Qalsody
tofersen
Species
MonkeyRatMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (IT, relevant species), CD-1 mouse (SC) and rat single-dose IT
“From the PK point of view, the monkey was the most relevant species for non-clinical efficacy and safety studies.”
Why that species
Single base-pair mismatch to monkey SOD1 (likely active); all other species have >=4 mismatches
“Furthermore, a single base-pair mismatch to the Cynomolgus monkey gene suggests it may be active in NHPs, thereby enabling assessment of possible on-target effects, while wild-type animals of all other species appear not to be suitable due to at least four or more mismatches in the target sequence.”
Surrogate molecule
No surrogate; no rodent SOD1-targeting ASO identified; clinical ASO tested in all species
“No ASO specifically targeting rat and mouse SOD1 was used in toxicology studies, due to the lack of sequence homology of tofersen in rodents.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Repeat IT dosing with 0, 4, 12, and 35 mg tofersen every 2 weeks for a 9-month period resulted in uncoordinated leg movement and transient impairments of patellar and foot-grip reflexes in HDM and HDF.”
Pivotal GLP studies
Monkey IT Q2W 13-week and 9-month; mouse SC 12- and 26-week; rat single-dose IT; full genetox and DART
“Nonclinical toxicity studies submitted to the NDA consisted of single dose (rat) and repeat dose (mouse and monkey) general toxicity studies, as well a complete battery of genetic toxicology and reproductive and developmental toxicology studies.”
Route in tox
Intrathecal bolus (monkey, rat; clinical route); subcutaneous (mouse, rabbit) for systemic exposure
“SC administration of 0, 6, 30, and 150 mg/kg tofersen every other week for 26 weeks in male and female CD1 mice resulted in dose-dependent reductions in platelet counts in males (up to 20%) and in HDF (13%).”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
“Tofersen was negative in a complete battery of genetic toxicology studies.”
Carcinogenicity
Not conducted pre-approval (severity of indication); to be assessed post-approval
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
Reproductive & developmental
Mouse fertility (seminiferous tubule degeneration, NOAEL 10 mg/kg), mouse/rabbit EFD and mouse PPND negative; pharmacologically non-relevant species
“There were no effects on embryofetal development in CD1 mouse or NZW rabbit, or on pre- and postnatal development in CD1 mouse.”
Safety pharmacology
Incorporated into single-dose IT rat (CNS) and 13-week IT monkey study (CNS, CV, respiratory); hERG in vitro
“Safety pharmacology assessments following IT administration of tofersen were incorporated into a single dose study in male and female SD rats (CNS) and a 13-week repeat (Q2W) dose toxicity study in cynomolgus monkeys (CNS, CV, and respiratory).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Monkey 9-month IT NOAEL 12 mg Q2W (neurological signs at 35 mg); ~1.2-fold margin by CSF-volume scaling; mouse platelet decreases, no NOAEL
“Based on neurological signs in the 9-month study, the NOAEL for IT administration of tofersen in cynomolgus monkey was 12 mg every 2 weeks, resulting in plasma Cmax and AUC0-24h of 4840 ng/mL and 30,000 µg·h/mL, respectively.”
Risksopen answer page →
Immune & cytokine safety
CSF inflammation at 35 mg in monkey; ADA not assessed in animal studies (58.4% of patients ADA-positive)
“The development of anti-tofersen antibodies was not investigated in the chronic toxicity studies in rat, mice and monkeys.”
Biodistribution & persistence
Rapid CSF-to-CNS tissue distribution with transfer to systemic circulation; long CSF/CNS half-life (20-45 days, monkey)
“The rapid distribution phase is due to the rapid and broad distribution from the CSF to the CNS tissues with additional clearance due to transfer to the systemic circulation.”
Modality-specific risk
CNS: neuronal vacuolation and transient neurological signs after IT ASO; class thrombocytopenia/renal risks considered
“In monkeys, IT administration of 0, 4, 12, and 35 mg tofersen in male and female cynomolgus monkeys every other week for 9 months resulted in histologic findings of neuronal vacuolation at all doses; however, vacuolation was not accompanied by neurodegeneration and was not present in recovery groups.”