Viltepso
viltolarsen
Species
MonkeyMouse
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
Male CD-1 mouse and male cynomolgus monkey (plus juvenile male mouse)
“Repeat-dose studies in adult male CD1 mice, and single and repeat-dose studies in adult male cynomolgus monkeys were conducted to evaluate the general toxicology of vitolarsen.”
Why that species
Exon 53 skipping shown in monkey; not pharmacologically active in rodents (mouse used for general/juvenile tox)
“In vivo assessment of exon 53 skipping was included in the 12- and 39-week toxicity studies in monkey; viltolarsen is not pharmacologically active in rodents.”
Surrogate molecule
No surrogate in tox; mouse-specific PMO (NDK-73) used only for mdx52 proof-of-concept
“In male mdx52 mice, IV administration of a mouse surrogate (NDK-73) as well as an additional morpholine oligonucleotide (NDK-33), which targets the Exon 53 3’ end of the mouse dystrophin gene”
Species: general tox
Male CD-1 mouse and male cynomolgus monkey
“The pivotal IV toxicity studies were conducted in male CD-1 mouse (13 and 26 weeks) and male cynomolgus monkey (12 and 39 weeks).”
Species: DART
Male CD-1 mouse fertility and early embryonic development only; EFD and pre/postnatal studies not conducted (male population)
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male. A fertility and early embryonic development study was conducted in male CD-1 mice, which were mated with untreated females.”
Species: carcinogenicity
Not conducted pre-approval; 26-week Tg.rasH2 mouse and 2-year rat required as PMRs
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
Surrogate used in
Pharmacology only: mouse surrogate NDK-73 (with NDK-33) in mdx52 mouse, 4.8% exon skipping; toxicity studies used viltolarsen
“In male mdx52 mice, IV administration of a mouse surrogate (NDK-73) as well as an additional morpholine oligonucleotide (NDK-33), which targets the Exon 53 3’ end of the mouse dystrophin gene, resulted in 4.8% skipping efficiency in the gastrocnemius muscle 2 weeks after administration of 1280 mg/kg combination (640 mg/kg of each oligonucleotide).”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Viltolarsen was administered by IV injection for 12 weeks (+4-week recovery) and 39 weeks (+8-week recovery) at doses of 0, 60, 200, and 600 mg/kg QW and 0, 10, 60, and 360 mg/kg QW, respectively.”
Pivotal GLP studies
Weekly IV: male mouse 13 and 26 weeks; male monkey 12 and 39 weeks; juvenile male mouse PND 7-70
“The pivotal IV toxicity studies were conducted in male CD-1 mouse (13 and 26 weeks) and male cynomolgus monkey (12 and 39 weeks).”
Route in tox
IV weekly (clinical route); juvenile mouse SC on PND 7 then IV; single IM in monkey
“In the pivotal study, viltolarsen (0, 15, 60, 240, and 1200 mg/kg) was administered weekly by SC injection on PND 7 and by IV injection on PNDs 14 through 70.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
“Viltolarsen was negative in a standard battery of in vitro (Ames, chromosomal aberration in CHL cells) and in vivo (mouse micronucleus) assays.”
Carcinogenicity
Not conducted pre-approval (agreed); rasH2 mouse and 2-year rat studies as PMRs
“Carcinogenicity studies of viltolarsen were not submitted to the NDA, as agreed to by the Division.”
Reproductive & developmental
Male mouse fertility study only (no effects); EFD/PPND waived for male population; juvenile mouse study
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”
Safety pharmacology
Dedicated single-dose studies: rat CNS (FOB), monkey CV/respiratory, in vitro hERG; no effects
“Dedicated single dose studies in rat (CNS) and monkey (cardiovascular and respiratory) did not indicate drug effects on safety pharmacology endpoints, and there was no effect on QT prolongation in CHO cell cultures exposed to up to 3 mg/mL vitolarsen.”
Genotox: Ames
Negative
“Viltolarsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative
“Viltolarsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Viltolarsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity model
Not conducted; SPA protocols for 26-week Tg.rasH2 mouse and 2-year rat reviewed by the Division and Executive CAC
“Protocols for a 26-week study in Tg.rasH2 mouse and a 2-year study in rat were submitted for review under Special Protocol Assessment and were reviewed by the Division and the Executive CAC under IND 127474 (Minutes dated July 12, 2018, and August 9, 2019, respectively).”
Carcinogenicity timing
Not conducted before approval; 26-week Tg.rasH2 mouse and 2-year rat studies are postmarketing requirements
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
hERG / QT
No hERG/QT effect in CHO cells up to 3 mg/mL; no effects in rat CNS and monkey CV/respiratory studies
“Dedicated single dose studies in rat (CNS) and monkey (cardiovascular and respiratory) did not indicate drug effects on safety pharmacology endpoints, and there was no effect on QT prolongation in CHO cell cultures exposed to up to 3 mg/mL vitolarsen.”
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 Viltepso 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: NOAEL 60 mg/kg/wk IV in monkey (39-wk) and mouse (26-wk); renal tubular vacuolation/dilation; mouse deaths at 1000 mg/kg (FDA pharmacology/toxicology review, p. 47)
NOAEL / key findings
NOAEL 60 mg/kg/wk IV in monkey (39-wk) and mouse (26-wk); renal tubular vacuolation/dilation; mouse deaths at 1000 mg/kg
“Based on the 39-week study, the NOAEL for IV administration of vitolarsen in male cynomolgus monkeys was 60 mg/kg (Cmax = 613.9 µg/mL; AUC0-24h = 261.1 µg*h/mL).”
