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CG100649, a Novel Dual-Acting COX-2 and Carbonic Anhydrase Inhibitor: Ascending Single CrystalGenomics, Inc.
6F, 2nd Building of Asan Institute for Life Sciences
388-1, Pungnap-2dong, Songpa-gu
Dose and Multi-Dose Pharmacokinetics and Safety Evaluation in Healthy Male Subjects
Asan Medical Center, Seoul, 138-736, Korea
Poster # 232
Tel) +82-2-3010-8618
Fax) +82-2-3010-8601
Seonggu Ro, Young-Ho Park, Timothy G. K. Mant, William K. Schmidt, and Joong Myung Cho
CrystalGenomics, Inc., Seoul, Korea and CG Pharmaceuticals,Inc., Emeryville,CA, USA
ABSTRACT
Table 2. Demography of multiple ascending dose study (Mean ± SD)
Table 4. Pharmacokinetic parameters of multiple ascending
Table 5. Daily pre-dose levels in the multiple ascending
Treatment (CG100649/placebo) #
CG100649 is a novel dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA) inhibitor which is dose study. Mean ± SD or Median (range)
dose study. Mean ± SD
Parameter
3 mg / 0.4 mg/day
6 mg / 0.8 mg day
being developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. Single oral doses of 1 Mean Pre-Dose Plasma Level (ng/ml)
3 mg loading +
6 mg loading +
(ng.hr/ml)
mg, 5 mg, 8 mg, and 12 mg of CG100649 were well tolerated when given to healthy male subjects (N=4 active Age (yrs)
0.4 mg/day for 7 days
0.8 mg/day for 7 days
and 2 placebo subjects per dose). There was statistically significant evidence for a linear dose-proportional increase, on average, in systemic exposure to CG100649 as measured by C . Single-dose CG100649 Weight (kg
demonstrates a long terminal elimination half-life of approximately 5 days. Multiple doses consisting of a single Height (cm)
loading dose followed by daily maintenance doses over 7 days (Group 1: 3 mg / 0.4 mg/day; Group 2: 6 mg / 0.8 BMI (kg/m2)
mg/day; N=6 active and 2 placebo subjects per dose) demonstrated rapid achievement of steady state and # Subjects received 3 mg on Day 1 and 0.4 mg on Days 2-8, or subjects received 6 mg on Day 1 and 0.8 mg on Days 2-8.
consistent systemic exposure. After repeated daily dosing, the degree of accumulation of CG100649 in plasma n=6; NC = Not calculated. (Ro) on Day 8 was not appreciably different from that observed on Day 1. On average, Ro values ranged from * Group 1: Subjects received 3 mg on Day 1 and 0.4 mg on Days 2-8. 1.1 to 1.2, consistent with rapid achievement of steady-state following a loading dose. Plasma CG100649 * Group 2: Subjects received 6 mg on Day 1 and 0.8 mg on Days 2-8. concentrations of 4 to 5 ng/mL (Group 1) and 6 to 9 ng/mL (Group 2) were maintained during the repeat-dose Singe Dose Study: CG100649 was well tolerated. A total of 14 treatment-emergent adverse events were
regimen. Maximum plasma concentrations of CG100649 were reached at approximately 3 to 12 hr post dose; reported by 8 of the 24 subjects; 25% of subjects in the treatment group and 50% of subjects in the placebo. thereafter, plasma CG100649 concentrations declined with a mean apparent terminal half life of approximately There was only one gastrointestinal related adverse event (mild flatulence) following treatment with CG100649. There was no evidence of occult gastrointestinal blood loss. No clinically significant laboratory abnormalities 100 to 109 h. Extrapolating from the preclinical efficacy data, the plasma concentrations with the higher were reported and there were no obvious trends in any of the laboratory data or in other safety including physical maintenance dose regimen exceeded probable therapeutic concentrations by at least four fold. All doses were examination, vital signs, and 12-lead ECG. well tolerated. Use of a loading dose + reduced maintenance dose regimen may reduce the time to reach steady state plasma concentrations to approximately one day. Following single administration, plasma concentrations of CG100649 were generally measurable up to 144 hr (1 mg), 240 hr (5 mg), 384 hr (8 mg) and 480 hr (12 mg) post-dose. Max plasma concentrations were reached at approximately 5.5 to 72 hr post-dose (median estimates), then declined with a mean apparent terminal half-life of approximately 111 hr (5 mg) and 133 hr (12 mg). CG100649 is a novel dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA) inhibitor which is being developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. The CA inhibitory There was statistically significant evidence for a dose-proportional increase, on average, in systemic exposure to 108 144 180 216 252 288 324 360 CG100649 as measured by C Time post-dose (hr)
Time post-dose (da y)
Time post-dose (hr)
activity of CG100649 is unlikely to affect CG100649's intended therapeutic effects since CG100649 is believed to dissociate from CA and increase its local concentration in tissues which have low CA activity, such as The prolonged half-life would result in steady state plasma concentrations being reached over approximately 20 Fig. 2. Day 1 mean pre-dose
Fig. 3. Days 2-8 mean pre-dose
Fig. 4. Day 8-23 terminal plasma
plasma concentration-time
plasma concentration-time profiles
concentration-time profiles
inflamed joints. Given that CAs are abundantly present in a variety of tissues and cells, the high affinity of days of fixed dosing. However the good tolerance of higher doses enables an oral loading dose to be used to profiles following 3 mg or 6 mg
following 3 mg + 0.4 mg/day, or 6 mg +
following final 0.4 or 0.8 mg dose
CG100649 for CAs may significantly affect the tissue distribution profile. CG100649 is expected to show reduce the time to reach steady state plasma concentration in future clinical studies. loading doses.
