basedon
onplatform
platformtechnology)
technology)
IPO
on
KOSDAQ
IPO on KOSDAQ
Established
EstablishedUS
USsubsidiary,
subsidiary,CG
CGPharmaceuticals,
Pharmaceuticals,Inc.
Inc.for
forclinical
clinicaldevelopment
development
Designated
Designatedbybythe
theKorean
Koreangovernment
governmentasasone
oneofofthe
theKIPC
KIPCcertified
certifiedcompanies
companies
Designated
by
the
Korean
government
as
one
of
the
K-BrainPower
companies
Designated by the Korean government as one of the K-BrainPower companies

Obtained
Obtainedthe
theNDA
NDAapproval
approvalfrom
fromMFDS
MFDSfor
forAcelex
AcelexininKorea
Korea(osteoarthritis)
(osteoarthritis)

Launch
of
Acelex
in Korea
Launch of Acelex in Korea

Next
Nextgeneration
generationNSAID,
NSAID,Acelex
Acelexfor
forosteoarthritis
osteoarthritis(first-in-class)
(first-in-class)
Novel
Novelantibiotic
antibioticcandidate
candidatefor
forMRSA
MRSAinfection,
infection,CG400549
CG400549(first-in-class)
(first-in-class)
Molecular-targeted
cancer
therapeutic,
CG200745
(best-in-class)
Molecular-targeted cancer therapeutic, CG200745 (best-in-class)

Platform Technology : Overview

Integration of in vitro experiments and in silico technology enables the company to streamline
the drug discovery process from gene to drug.
Lead Discovery ( SCPTM )

Structure Determination ( SPSTM )

SCPTM Library
SCPTM Screening

AGTC
TCAG

SCPTM NMR

Virtual
Screening
Target
Selection

In vitro Assay

Synchrotron, NMR

Lead Optimization and Candidate Selection ( SDFTM )

Drug Design &
MediChem

Lead / Target
Complex

Biological
Evaluations

SDFTM X-ray
Target Assays
TM
SDF Informatics Cellular Assays
Parallel Synthesis In vitro DMPK

In vivo
Evaluation
DMPK
Toxicology
Pharmacology

O
R2
R3
O

IND-enabling Tox
(CRO in EU,USA)

N
R1

Pre-clinical
Candidate
3

CG Has Global Standard Drug Discovery Capabilities

CrystalGenomics was the first group to solve the complex crystal structure of PDE5 using
SPS technology: Nature 425, 98-102 (2003).

Viagra
(sildenafil)

Cialis
(tadalafil)

Levitra
(vardenafil)

Former & Current Alliance Partners

SBI BIOTECH CO., LTD.

Novel Therapeutics Pipeline

Area

Product

Indication

R&D Pipeline
Inflammation

Acelex

Osteoarthritis

Disease Target
Area

Candidat
e

Indication
Indication

Current Status

Approved by the MFDS (Feb. 2015),

Launched in Korea (Sep. 2015)
Partnered with TR-Pharm for Turkey & MENA (Jan. 2016)

Infectious Disease

MRSA

Cancer

MDS

Cancer

Pancreatic cancer

Cancer

AML

CNS

Alzheimers Disease

Metabolic

Anemia

Partners

Discovery

Phase I
Preclinical

Ph I

Ph II

PhIIIII
Ph

Ph III
NDA

1. First-in-class , 2. Best-in-class
6

Next Generation NSAID,

Acelex (polmacoxib)
(Novel NSAID with Tissue-Selective Activity)

Acelex, A Novel NSAID for Osteoarthritis

Acelex 2mg Capsule
Novel NSAID for the relief of signs and symptoms of osteoarthritis
Global market for arthritis drugs was USD 50B, of which
$17.5B consisted of COX-2 drugs & NSAIDs but existing
therapies have CV and GI safety issues and there is a great
unmet medical need for a safer drug1
16,344 deaths and 545,452 hospital admissions from GI
bleeding in 2006 and heavy NSAID usage partially to blame2
Celebrex (Pfizer) - 2012 global sales was USD 2.7B and
USD 51M+ sales in Korea with double digit CAGR (2012)
Approved by the MFDS of Korea (Feb. 5, 2015)
Launched in September 2015 (marketed and sold by
Dong-A ST)
Partnered with TR-Pharm for commercialization of
Acelex in Turkey & MENA region, covering 19 countries
(Jan. 2016)
1
2

