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.”
Species: general tox
Mouse and cynomolgus monkey (NHP) chronic toxicity studies
“In agreement with the CHMP (EMA/CHMP/SAWP/229464/2019) carcinogenicity studies with tofersen are regarded dispensable with respect to the life-threatening nature of ALS, the negative genotoxic potential and the absence of (pre)neoplastic changes, cell proliferation, and immune or endocrine dysfunction in chronic toxicity studies in mice and NHP’s.”
Species: DART
Mouse (combined fertility/EFD and pre/postnatal) and rabbit (EFD)
“The reproductive and developmental toxicity of tofersen was investigated in a combined study on fertility and embryo-foetal development in mice, a study on embryo-foetal development in rabbits, and on prepostnatal development in mice.”
Species: 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.”
Surrogate used in
No surrogate used: no rodent SOD1-targeting ASO, as tofersen lacks rodent sequence homology
“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).”
Genotox: Ames
Negative
“Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.”
Genotox: in vitro mammalian
Mammalian cell chromosomal aberration: negative
“Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.”
Genotox: in vivo
Mouse micronucleus: negative
“Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.”
Carcinogenicity model
Not conducted (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.”
Carcinogenicity timing
Not conducted before approval; carcinogenicity studies to be conducted after approval given the severity of the indication
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
hERG / QT
hERG IC50 >34 µM
“The IC50 for hERG inhibition in transfected HEK cells was greater than 34µM.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Qalsody don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA integrated review, p. 180)
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.”
Anti-drug antibodies: animals
Not investigated in chronic toxicity studies (rat, mouse, monkey)
“The development of anti-tofersen antibodies was not investigated in the chronic toxicity studies in rat, mice and monkeys.”
Anti-drug antibodies: patients
58.4% (97 patients) treatment-emergent ADA, 83 persistent; ADA decreased plasma tofersen clearance by 32%
“Overall, 97 QALSODY-treated patients (58.4%) developed treatment-emergent ADAs, of which 14 were transient and 83 were persistent. The presence of anti-drug antibodies (ADA) appeared to decrease plasma tofersen clearance by 32%.”
Label warnings
- Myelitis and/or Radiculitis
- Papilledema and Elevated Intracranial Pressure
- Aseptic Meningitis
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Qalsody don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA integrated review, p. 180)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (intrathecal, every other week) with recovery groups; recovery duration not stated
“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.”
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.”
DART package
Species: DART
Mouse (combined fertility/EFD and pre/postnatal) and rabbit (EFD)
“The reproductive and developmental toxicity of tofersen was investigated in a combined study on fertility and embryo-foetal development in mice, a study on embryo-foetal development in rabbits, and on prepostnatal development in mice.”
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.”
PPND / ePPND: when
PPND in CD1 mouse completed before the marketing application; no effects on pre- and postnatal development
“There were no effects on embryofetal development in CD1 mouse or NZW rabbit, or on pre- and postnatal development in CD1 mouse.”
Carcinogenicity
Species: 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.”
Carcinogenicity model
Not conducted (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.”
Carcinogenicity timing
Not conducted before approval; carcinogenicity studies to be conducted after approval given the severity of the indication
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 9-month IT NOAEL 12 mg (HED 120 mg) ~1.2x the 100 mg human dose by CSF-volume scaling
“The NOAEL from the 9-month NHP toxicology study was determined to be 12 mg, which converts to a HED of 120 mg (based on the monkey-to-human CSF volume scaling) thus providing safety margins of 1.2-fold, based on CSF volumetric scaling (10x), relative to the human dose of 100 mg.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Clinical molecule in transgenic human SOD1G93A mice and rats: SOD1 mRNA reduction; improved lifespan and rotarod in mouse
“In vivo studies conducted in transgenic mice and rats that express human mutant SOD1 (i.e., SOD1G93A), indicated reductions in SOD1 MRNA in tissue, and improved lifespan and rotorod performance in mouse.”
Why that model
Tofersen binding site not conserved in wild-type mouse or rat, so human SOD1 transgenic models were used
“This transgenic mouse model was chosen because the binding site of tofersen is not conserved in wild-type mouse or rats.”
Reviewer's view of the efficacy data
Activity shown in human SOD1 G93A transgenic mice/rats and monkeys; provides mechanistic rationale and supports a delayed treatment effect
“In vivo pharmacological activity of tofersen was demonstrated in transgenic mouse and rat models, each expressing human SOD1 with a G93A mutation, and in Cynomolgus monkeys. The non-clinical findings provide a mechanistic rational for the effect of tofersen and support a delay in the treatment effect of tofersen.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; carcinogenic potential to be assessed post-approval
Why: Life-threatening ALS, negative genotoxicity and no (pre)neoplastic changes in chronic mouse and monkey studies · Serious disease · Weight of evidence
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
“In agreement with the CHMP (EMA/CHMP/SAWP/229464/2019) carcinogenicity studies with tofersen are regarded dispensable with respect to the life-threatening nature of ALS, the negative genotoxic potential and the absence of (pre)neoplastic changes, cell proliferation, and immune or endocrine dysfunction in chronic toxicity studies in mice and NHP’s.”
DARTAccepted with a conditionBeyond the letter
DART studies only in mice and rabbits, species in which tofersen is not pharmacologically active
Why: Literature on SOD1 down-regulation suggests low but unknown risk; gap reflected in SmPC sections 4.6 and 5.3 · Weight of evidence · No relevant species
“Considering that tofersen is not pharmacologically active in mice and rabbits, these studies do not provide data regarding the pharmacological activity of tofersen in terms of its potential effects on reproduction or development. This limits the predictive value of these studies in terms of human safety.”
“A literature review of the available data on the effects of SOD1 down-regulation indicates that the potential effects of ASO (tofersen) on reproduction and development are likely to be low; however, they are currently unknown. The lack of pharmacologically relevant studies with regard to pregnancy and fertility is now also adequately reflected in sections 4.6 and 5.3 of the SmPC.”
Safety marginVerdict not stated
Only 1.2-fold margin at the 9-month monkey NOAEL (12 mg, CSF-volume scaled) to the 100 mg human dose
“The NOAEL from the 9-month NHP toxicology study was determined to be 12 mg, which converts to a HED of 120 mg (based on the monkey-to-human CSF volume scaling) thus providing safety margins of 1.2-fold, based on CSF volumetric scaling (10x), relative to the human dose of 100 mg.”
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