0.8 mg/day.
reduced COX-2 inhibition in tissues or cells highly enriched with CAs (GI tract, blood, and kidney) due to substantial uptake of CG100649 by CAs; this may provide protection for organs of toxicity concern for NSAIDs. Table 3. Pharmacokinetic parameters of single ascending dose
These data represent the first-in-man Phase I data for CG100649 in healthy male volunteers. CG100649 is study Mean ± SD or Median (range)
currently in phase II clinical trials in Europe. CONCLUSIONS
(ng.hr/ml)
1. CG100649 was well tolerated by the healthy male subjects participating in this study. Two phase I studies were performed in the UK to investigate the safety, tolerability and pharmacokinetics (PK) 2. The subject incidence of adverse events was higher in subjects receiving the lower dose (83% of subjects of CG100649 administered orally to healthy male volunteers. The first study was a double-blind, receiving 3 mg / 0.4 mg CG100649 compared to 50% of subjects receiving 6 mg / 0.8 mg CG100649). All placebo-controlled, randomized, single escalating dose study (1, 5, 8, or 12 mg) in four sequential groups of 6 adverse events were mild in intensity. healthy male subjects (24 total subjects; 2:1 active: placebo randomization). The second study was a n=4 unless otherwise stated [ ]; NC = Not calculated. Time post-dose (hr)
3. Plasma concentrations were measurable up to 480 hr after the 1st dose and up to 360 hr after the 8th dose. double-blind, randomized, placebo-controlled study to evaluate the safety and PK of two oral multiple rising Fig. 1. Mean plasma concentrations following
dose regimens of CG100649 administered as a loading dose (3 or 6 mg) followed by 7 daily doses (0.4 or 0.8 single oral administration of 1, 5, 8, or 12 mg
4. Plasma CG100649 concentrations of 4 to 5 ng/mL (Group 1) and 6 to 9 ng/mL (Group 2) were maintained mg/day) which was designed to achieve rapid steady-state blood levels based on the initial Phase I data. CG100649
during the repeat-dose regimen. Maximum plasma concentrations of CG100649 were reached, on average, at approximately 3 to 12 hr post-dose. Table 1. Demography of single ascending dose study (Mean ± SD)
Multi-Dose Study: CG100649 was well tolerated. There were 24 treatment-emergent adverse events; 16 were
5. The mean apparent terminal half-life was 100 to 109 hr. Treatment (CG100649/placebo)
reported by 8 subjects receiving CG100649 (67% of subjects) and 8 events were reported by 4 subjects receiving placebo treatment (100% of subjects). All adverse events were mild in intensity. No clinically significant laboratory Parameter
6. Between-subject (inter-individual) variability in the extent of systemic exposure was generally low, with abnormalities were reported and there were no apparent trends in the other safety parameters (physical coefficients of variation ranging from 12% to 30%. examination, vital signs, 12-lead ECG. Age (yrs)
7. Systemic exposure to CG100649 on Day 8 was not appreciably different to that observed on Day 1. Plasma concentrations of 4 to 5 ng/mL (Group 1) and 6 to 9 ng/mL (Group 2) were maintained during the repeat-
Weight (kg)
dose regimen. Max plasma concentrations were reached at approximately 3-12 hr post-dose; thereafter, plasma CG100649 concentrations declined with a mean apparent terminal half-life of approximately 100-109 hr. Between- Supported by a grant from CrystalGenomics, Inc. Height (cm)
subject (inter-individual) variability in systemic exposure (AUC ) was generally low, with coefficients of variation ranging from 12% to 30%. Following a loading dose + daily maintenance dose regimen, systemic exposure on Day
BMI (kg/m2)
8 was not appreciably different from Day 1.