Acelex Target Market

IMS Top Line Industry Data (2009)

Statistical Brief #65 Healthcare Cost and Utilization Project Jan. 2009 Agency for Healthcare Research & Quality, Rockville, MD
8

Acelex, Tissue Selective NSAID for Osteoarthritis

< Acelex 2mg Capsule >
Tissue-Selective NSAID for the Relief of Signs Symptoms of Osteoarthritis (OA)
Approved by the MFDS (Feb. 2015),
Launched in Korea by Dong-A ST (Sep. 2015)
Partnered with TR-Pharm for Turkey & MENA (Jan. 2016)

Category
Efficacy
Dose
Administration
Frequency

Projected Advantages of Acelex

Quicker onset of relief from the signs and symptoms of OA over celecoxib.
Achieved superior PGA (Physicians Global Assessment) scores compared to celecoxib.
Only 2 mg/day dose, the lowest daily dose among all known NSAIDs.
Convenient once-a-day dosing regimen unlike most other NSAIDs.

Gastrointestinal
Significantly improved GI safety in comparison with traditional NSAIDs on the market.
Side Effects
Cardiovascular
Side Effects

Acelexs tissue-selective-COX2-inhibition mechanism is projected to provide a meaningful

enhancement of cardiovascular safety over currently available NSAIDs.
9

OA Market Characteristics
Osteoarthritis (OA) is characterized by
deterioration of cartilage tissue within joint
and involves entire joint1

Nearby muscles
Underlying bone
Ligaments
Joint lining (synovium)
Joint cover (capsule)

The cause is still not completely known and there is no cure

Aging of population is driving growth of OA market
Cartilage degradation is positively correlated with increasing age and is most
common in people over 55 years of age

Obesity epidemic resulting in more wear and tear on joints is also contributing to
growth of OA market
1

Business Insights 2009; The Autoimmune Outlook to 2013

10

Positioning of A Novel NSAID, Acelex for Osteoarthritis

Acelex would be the first, tissue-selective and once-a-day osteoarthritis drug with a novel
mode of action that specifically targets affected joints to relieve pain and restores
mobility
Acelex 2 mg once-a-day could provide more rapid onset of relief from the signs and
symptoms of osteoarthritis in comparison with Celebrex 200 mg once-a-day without
added safety risk.

11

Product Profiles of Marketed NSAIDs and COX-2 Inhibitors

Classification

Traditional
NSAIDs

COX-2
Inhibitors

Drug Products

Characteristics

GI Risk

CV Risk

Traditional NSAIDs:
naproxen,
ibuprofen,
diclofenac

- Low selectivity
- 24 times/day (752,400 mg/day)

Very high

Moderate or
high

Vimovo (Pozen,
AstraZeneca)

- Naproxen + Esomeprazole
-Twice/day
- FDA warning for long-term use
- Sales volume is small.

Moderate

Moderate

Celebrex
(Celecoxib: Pfizer)

- Sales in 2010 was $2,374M

- Once or twice/day (200400
mg/day)

Low

Moderate

Arcoxia
(Etoricoxib: Merck)

- Sales in 2010 was $398M in EU

- Not approved in the US
- Once/day (30120 mg/day)

Low

High

Low

None
observed
to date

Tissue
Acelex
Selective
(Polmacoxib: CG)
COX-2 Inhibitor

- Tissue selective COX-2 inhibitor

- Once/day (2 mg/day)

12

Mechanism of Polmacoxib
Polmacoxib, a dual inhibitor of COX-2 and human CA (carbonic anhydrase), does
not inhibit COX-2 in CA-rich tissues (e.g. CV system), but it fully inhibits COX-2 in
CA-deficient tissues (inflamed joints).
Whole Blood, Blood
Vessels, CV Tissues

Inflamed Joints (OA, RA)

