Table 2.

ARX788-related observed toxicity in rat (single dose only) and monkey (single and repeat dose) safety studies.

Parameters/speciesRatMonkey
MTD (single dose)>90 mg/kg20 mg/kg
Highest nonseverely toxic dose (4× repeat dose)NA10 mg/kg
Serum chemistry/hematology findingsIncreases in WBC, RET, platelet, and decreases in RBC, HGB, HCT, MPVIncreases in WBC, RDW, RET, and decreases in PLT (single-dose study only and trended toward recovery on day 22), HGB
Increases in FIBIncreases in PT, APTT, FIB
Increases in ALT, AST, ALP, CRE, TCHO, TG, and decreases in ALB, ALB/GLB ratio, TBILIncreases in ALT, AST, ALP, CRE, TCHO, TG, and decreases in ALB, ALB/GLB ratio, TBIL
Clinical observationsDecreased activity, cold to touch and unkempt appearanceProstration, unconscious, cold to touch Abnormal stool, decreased appetite, ulcer on the tail, discolored skin, skin scaling
Slight body weight decreaseSlight to severe (repeat dose) body weight decrease
Gross necropsy findingsSmall thymus, enlarged spleen, depressed mucosa in the stomachMild small thymus, minimal spleen enlargement, depressed mucosa in the stomach, red discoloration at the injection site
Increased organ weights for kidneys, liver, spleen, adrenal gland. Decrease in thymus and epididymis.BW: slight increase in liver and kidney; thymus decrease; increase in spleen weight
HistopathologyKidney: glomerulonephropathy—glomerular and tubular changes (hypercellularity/necrosis)Kidney: glomerulonephropathy—glomerular and tubular changes (necrosis)
Liver: hepatocellular hypertrophy—increased cells were mainly Kupffer cells, mononuclear cells, and few neutrophilic cellsLiver: Increased mitotic phase in hepatocytes; minimal hepatocellular hypertrophy; minimal multifocal hemorrhage; minimal multifocal hepatic sinus dilatation
Lungs: hypercellularity in the alveolar septum—increase in alveolar macrophages, mononuclear infiltrationLung: minimal thickening of alveolar septa and minimal increased alveolar macrophages
Bone marrow—hypercellularity of myeloid cellsBone marrow—mild hypercellularity
Spleen—lymphoid depletion in the white pulp, increased necrosis, increased macrophagesSpleen: increased necrosis, macrophages in the red pulp—lymphoid depletion white pulp