CG100649, a Novel Dual-Acting COX-2 and Carbonic Anhydrase Inhibitor: Multi-Dose
CrystalGenomics, Inc.
6F, 2nd Building of Asan Institute for Life Sciences
Pharmacokinetics and Safety Evaluation in Healthy Male and Female Subjects
388-1, Pungnap-2dong, Songpa-gu
Asan Medical Center, Seoul, 138-736, Korea
Poster # 234
Tel) +82-2-3010-8618
William K. Schmidt, Bernard Chung, Kei-Lai Fong, Suzanne Swan, Harry Alcorn Jr., Cheol-Soon Lee,
Fax) +82-2-3010-8601
Cheol Min Kim, Sun Nam Kim, Ming Guan Piao, Min Suh Kang, Ho-Jin Chang, Seonggu Ro, and Joong Myung Cho
CrystalGenomics, Inc., Asan Medical Center, Seoul, Korea and CG Pharmaceuticals,Inc.,Emeryville, CA, USA
ABSTRACT
No clinically significant changes in laboratory parameters, physical examinations, vital sign parameters, Table 2. Baseline subject characteristics at screening
physical examination results, or ECG recordings were reported in this study. The total number, the nature, and Oral CG100649 was administered in 3 escalating loading and maintenance dose regimens for 5 days in 47 Active Treatment A
Active Treatment B
Active Treatment C
the severity of reported AEs were similar among the 4 treatment groups. All of adverse events were considered healthy male and female volunteers. Subjects in Cohort A received 2.0 mg (Day 1) followed by 0.3 mg/day to be mild or moderate in severity and resolved by the end of the study. The percentage of adverse events that (Days 2-5). Subjects in Cohort B received 4.0 mg (Day 1) followed by 0.6 mg/day. Subjects in Cohort C were considered related to the study drug was highest in the placebo group (3/12; 25.0%). The most frequently received 8.0 mg (Day 1) followed by 1.2 mg/day. Within each dose cohort, 12 subjects (6 male and 6 female) reported adverse events were headache (31% of active treatment subjects and 42% of placebo subjects), rash were randomized to receive active compound and 4 subjects (2 male and 2 female) received placebo. PK and Ethnic origin
(23% of active treatment subjects and 33% of placebo subjects), ecchymosis (11% of active treatment subjects safety evaluations continued through Day 31. All doses were well tolerated. CG100649 was well absorbed with and 0% of placebo subjects), and pain in extremity (9% of active treatment subjects and 0% of placebo linear dose-proportionality in among the 3 treatment groups. Inter-subject variability was low (generally 20% or less). Nearly all subjects achieved peak blood & plasma levels in 4-8 hr after the initial loading dose and maintained approximately steady-state blood levels for the remaining 4 days. Due to its preferential high-affinity No clinically significant ECG abnormalities occurred during the course of the study. One subject (0.6 mg/d) showed a "short burst of atrial fibrillation" on Day 5 of the Holter ECG monitoring, but follow-up evaluations binding to red blood cell carbonic anhydrase (CA), CG100649 showed 85-100x higher concentrations in whole CG100649 was well absorbed following oral administration. Nearly all subjects achieved peak blood and plasma indicated that the subject had no abnormal findings on stand alone ECG readings or continuous telemetry blood than plasma in all 3 dose cohorts, in both males and females, from Day 1 through Day 5. The terminal concentrations in 4-8 hr after the initial loading dose and maintained approximately steady-state blood and plasma ECG readings. The safety review board determined that the Holter recording on Day 5 was an isolated incident. half-life in both blood and plasma was 5-6 days. One female subject in Cohort C appeared to have faster drug levels with daily maintenance dose for the remaining 4 days. Due to its preferential high-affinity binding to red blood cell carbonic anhydrase, CG100649 showed approximately 85-100 times higher concentrations in whole Systolic and diastolic pressures were very stable as depicted in Fig. 3. elimination, so progressively declining blood levels were observed from Days 2-5; plasma levels were blood than plasma in all 3 dose cohorts, in both males and females, from Day 1 through Day 5. The mean maintained at steady-state. No gender differences were apparent in drug exposure. Consistent with its potent terminal half-life in both blood and plasma ranged from 4-6 days. CA inhibitory activity, dose-related increases were observed in serum chloride (females much more than males) and in plasma aldosterone (females possibly more than males). These data provide the first evidence of a Table 3. Blood PK parameters for CG100649 following single oral loading