CA >> COX-2
Preferred binding to CA

CA << COX-2
Preferred binding to COX-2

Polmacoxib
COX-2
CA

Limited side effects

Good efficacy
13

Summary of Clinical Studies for Acelex

Phase

Type

ClinicalTrials.gov
Identifier

Trial
Size

Status

Location

First-in-human study
Single ascending dose (SAD) study

24

Completed

UK

Multiple ascending dose (MAD) study

Safety and Pharmacokinetic (PK) Study

16

Completed

UK

MAD study
Safety and pharmacokinetic study

48

Completed

US

Pilot biomarker study

Drug-drug interaction (DDI) study

NCT00780325
NCT01154764

24
26

Completed
Completed

US (Univ. of Penn)
Seoul, Korea

Supra-therapeutic MAD study

safety and PK study

NCT01154790

48

Completed

Seoul, Korea

Placebo controlled proof-of-concept study

NCT00530452

248

Completed

EU

Celecoxib controlled dose finding study

NCT01341405

125

Completed

Seoul, Korea

Placebo and Celecoxib controlled pivotal

Ph 3 efficacy & safety for approval
and extended safety study

NCT01765296

362

Completed

Seoul, Korea

14

Compiled Summary of Completed Studies

Clinical Studies

Phase 1 studies

Phase 2a study

Summary
Dose dependent exposure observed.
No significant PK differences among different ethnic and gender groups.
Clearly differentiated whole blood vs. plasma distribution of polmacoxib Proof of
polmacoxib-CA binding (7580x higher conc. in whole blood vs. plasma).
No drug-drug interaction observed.
Stable blood pressure maintained throughout entire duration of clinical studies
Absence of significant side effects even in the supra-therapeutic MAD Study
Cardiovascular safety Various measurements including ECG, Holter monitoring, vital
signs, and blood chemistry lab tests did not indicate signs of CV adverse events.
Gastrointestinal safety Absence of significant GI adverse events

Clinically significant efficacious dose = 1.2 mg per day

No drop outs due to lack of efficacy
Maintenance of stable blood pressure throughout entire study

15

Compiled Summary of Completed Studies

Clinical Studies

Summary

Phase 2b study

Phase 3 study

Non-inferiority tests: polmacoxib 2 mg/day and 4 mg/day vs. celecoxib 200 mg/day
Uniform dosing on Days 1-28 (no loading dose)
Very high study drug compliance rates (81-85% in all groups)
Few dropouts (93-95% completion rate among all 3 treatment arms)
Polmacoxib 2 mg and 4 mg were non-inferior to celecoxib 200 mg for all efficacy
measures
Polmacoxib 2 mg dose produced higher efficacy than celecoxib 200 mg, though not
statistically significant (study was not powered for superiority)
No drop outs due to lack of efficacy
Polmacoxib 2 mg has a favorable adverse effect profile (comparable to celecoxib 200 mg)
Polmacoxib 2 mg dose selected for Phase 3 clinical studies

Effficacy (6 week study)

Superiority of polmacoxib 2 mg once-daily vs. placebo
Non-inferiority of polmacoxib 2 mg once-daily vs. celecoxib 200 mg once-daily
Long Term Safety (6 month study)
No drug-related serious adverse events in either of the polmacoxib or celecoxib groups.
Most of the adverse events were mild to moderate and were expected to happen in this
type of trial.
16

Phase III Clinical Study

Summary

17

Phase III Study: Study Title & The Objectives

Study Title and the Objectives of the Study
Study Title:
A Double-blind, Randomized, Multicenter, Active- and Placebo-Controlled Phase III
Study to Evaluate the Efficacy and Safety of CG100649 in Osteoarthritis Patients
Objectives:
The objective of the 6-week Efficacy Study was to evaluate the safety and
non-inferiority of the analgesic efficacy of polmacoxib (formerly CG100649) 2 mg
vs. celecoxib 200 mg, and the analgesic superiority of polmacoxib 2 mg vs.
placebo, when administered once daily in subjects with osteoarthritis of
the hip or knee over the 6 week treatment period.
The objective of the Extension Study was to collect a total of 24 weeks of
safety data for those subjects who agreed to continue into the extension.

