Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Izervay: what was done before first-in-human, and what came after?
avacincaptad pegol · C5 (aptamer)
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
Rabbit and dog repeat-dose intravitreal studies; interim data up to week 13 submitted under the initial IND
“Repeat-dose ocular toxicity studies were conducted in New Zealand White rabbits and Beagle dogs. An interim report (with data up to week 13) was submitted under the initial IND.”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Izervay 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: Rabbit NOEL 0.5 mg/eye, NOAEL >=1.5 mg/eye; dog NOAEL 1.0 mg/eye; reversible retinal ganglion cell vacuolation, optic tract vacuolation in dog (FDA pharmacology/toxicology review, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rabbit intravitreal study, 10 monthly doses through Week 37, with 4-week recovery (dog study of the same design)
“On Week 37 (after 10 monthly doses), mild retinal vacuolation was observed in the high dose group. The finding did not increase in severity between Doses 1 and 10. The finding was again reversible following a 4-week recovery period (Day 281).”
Pivotal GLP studies
GLP 1-month and 9-month (10 monthly doses) IVT studies in rabbit and dog +/- Lucentis; 7-day IV rat and monkey studies
“Repeat-dose IVT toxicity studies were conducted in New Zealand White rabbits (0, 0.15, 0.5, and 1.5 mg/eye) and Beagle dogs (0, 0.3, 1, and 3.0 mg/eye).”
DART package
Species: DART
Rat and rabbit (EFD only); fertility and pre/postnatal studies waived
“In the embryofetal development (EFD) toxicity studies in rats and rabbits, there was no avacincaptad pegol-related adverse effects on any measured maternal or fetal parameter at doses up to 1.2 mg/kg/day (NOAEL).”
Reproductive & developmental
EFD studies in rat and rabbit (IV, NOAEL 1.2 mg/kg/day); FEED and PPND waived
“In the embryofetal development (EFD) toxicity studies in rats and rabbits, there was no avacincaptad pegol-related adverse effects on any measured maternal or fetal parameter at doses up to 1.2 mg/kg/day (NOAEL).”
PPND / ePPND: when
Not conducted: PPND (and FEED) waived; weight of evidence showed studies not necessary for the dosing regimen and indication
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
Carcinogenicity
Species: carcinogenicity
Not conducted (waiver)
“No studies were conducted. The Applicant submitted a justification to support a waiver request not to conduct the carcinogenicity studies”
Carcinogenicity model
Not conducted: waiver based on mechanism of action, route, literature, class effects and existing data
“The Applicant justification to omit the conduct of nonclinical carcinogenicity studies is based on avacincaptad pegol mechanism of action, route of administration, a supportive literature review, an analysis of pharmacological class effects, and nonclinical and clinical data collected to date.”
Carcinogenicity timing
Not required: carcinogenicity waiver accepted on weight of evidence
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
Same question, other oligonucleotides
Givlaari
givosiran · ALAS1 (siRNA)US, UK and Sweden: 6 clinical study centers (4 US, 1 UK, 1 Sweden)
Oxlumo
lumasiran · HAO1 (siRNA)UK: single ascending dose in healthy subjects (Study 001 Part A)
Zanvastro
zilganersen · GFAP (ASO)United States and other countries: ION373-CS1, the single combined first clinical and pivotal trial in AxD patients
Amondys 45
casimersen · DMD exon 45 (PMO)Not stated in public reviews
Amvuttra
vutrisiran · TTR (siRNA)Not stated in public reviews
Defitelio
defibrotide · Fragmented DNA oligonucleotidesNot stated in public reviews
Exondys 51
eteplirsen · DMD exon 51 (PMO)Not stated in public reviews
Hibsago
bepirovirsen · HBV RNA (ASO)Not stated in public reviews
Kynamro
mipomersen · APOB (ASO)Not stated in public reviews
Leqvio
inclisiran · PCSK9 (siRNA)Not stated in public reviews
Macugen
pegaptanib · VEGF-165 (aptamer)Not stated in public reviews
Onpattro
patisiran · TTR (siRNA)Not stated in public reviews
Qalsody
tofersen · SOD1 (ASO)Not stated in public reviews
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)Not stated in public reviews
Redemplo
plozasiran · APOC3 (siRNA)Not stated in public reviews
Rivfloza
nedosiran · LDHA (siRNA)Not stated in public reviews
Rytelo
imetelstat · Telomerase (oligo)Not stated in public reviews
Spinraza
nusinersen · SMN2 (ASO)Not stated in public reviews
Tegsedi
inotersen · TTR (ASO)Not stated in public reviews
Tryngolza
olezarsen · APOC3 (ASO)Not stated in public reviews
Viltepso
viltolarsen · DMD exon 53 (PMO)Not stated in public reviews
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)Not stated in public reviews
Vyondys 53
golodirsen · DMD exon 53 (PMO)Not stated in public reviews
Wainua
eplontersen · TTR (ASO)Not stated in public reviews
Waylivra
volanesorsen · APOC3 (ASO)Not stated in public reviews