COX-2 inhibitor with functional CA activity which may improve its overall safety profile by reducing effective free dose and 4 daily maintenance dose (N=6 per gender). Mean ± SD or
Median (range)
Cohort A; M
concentrations in tissues with high CA activity. Cohort A; F
Cohort B; M
Cohort B; F
Cohort C; M
(ng.hr/ml)
Cohort C; F
2 mg + 0.3 mg/day
CG100649 is a novel dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA) inhibitor which is 7 (4-12) 275±23 being developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. Given that CAs are 316±59 6277±1186 6638±1665 120.6 abundantly present in a variety of tissues and cells, the high affinity of CG100649 for CAs may significantly affect 4 mg + 0.6 mg/day
the tissue distribution profile. CG100649 is expected to show reduced COX-2 inhibition in tissues or cells highly 8 (4-12) 519±98 10306±1900 3.5 (2-12) 551±89 11978±1945 147.9 enriched with CAs (GI tract, blood, and kidney) due to substantial uptake of CG100649 by CAs; this may provide protection for organs of toxicity concern for NSAIDs. CG100649 is believed to dissociate from CA and increase 573±45 11180±1056 538±49 11186±1287 103.4 Dosi ing (
ng (hr) h)
its local concentration in tissues which have low CA activity, such as inflamed joints. CG100649 is currently in 8 mg + 1.2 mg/day
Fig. 3. Systolic and diastolic blood pressure (mmHg) – Mean course and SE bars by treatment,
phase II clinical trials in Europe. 6 (3-8) 847±111 17816±2387 3.5 (0-4) 936±145 20260±2906 129.9 gender and time of all subjects
6 (4-12) 1156±222 22402±3700 3.0 (0-4) 1091±232 21882±4452 116.2 CONCLUSIONS
Time post-dose (hr)
a: median (range); b: t was estimated using data from Day 5 through Day 30 (if available); Fig. 1. Logarithmic blood concentrations
(Day 1), calculated using individual values; d: N=5 following last dose on Day 5
CG100649 was well tolerated in this U.S. Phase I study in 47 healthy male and female study. A Phase I double-blind, multi-dose, placebo-controlled study was conducted in 47 healthy male and female Table 4. Plasma PK parameters for CG100649 following single oral
volunteers in the United States. The objectives were to assess the safety, tolerability, and pharmacokinetics of 3 All subjects achieved peak blood and plasma concentrations in 4-8 hr after the initial loading dose and loading dose and 4 daily maintenance dose (N=6 per gender). Mean ± SD
Cohort A; M
escalating loading and maintenance dose regimens of CG100649 administered orally for 5 total days. Normal maintained approximately steady-state blood and plasma levels with daily maintenance dose for the Cohort A; F
or Median (range)
remaining 4 days. healthy male and female subjects (1:1 randomization within each treatment group) received a loading dose (Day Cohort B; M
Cohort B; F
1) and 4 daily maintenance doses (Days 2-5) of 2 mg / 0.3 mg (Cohort A), 4 mg / 0.6 mg (Cohort B), 8 mg / 1.2 CG100649 showed approximately 85-100 times higher concentrations in whole blood than plasma due to Cohort C; M
mg (Cohort C) or placebo. Active doses were designed to maintain quasi-steady-state blood levels during the Cohort C; F
its preferential high-affinity binding to RBC carbonic anhydrase. No gender differences were apparent in dosing period. There were no Serious Adverse Events (SAEs) in any dose group. (ng.hr/ml)
drug exposure for cohorts A and B. In cohort C (high dose), exposure in female subjects was noticeably 2 mg + 0.3 mg/day
higher than in male subjects. Table 1. Demography of the study (Mean ± SD)
7 (4-12 2.9 ± 0.4 These data provide the first evidence for a COX-2 inhibitor with functional CA activity which may improve Active Treatment A
Active Treatment B
Active Treatment C
10 (6-24 3.7 ± 0.6 its overall safety profile by reducing effective free drug concentrations in tissues with high CA activity Parameter
4 mg + 0.6 mg/day
(blood vessel endothelial cells) while enhancing free drug concentrations in tissues with low CA activity (Female 6)
(Female 6)
(Female 5)
(Female 6)
(Female 23)
8 (4-8) 6.5 ± 0.7 Age (yrs)
6(4-12) 7.8 ± 1.9 4 (0.5-8) 8.0 ± 1.8 8 mg + 1.2 mg/day
Weight (kg)
This study was supported by Bio-star project of Ministry of Knowledge Economy of Korea.