18

Acelex, Phase III Study Results

Acelex showed SUPERIOR EFFICACY over celecoxib with statistical significance (p = 0.005)

71.9% of subjects taking Acelex experienced improvement in

signs and symptoms of osteoarthritis
Overall improvement of signs and symptoms of osteoarthritis in terms of PGA* scores at week 3

*PGA (Physicians Global Assessment ): Evaluation of the test subjects by the investigators (physicians)
19

Acelex, Phase III Study Results

Acelex showed QUICKER ONSET OF RELIEF from osteoarthritis symptoms over celecoxib

Acelex showed statistically significant superiority over placebo at

Week 3 (p=0.003), but celecoxib did NOT show statistically
significant differentiation from placebo at Week 3 (p=0.069)
WOMAC Physical Function scores at Week 3

Acelex demonstrated non-inferior or better efficacy against celecoxib in all other efficacy endpoints
including WOMAC-pain and stiffness subscales at week-3 and week-6
20

Phase III Study: Safety (6-week Treatment Period)

Safety Results from the 6-week Efficacy Study
There were no drug-related serious adverse events in either of the polmacoxib or
celecoxib treatment groups.
Most of the adverse events were mild to moderate and were expected to happen
in this type of trial.
There were no statistically significant differences in all three groups.

21

Phase III Study: Conclusions (6-week Treatment Period)

Conclusions
Polmacoxib has successfully met the clinical study endpoints as the 2 mg dose of
polmacoxib was tolerated well and based on the results of the 6week treatment period,
polmacoxib 2 mg demonstrated analgesic efficacy and safety similar to that of celecoxib
200 mg, and analgesic superiority over that of placebo.
However, based on the secondary endpoints of WOMAC-Physical function at Week 3 and
PGA at Week 3, the efficacy profile of polmacoxib was superior in comparison with
celecoxib. This suggests that polmacoxib 2 mg achieves a quicker onset of relief from the
signs and symptoms of osteoarthritis compared to celecoxib 200 mg.
The Treatment Emergent Adverse Events (TEAEs) were reported in this study were
generally mild and of the type expected for COX-2 inhibitor drugs.
There were no clinically meaningful or statistically significant differences in the number of
TEAEs among the groups treated with polmacoxib 2 mg, celecoxib 200 mg or placebo.
22

Phase III Study: Extended Safety Study

Safety Conclusions from Safety Extension Study (24 weeks)
Only polmacoxib 2mg administered (open-label, single arm)

There were no drug-related serious adverse events.

During the safety extension study, the 2mg dose of polmacoxib was tolerated well
and TEAEs were generally mild.
There were no notable increases in the incidence of any TEAEs during the 18-week
safety extension period, or the combined 24-week extended safety period.
There were no clinically relevant findings in the analysis of clinical laboratory tests,
vital signs, ECGs, or physical examination results.

23

Product Profile of Acelex

Category

Projected Advantages of Acelex

Efficacy

Demonstrated quicker onset of relief from the signs and symptoms of OA over Celebrex.
Achieved superior PGA (Physicians Global Assessment) scores, than Celebrex with
statistically significance, an efficacy endpoint for measuring the physicians perception of
patient improvement in terms of the OA signs and symptoms.

Dose

Able to achieve therapeutic efficacy (OA) with only 2 mg/day dose, the lowest dose
among all known NSAIDs (both non-selective and selective COX-2 inhibitors).

Administration
Frequency

Convenient once-a-day dosing regimen

The administration frequencies of most commercially available traditional NSAIDs and
incrementally modified NSAID containing products for OA range between b.i.d (twice
daily) through t.i.d (three times daily).

Gastrointestinal
Side Effects

Acelex has significantly improved GI safety profile in comparison with other commercially
available NSAIDs.
The GI safety profile of Acelex eliminates the need for concomitant administration of GI
protectant agents.

Cardiovascular
Side Effects

Acelexs unique mode of action is projected to provide a meaningful enhancement of

cardiovascular safety from currently available NSAID products.
24

Acelex, Lifecycle Management Strategy

Expansion of Acelex portfolio through development of combination products,
incrementally modified products, new dosage forms, and additional indications.
Goal is to maintain exclusive position up to 2026~2034 and maximize revenues.

Launch of 2 mg
Capsule 2015

Generic Entry Block

2026~2034

Launch in Korea
Export or Out-Licensing

Strengthening of the Acelex brand name through launch of multiple products

25

CrystalGenomics, Inc.
5th F. Bldg.A, Korea Bio Park
700 Daewangpangyo-ro, Bundang-gu,
Seongnam-si, Gyeonggi-do 463-400
Korea

CG Pharmaceuticals, Inc.
5980 Horton Street, Suite 610
Emeryville, CA 94608
U.S.A.

26