Risksopen answer page →
Immune & cytokine safety
No cytokine or immunophenotype effects; transient ~2-fold C3 rise at high dose in mouse; no anti-drug antibodies
“There were no drug effects on C3 after dosing on Day 0; however, on Day 175, there was an approximate 2-fold elevation in serum C3 24 h after dosing in HDM.”
Biodistribution & persistence
Radiolabel in monkey: highest in kidney cortex, low skeletal muscle levels; low protein binding
“With multiple doses (20 mg/kg/week for 8 weeks), highest levels of dose radioactivity were in kidney cortex (819 µg-Eq/g), with concentrations in skeletal muscle of 0.331- 0.479 µg-Eq/g.”
Modality-specific risk
PMO renal tubular toxicity (nephrotoxicity, deaths in mouse); off-target hybridization (APCDD1) assessed in silico
“Kidney toxicity in the pivotal study, which resulted in unscheduled death of two HDM, was characterized by slight increases in urea nitrogen and creatinine, increases in kidney weight in HDM, and histologic findings of intratubular dilation and epithelial vacuolation in the distal tubule and collecting duct in MDM and HDM.”
Anti-drug antibodies: animals
Anti-drug antibodies not detected in the 26-week mouse study
“Increases in Cmax and AUC were dose-proportional. Anti-drug antibodies were not detected.”
Anti-drug antibodies: patients
No anti-viltolarsen antibodies: all samples from 16 patients negative in Study 1
“For Study 1, samples collected from all 16 patients at Day 1 (pre-dose), Week 5, Week 13, and Week 24 were assessed for anti-viltolarsen antibodies. All samples were determined to be antibody negative.”
Label warnings
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 Viltepso 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: NOAEL 60 mg/kg/wk IV in monkey (39-wk) and mouse (26-wk); renal tubular vacuolation/dilation; mouse deaths at 1000 mg/kg (FDA pharmacology/toxicology review, p. 47)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV cynomolgus monkey study with 8-week recovery
“Monkey: Viltolarsen was administered by IV injection for 12 weeks (+4-week recovery) and 39 weeks (+8-week recovery)”
Pivotal GLP studies
Weekly IV: male mouse 13 and 26 weeks; male monkey 12 and 39 weeks; juvenile male mouse PND 7-70
“The pivotal IV toxicity studies were conducted in male CD-1 mouse (13 and 26 weeks) and male cynomolgus monkey (12 and 39 weeks).”
DART package
Species: DART
Male CD-1 mouse fertility and early embryonic development only; EFD and pre/postnatal studies not conducted (male population)
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male. A fertility and early embryonic development study was conducted in male CD-1 mice, which were mated with untreated females.”
Reproductive & developmental
Male mouse fertility study only (no effects); EFD/PPND waived for male population; juvenile mouse study
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”
PPND / ePPND: when
Not conducted: waived because the patient population is almost exclusively male
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”
Carcinogenicity
Species: carcinogenicity
Not conducted pre-approval; 26-week Tg.rasH2 mouse and 2-year rat required as PMRs
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
Carcinogenicity model
Not conducted; SPA protocols for 26-week Tg.rasH2 mouse and 2-year rat reviewed by the Division and Executive CAC
“Protocols for a 26-week study in Tg.rasH2 mouse and a 2-year study in rat were submitted for review under Special Protocol Assessment and were reviewed by the Division and the Executive CAC under IND 127474 (Minutes dated July 12, 2018, and August 9, 2019, respectively).”
Carcinogenicity timing
Not conducted before approval; 26-week Tg.rasH2 mouse and 2-year rat studies are postmarketing requirements
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
NOAEL 60 mg/kg/wk IV in monkey (39-wk) and mouse (26-wk); renal tubular vacuolation/dilation; mouse deaths at 1000 mg/kg
“Based on the 39-week study, the NOAEL for IV administration of vitolarsen in male cynomolgus monkeys was 60 mg/kg (Cmax = 613.9 µg/mL; AUC0-24h = 261.1 µg*h/mL).”
Efficacy evidenceopen answer page →
Efficacy evidence
DMD patient fibroblasts differentiated into myotubes: exon 53 skipping (EC50 0.63-2.3 µM) and dystrophin production
“Primary: In vitro proof-of-concept studies, conducted primarily in DMD patient fibroblasts differentiated into myotubes, demonstrated viltolarsen-induced exon 53 skipping (EC50 values of 0.63-0.90 µM and 2.3 µM) and production of dystrophin protein in cells from DMD patients with deletion of exons 45-52 and exons 48-52, respectively.”
Why that model
Viltolarsen not pharmacologically active in rodents; in vivo exon skipping assessed only in monkey toxicity studies
“In vivo assessment of exon 53 skipping was included in the 12- and 39-week toxicity studies in monkey; viltolarsen is not pharmacologically active in rodents.”
Reviewer's view of the efficacy data
Human relevance judged from human rhabdomyosarcoma cells (EC50 3.4-5.9 nM) and DMD patient-derived myoblasts (83.1% skipping, presumably truncated dystrophin)
“Potential effects in humans were evaluated in using isolated human rhabdomyosarcoma cells, in which the EC50 for exon 53 skipping by vitolarsen ranged from 3.4 to 5.9 nM. Additionally, 83.1% exon 53 skipping efficiency was observed 1 week after transfection of myoblasts derived from DMD patient fibroblasts with 10 uM vitolarsen, correlating with expression of a presumably truncated dystrophin protein.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; Tg.rasH2 mouse and two-year rat studies required as postmarketing requirements
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
“Carcinogenicity was not evaluated but is to be assessed as a postmarketing requirement. The nonclinical data support approval vitolarsen.”
DARTAcceptedBeyond the letter
No embryo-fetal or pre/postnatal development studies; male mouse fertility study only
Why: Patient population almost exclusively male · Other reason
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”
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