Height (cm)
Supported by a grant from CrystalGenomics, Inc. Time post-dose (hr)
BMI (kg/m2)
a: median (range); b: t was estimated using data from Day 5 through Day 30 (if available); Fig. 2. Logarithmic plasma concentrations
(Day 1), calculated using individual values; d: N=5 following last dose on Day 5

CG100649, a novel dual-acting COX-2 and carbonic anhydrase inhibitor:
CrystalGenomics, Inc.
6F, 2nd Building of Asan Institute for Life Sciences
388-1, Pungnap-2dong, Songpa-gu
Preclinical pharmacology
Asan Medical Center, Seoul, 138-736, Korea
Poster # 118
Tel) +82-2-3010-8618
Fax) +82-2-3010-8601
Seonggu Ro, Cheol Soon Lee, Cheol Min Kim, Sun Nam Kim, Ming Guan Piao, Ho-Jin Chang, William K. Schmidt and Joong Myung Cho
CrystalGenomics, Inc., Seoul, Korea and CG Pharmaceuticals,Inc., Emeryville,CA, USA
ABSTRACT
Table 2. Inhibitory activity of CG100649 against CAs
The OA therapeutic plasma level of CG100649 was estimated from the efficacy of CG100649 in the adjuvant- CA-I IC50, nM
CA-II IC50, nM
Remark a,b
induced arthritis (AIA) model. In this model, the CG100649 showed superior efficacy to indomethacin and CG100649 is a novel dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA) inhibitor which is being CG100649
developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. CG100649 has moderate COX-2 selectivity over COX-1, ranging from 15-fold in human cells (whole blood, platelets and macrophages) to 45-fold in mouse peritoneal macrophages. In the ex vivo COX-1 activity assay, CG100649 showed weaker COX-1 inhibitory Inhibition
activity than indomethacin in rat whole blood. CG100649 was a potent inhibitor of inflammation in adjuvant-induced Celecoxib
CG10649,
100649, 0.
arthritis and collagen-induced arthritis in Lewis rats (paw swelling ED50s were 0.10 and 0.22 mg/kg/day, respectively). a. Assayed by the CA catalyzed hydrolysis of p-nitrophenylacetate in 5% DMSO aqueous buffer CG10649,
100649, 0.
CG100649 and indomethacin showed similar potencies in the mouse acute air pouch and rat acute paw edema b. Values of in-house study unless noted otherwise CG10649,
100649, 0.
inflammatory animal models. CG100649 was 5x more potent than indomethacin in the thermal hyperalgesia rat model c. Literature values cited from Weber A. et al. J Med Chem 2004, 47, 550-557 CG10649,
100649, 1
CG100649
and had significantly greater anti-pyretic potency than ibuprofen. CG100649 inhibited hCA I and II activity with IC50s of * CG100649 is a potent inhibitor of CA-I & CA-II 0.336 µM and 0.062 µM, respectively (acetazolamide IC50s were 0.68 µM and 0.0091 µM, respectively). The CA * Celecoxib inhibits CA-II but it is almost inactive against CA-I inhibitory activity of CG100649 is unlikely to affect CG100649's intended therapeutic effects since CG100649 is believed - The assay medium contains 5% DMSO and does not reflect in vivo conditions to dissociate from CA and increase its local concentration in tissues which have low CA activity, such as inflamed joints. Given that CAs are abundantly present in a variety of tissues and cells, the high affinity of CG100649 for CAs may CG100649 is a dual inhibitor of COX-2 and carbonic anhydrase. The working hypothesis is that CG100649 significantly affect the tissue distribution profile. CG100649 is expected to show reduced COX-2 inhibition in tissues or Rofecoxib
ED = 0.74 mg/kg/day b cannot inhibit COX-2 in CA-rich tissues (CV & GI), but it fully inhibits COX-2 in CA-lacking tissues such as cells highly enriched with CAs (GI tract, blood, and kidney) due to substantial uptake of CG100649 by CAs; this may inflammatory joints. Thus, CG100649 should have reduced COX-2 effects in blood, blood vessels and kidneys provide protection for organs of toxicity concern for NSAIDs. It is possible that the high affinity of CG100649 for CA could a. 10 Lewis rats per group, mg/kg/day and BID by binding to CA and not binding to COX-2. Day of Treatment produce a reduction in blood pressure similar to the potent CA inhibitor acetazolamide. CG100649 is currently in phase II clinical trials in Europe. Figure 2. Efficacy of CG100649 in the adjuvant-
Inflamed joints
Induced arthritis (AIA) animal model.
