Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Rytelo: what was done before first-in-human, and what came after?
imetelstat · Telomerase (oligo)
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 Rytelo 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 oncology oligonucleotides (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Mouse NOAEL 20 mg/kg; monkey HNSTD 15 mg/kg/week; cytopenias, complement activation, aPTT prolongation, liver/kidney (EMA assessment report, p. 32)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (IV infusion, weekly) with 14-week recovery
“002-TOX-2008 was a 9-month toxicity study of GRN163L in Cynomolgus Monkeys followed by a 14- week recovery period.”
Pivotal GLP studies
GLP IV: 6-month mouse (bolus BIW) and 9-month cynomolgus monkey (2-h infusion weekly); mouse and rabbit EFD
“Additional imetelstat toxicities observed in the chronic pivotal toxicity studies, ie, the 6-month study in mice (003-TOX-2008) and the 9-month study in monkeys, included microscopic findings in the liver and kidney”
DART package
Species: DART
Mouse and rabbit (EFD)
“The mouse and monkey were used for the single- and repeat-dose toxicity studies, and mouse and rabbit were used for the EFD toxicity studies.”
Reproductive & developmental
EFD in mice and rabbits: post-implantation loss/resorptions; no fertility or PPND studies
“Increased rates of post-implantation loss and early resorptions that resulted in a decreased number of viable fetuses and litter size per animal, and decreased uterine weight were observed at”
PPND / ePPND: when
No PPND study: considered acceptable for an indication mainly in older people and negligible oral bioavailability
“No PPND study has been submitted. This was considered acceptable based on the proposed indication which is primarily relevant for older people and that imetelstat has little or no oral bioavailability thereby removing the likelihood of postnatal exposure via lactation.”
Carcinogenicity
Species: carcinogenicity
Not conducted; mouse and rat carcinogenicity studies required as PMRs
“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”
Carcinogenicity model
Not conducted pre-approval; mouse and rat studies to follow as PMRs
“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”
Carcinogenicity timing
Not conducted before approval; mouse and rat carcinogenicity studies are postmarketing requirements
“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”
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
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Defitelio
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Exondys 51
eteplirsen · DMD exon 51 (PMO)Not stated in public reviews
Hibsago
bepirovirsen · HBV RNA (ASO)Not stated in public reviews
Izervay
avacincaptad pegol · C5 (aptamer)Not stated in public reviews
Kynamro
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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
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