1. Lack of Effect of CMX001 on Renal and Myeloid Parameters
in Humans, Monkeys, and Rodents
W Painter, RS Verhoeven, AT Robertson, H Mommeja-Marin, GR Painter, and LC Trost
Chimerix, Inc., Durham, North Carolina USA
Congress of the European
Societies for Toxicology
17-20 June 2012
Abstract # 203/269
INTRODUCTION
RESULTS
RESULTS
CMX001 is a novel, phospholipid-modified small molecule (NCE) (acyclic nucleotide) providing unique intracellular delivery of a potent antiviral, broadly active against multiple dsDNA viruses through inhibition of DNA polymerase. CMX001 is in development for prevention and treatment of CMV and adenovirus in transplant recipients and as a therapeutic countermeasure for smallpox. CMX001, was designed to take advantage of the broad-spectrum antiviral activity of cidofovir while eliminating its dose-limiting renal toxicity. CMX001 is stable in plasma and generates high intracellular concentrations of the active antiviral while concentrations of circulating CDV remain low. Studies in animals and humans have been conducted to evaluate the safety of CMX001.
Toxicology Studies
Clinical Studies
Table 3. Toxicology Studies in Rats and Monkeys: Clinical Pathology Parameters of Nephro- and Myelotoxicity, Percent Change From Control
Table 5. Clinical Studies in Humans: Clinical Pathology Parameters of Nephro- and Myelotoxicity
Parameter
Week 13 in Rats
15 mg/kg
Week 13 in Monkeys
Week 39 in Monkeys
25 mg/kg
Urinalysis
No CMX001-related effects
No CMX001- related effects
Creatinine*
-1.6%
-6.3%
+9.5%
BUN*
-2.4%
-4.2%
+5.3%
WBC*
+16.8%
+2.8%
+15.8%
ANC*
+7.7%
+29.7%
+29.2%
Platelets*
+2.1%
-0.2%
-6.1%
Parameter
Duration of CMX001 dosing
Adults
Pediatrics N=
Median change from Baseline
Median change from Baseline
Creatinine (mg/dL)
< 4 weeks 92 59
-0.01
Week 4 61 45
0.00
Week 8 20
-0.07 31
-0.10
Week 12 11
-0.40 19
-0.04
BUN (mg/dL) 86 2 57 3 4 44 -3 30 5 1
WBC (x10^3/uL) 34
0.04 26
0.36 12 16
0.22 6
0.17 8
0.21
ANC (x10^3/µL) 79
0.20 53 52
0.60 40
-0.02 15
-0.50 25
0.52
-0.15
Platelets (x10^3/µL) 58 60 -2 10 -5 7
-11 18
CMX001
* Percent change in mean high dose value compared to control
METHODS
No CMX001-related findings were noted in the assessment of clinical pathology parameters indicative of nephrotoxicity or myelosuppression following twice weekly oral administration for 13 weeks in rats or 39 weeks in monkeys.
Toxicology Studies
GLP toxicology and toxicokinetic studies of CMX001 administered twice weekly by the oral route were conducted in Sprague-Dawley rats at durations up to 13 weeks and in cynomolgus monkeys at durations up to 39 weeks at doses >10 fold the anticipated clinical dose.
Standard toxicology endpoints were evaluated in all animal studies, including body weight, food consumption, clinical observations, clinical pathology, organ weights, gross observations at necropsy, and histopathology of standard tissues.
Changes in anatomic and clinical pathology parameters relevant to potential renal and hematologic effects are discussed.
Table 4. Toxicology Studies in Rats and Monkeys: Histopathology Parameters of Nephro- and Myelotoxicity
Parameter
13-Wk Study in Rats
13-Wk Study in Monkeys
39-Wk Study in Monkeys
Bone Marrow Cellularity
No CMX001- related effects
No CMX001-related effects
Kidney Weights
Gross Observation of Kidneys
Mild pale discoloration in 4 of 20 animals at 25 mg/kg
Kidney Histopathology
Minimal or mild karyomegaly of tubular epithelial cells in 13 of animals at 25/mg/kg
In this severely ill patient population there was no effect on hematologic parameters or on renal function as indicated by changes in BUN and creatinine.