[CA] >>> [COX-2] [CA] <<< [COX-2] Many NSAIDs are available for curing arthritic pain through the inhibition of COX-2 or COX-2. However, there is still a large CG100649 showed an ED of 0.1 mg/kg/day BID against AIA in male Lewis rats. Assuming linear unmet medical need for better antiinflammatory analgesics because adverse effects in the gastrointestinal (GI) track and pharmacokinetics for doses lower than 1mg/kg, the plasma C for 0.1 mg/kg/day BID may be extrapolated cardiovascular (CV) system. Adverse effects on GI tract are believed to be due to inhibition of COX-1 that reduces the protective to be 4 ng/ml as Table 5. of prostaglandins on gastric and intestinal mucosa. On the other hand, adverse effects on the CV system may be caused by COX-2 inhibition that may result in thrombosis and vasoconstriction. We hypothesized that it may be possible to avoid GI and CV Table 5. Plasma PK Data in Male SD Rats for CG100649 (po)
side effects by tissue-specific inhibition of COX-2. CG100649 is an orally available, small molecule dual inhibitor of COX-2 and ng•hr/ml
carbonic anhydrase (CA). Oral administration of CG100649 produces significant levels of free active drug in joints, synovial fluid, and the CNS which are devoid of CA activity, but it is sequestered in an inactive form in many other tissues because the drug is High CA = limited side effects No CA = Good efficacy 1.0 mg/kg
tightly bound to CA-I and CA-II, a known family of proteins that are prevalent in the blood and in sites of potential COX-2 toxicity. Figure 1. Working hypothesis for the tissue specific inhibition of COX-2 by dual inhibition
0.5 mg/kg
CG100649 is currently under development for rheumatoid arthritis, osteoarthritis and acute pain. of COX-2 and CA to avoid side effects of NSAIDs.
0.05 mg/kg
IN VITRO PHARMACOLOGY
IN VIVO PHARMACOLOGY
Thus, the projected OA therapeutic plasma level of CG100649 is 4 ng/ml and the OA therapeutic plasma exposure is [4 ng/ml x 24 hr] or about 100 ng•hr/ml. CG100649 is an orally available small molecule dual inhibitor of COX-2 and CA. The compound is a highly active Table 4. Efficacy of CG100649 in the standard preclinical animal models.
inhibitor for COX-2 and is moderately selective for COX-2 over COX-1. It inhibits CAs at nM concentrations. Animal Model
CONCLUSIONS
(male rats)
CG100649
Celecoxib
Rofecoxib
Table 1. Inhibitory activity of CG100649 against COX
Adjuvant-induced Arthritis b
0.5-1.0 mg/kg/day 0.74 mg/kg/day c IC50, ng/ml
1) CG100649 is a highly active inhibitor of COX-2 which is moderately selective for COX-2 over COX-1. It also Collagen-induced Arthritis
Selectivity
inhibits CAs in the nanomolar level. Such dual inhibition is designed to avoid COX-2 inhibition in CA-rich tissues (CV & GI) but fully inhibit COX-2 in CA-lacking tissues such as inflammatory joints. LPS-induced Pyresis
42% @ 30 mg/kg c CG100649
Platelets (COX-1) Yeast-induced Pyresis
2) CG100649 showed equal or higher efficacy and potency vs. celecoxib, indomethacin and rofecoxib in a Rat Paw Edema f
variety of preclinical animal models such as adjuvant-induced arthritis (AIA) model. Platelets (COX-1) a. Values of in-house studies unless noted otherwise; b. Preventive model & BID; 3) The OA therapeutic plasma level of CG100649 is projected to be 4 ng/ml. c. Drug manufacturer's data; d. Carrageenan-induced thermal hyper hyperalgesia; e. by Randall-Selitto method; f. Carrageenan-induced rat paw edema. Rofecoxib
Supported by a grant from CrystalGenomics, Inc. - CG100649 is 23x more potent than rofecoxib vs. COX-2 in isolated PBMCs - CG10649 shows a modest COX-2 selectivity over COX-1 CG100649 produces potent anti-inflammatory and analgesic activity in animal models of arthritis. It shows less - CG10649's effects are markedly attenuated in whole blood due to plasma protein binding and CA binding in RBCs activity against acute inflammation than chronic inflammation because of abundant presence of CAs in cells involved in acute inflammation. Thus CG100649 is suitable for use in chronic inflammation.

CG100649, a novel dual-acting COX-2 and carbonic anhydrase inhibitor:
CrystalGenomics, Inc.
6F, 2nd Building of Asan Institute for Life Sciences
388-1, Pungnap-2dong, Songpa-gu
Preclinical safety evaluations
Asan Medical Center, Seoul, 138-736, Korea
Poster # 121
Tel) +82-2-3010-8618
Fax) +82-2-3010-8601
Cheol Soon Lee, Cheol Min Kim, Sun Nam Kim, Ming Guan Piao, Ho-Jin Chang, William K. Schmidt, Joong Myung Cho, and Seonggu Ro
CrystalGenomics, Inc., Seoul, Korea and CG Pharmaceuticals,Inc., Emeryville,CA, USA
ABSTRACT
Table 2. Results of 4 Week repeat dose toxicity study of CG100649 in monkey
CG100649 is a novel dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase (CA) inhibitor which is currently in phase II clinical trials in Europe. CG100649 was negative in the bacterial Ames assay and in the in CG100649 has completed the following the GLP toxicity studies in the UK or US: Daily Dose
Plasma Exposure (Day 28)
vivo mouse micronucleus assay at oral doses up to 1250 mg/kg). The mutagenic potential of CG100649 was further investigated in the unscheduled DNA synthesis assay in rat liver. CG100649 administered to rats at oral (2,420 + 1,260) – (12,500 + 9,770) ng•hr/ml Table 1. GLP Toxicity studies of CG100649
doses of 62.5 and 125 mg/kg (male) and 7.5 and 15 mg/kg (female) failed to induce repairable DNA lesions in liver. Male rats tolerated target doses up to 5.0 mg/kg/day for 28 days, however females showed treatment- Animal Toxicity Studies
(2,010 + 1,180) – (12,700 + 8,610) ng•hr/ml related histopathological findings in the intestines at target doses of 1.0 mg/kg/day and higher. The systemic exposure was greater in females rats which is commonly observed in rats due to a lower metabolizing capacity in Safety pharmacology studies
Wide GI safety margins were observed despite the modest COX-2 selectivity. Rats did not show gastric females. The general activity and behavior in rats was not altered by the oral administration of CG100649 at Genetic toxicity studies
findings even at an exposure of 30,000 ng•hr/ml. Monkeys did not show gastric findings up to an exposure single dose levels of up to 30 mg/kg. Similarly, oral treatment of CG100649 did not significantly affect the larger than 20,000 ng•hr/ml. respiration rate or end tidal volume in conscious rats. Administration of oral doses up to 30 mg/kg CG100649 to Single dose toxicity studies
awake cynomolgus monkeys had no marked effect on arterial blood pressure, heart rate or lead II ECG Repeat dose toxicity studies
Safety margins were estimated for OA treatment, assuming that the therapeutic plasma level is 4 ng/ml and parameters (RR, PR, QT, QTcF and QTcQ intervals or QRS duration), waveform or rhythm in the 8 hours 4-week rat
daily therapeutic exposure is 100 ng•hr/ml. following dosing. Treatment with 2 µg/ml CG100649 in HEK293 cells stably transfected with hERG cDNA produced no inhibition of hERG tail current. In whole body radiography (QWBPI) studies in rats, the highest 4-week monkey
radioactivity was associated with whole blood and tissues with high blood perfusion such as liver, lung, kidney, 90-day rat
Table 3. GI safety margins of CG100649
and bone marrow which also have the highest CA activity. These data project a favorable safety profile for 90-day monkey
CG100649 in humans. Safety Margin
Developmental toxicity studies
Reproductive toxicity studies
Intestinal
Estimated from NOAEL exposure Cyclooxygenase inhibition by classical non-steroidal anti-inflammatory drugs (NSAIDs) effectively treats acute and Dog renal studies
Calculated from exposure with gastric finding chronic pain. However, 2% to 4% of patients taking NSAIDs have symptomatic gastrointestinal (GI) ulcers and their complications. Further studies suggest that COX-2 inhibition mediates the anti-inflammatory effects of NSAIDs, whereas COX-1 inhibition is responsible for adverse effects on the GI tract. This lead to the development of COX-2 selective In vitro genotoxicity studies showed that CG100649 does not induce reverse mutations in the Ames test. CONCLUSIONS