Table 6. Clinical Studies in Humans: Creatinine Concentrations Pre- and Post-treatment with CMX001
Table 1. Toxicology Studies of CMX001 Conducted in Rats and Monkeys
Parameter
Adults n = 87
Pediatrics n = 56
Baseline
Post-Treatment
Post- Treatment
Mean (mg/dL)
1.59
1.67
0.83
0.82 SD
1.18
1.64
0.84
0.85
Median (mg/dL)
1.12
1.00
0.5
 Species
Rat
Monkey
Study Duration
13 Weeks
39 Weeks
Animal Number
10/sex/group
4-6/sex/group
Dose (mg/kg) Twice Weekly
0, 1, 4, 15
0, 5, 15, 25
Parameters Evaluated
Hematology, serum chemistry, urinalysis, gross & microscopic pathology
There were no changes in bone marrow cellularity indicative of myelotoxicity in either rats given up to 15 mg/kg CMX001 for 13 weeks or in monkeys given up to 25 mg/kg CMX001 for 39 weeks.
Analysis of kidney weights, gross observations of the kidneys, and renal histopathology demonstrated that there were no test article-related effects in these tissues in either rats or monkeys following 13 weeks of administration.
In the 39 week monkey study, diagnosable kidney change (minimal or mild karyomegaly) was observed in about half of the animals at the high dose (25 mg/kg). There were no related clinical pathology changes and the dose was well tolerated for the entire duration of the study. The changes were not dose-limiting and were judged to be related to exposure to CDV, a metabolite of CMX001 to which monkeys receive much higher relative exposure than humans following administration of CMX001 (AUCm/AUCp = 20 in monkeys vs 0.6 in humans, a 33-fold difference.)
Many patients entered the study with pre-existing renal impairment (often due to previous treatment with CDV). There was no evidence of decreased renal function following treatment with CMX001 for up to 9 months as indicated by creatinine values prior to treatment compared with the value obtained following the last dose of CMX001.
Clinical Studies
Renal and hematologic parameters from 210 patients administered CMX001 either once or twice weekly under Emergency Investigational New Drug (EIND) regulations (or foreign equivalent).
Subjects were treated in the US, Canada, France, Switzerland, Spain, United Kingdom, Austria, Israel and Chile.
In the US, Emergency INDs were granted by the FDA for patients with life-threatening dsDNA viral infection with no treatment alternative, predominantly caused by CMV and adenovirus.
SUMMARY
Single doses of VISTIDE have been reported to cause acute renal failure and death. VISTIDE also has a black box warning for neutropenia.
There were no changes in clinical or anatomic pathology parameters indicative of nephrotoxicity or myelosuppression following administration of CMX001 for up to 39 weeks in animals at doses exceeding the likely clinical dose by >10-fold
Similarly, no changes in corresponding parameters were observed following up to 9 months of administration of CMX001 in patients, including those with pre-existing renal impairment.
Table 2. Clinical Studies in Humans: Baseline Characteristics
Characteristic
Adults
n=123
Pediatrics
n=87
Gender Number(%)
Male/Female
71 (58%)/52 (42%)
44 (51%)/42 (48%)
Age (years)
Median/Mean
50.4/48.9
7.6/8.0
Weight (kg)
70.1/71.2
26.0/30.0
Race (n (%))
Caucasian
Black
Asian
Other
Unknown*
59 (48%)
10 (8%)
7 (6%)
5 (4%)
42 (34%)
28 (32%)
12(14%)
1 (1%)
3 (4%)
43 (49%)
CONCLUSION
Unlike CDV and other antivirals used to treat severe dsDNA virus infections, there was no evidence of nephrotoxicity or myelosuppression associated with administration of CMX001 in animals at significant multiples of the anticipated clinical dose, or in humans administered CMX001 for treatment of life-threatening dsDNA viral infections.
* Race was frequently not recorded
REFERENCES
ACKNOWLEDGEMENTS
The authors would like to thank the staff of BASi, MPI, and SNBL for their work conducting the toxicology studies, as well as the clinicians and their patients.
Lacy, et al. (1998). Effect of Oral Probenecid Coadministration on the Chronic Toxicity and Pharmacokinetics of Intravenous Cidofovir in Cynomolgus Monkeys. Tox. Sci. 44,
VISTIDE Summary Basis of Approval