inhibitors (coxibs) that have the same anti-inflammatory benefits of nonselective NSAIDs but fewer GI side effects. However, it increased chromosomal aberrations in CHO cells at 200 μg/mL which also produced 50% cellular Effects of COX-2 inhibition on the cardiovascular (CV) system are not straightforward. Inhibition of COX-2–derived PGI Safety pharmacology, genetic toxicity, single and repeat dose toxicity (4-week and 90-day studies in rat toxicity. In vivo studies showed that CG100649 did not produce genotoxic effects in the mouse bone marrow removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo (2) leading to an elevated and monkey), developmental toxicity, reproductive toxicity, and dog renal studies show a favorable safety micronucleus test or in the unscheduled DNA synthesis (UDS) assay in rat liver. The weight of evidence risk of myocardial infarction and stroke. Thus, all commercially available NSAIDs and coxibs produce adverse GI or CV suggests that the genotoxicity risk is low. profile for CG100649. side effects in susceptible patients. Since the CV side effects of NSAIDs may be generated by COX-2 inhibition, we hypothesized that tissue-specific inhibition of COX-2 in inflamed joints may be a novel way to prevent adverse CV side effects in vascular tissues. CG100649 produced large GI safety margins in rats and monkeys despite its modest COX-2 selectivity Oral 4-week toxicokinetic studies in rats at doses up to 3-5 mg/kg/day showed that systemic exposure in females was greater than in males due to the longer half-life in females (9-12 hr) compared to males (4-7 hr). A over COX-1. The tight binding of CG100649 to carbonic anhydrase (CA) in the GI tract may be CG100649 achieves tissue specific inhibition of COX-2 through dual inhibition of COX-2 and carbonic anhydrase (CA). As summarized in the Figure 1, the working hypothesis is that CG100649 cannot inhibit COX-2 in CA-rich tissues (CV & sex related difference in systemic exposure is commonly observed in rats and is usually attributed to a lower responsible for its good GI safety. GI), but it can fully inhibit COX-2 in tissues that lack CA activity such as inflammatory joints. CG100649 binds metabolizing capacity of female rats. In male and female monkeys, following single and repeat oral doses of preferentially to CA in blood, blood vessels, and kidneys. In inflamed tissues, CG100649 is a highly active COX-2 was generally reached in 2- 4 hours post dose and the terminal half-life was shown to Small effects on the renal hemodynamics suggest negligible COX-2 inhibition in the renal vasculature inhibitor which is moderately selective for COX-2 over COX-1. In preclinical analgesia and antiinflammatory models, approximately 60 hr. Systemic exposure at week 4 was greater than on Day 1 (the degree of accumulation, R , owing to the significant enrichment of CAs in the renal vasculature. Likewise, COX-2 inhibition is expected CG100649 is more potent than indomethacin, celecoxib and rofecoxib. The projected clinical therapeutic plasma level of CG100649 is estimated as 4 ng/ml on the basis of the efficacy in the adjuvant-induced arthritis (AIA) model in rats. was approximately 1.6 to 3.8). The overall extent of exposure was not appreciably different in male and female to be low in other types of blood vessels conferring a benefit for CV safety REFERENCES
Inflamed joints
The oral maximum tolerated dose (MTD) for CG100649 was determined to be approximately 1500 mg/kg in [CA] >>> [COX-2] [CA] <<< [COX-2] mice. In rats, the MTD was 125 mg/kg in males and 15 mg/kg in females. Clinical findings were generally of 1) Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti- inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:1247–55. Oral safety studies were conducted in rats and monkeys for 28 days. In male rats, target doses up to 5.0 (3.6 2) Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 actual dose) mg/kg/day were well tolerated and produced no obvious signs of toxicity. Female rats showed inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 2000;116:4–15 . treatment-related histopathological findings in the intestines at target doses of 1.0, 1.5 and 3.0 mg/kg/day. Cynomolgus monkeys treated at 12 mg/kg/day showed a low incidence pathological finding in the stomach and in blood chemistry. At 5 mg/kg/day, blood chemistry changes were noted in one male only. On the basis of these findings it was concluded that 2 mg/kg/day was a no observed effect level (NOEL), and 5 mg/kg/day was High CA = limited side effects This study was supported by Bio-star project of Ministry of Knowledge Economy of Korea. No CA = Good efficacy Figure 1. Working hypothesis for the tissue specific inhibition of COX-2 by dual inhibition
a no observed adverse effect level (NOAEL). of COX-2 and CA to avoid side effects of NSAIDs.
Supported by a grant from CrystalGenomics, Inc.

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