Nonclinical precedent Request an invite
Precedia/Oligonucleotides/Rytelo/First dose

Rytelo: how was the first human dose set?

imetelstat · Telomerase (oligo)
Check my plan vs. these
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.”
✓ VerifiedICH 2009: ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, p. 13Source ↗
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)

Full method, every step sourced →

NOAEL / key findings
Mouse NOAEL 20 mg/kg; monkey HNSTD 15 mg/kg/week; cytopenias, complement activation, aPTT prolongation, liver/kidney
“No NOAEL could be determined. Instead, a highest non-severely toxic dose (HNSTD) of 15 mg/kg was established, as no mortalities or life-threatening were observed at this dose.”
✓ VerifiedEMA assessment report, p. 32Source ↗

Email me this as a cited memo

First dose for Rytelo, each with the regulator's own words, the page and a link. Ready to paste into a briefing document or send to your team.

Same question, other oligonucleotides

Kynamro

mipomersen · APOB (ASO)
Applicant estimated safe starting dose from nonclinical results; method not specified

Zanvastro

zilganersen · GFAP (ASO)
Starting-dose rationale not stated; FDA capped clinical IT dose at 25 mg (~1/10 mouse/monkey NOAEL), later 50 mg Q12W

Amondys 45

casimersen · DMD exon 45 (PMO)
Not stated in public reviews

Amvuttra

vutrisiran · TTR (siRNA)
Not stated in public reviews

Dawnzera

donidalorsen · Prekallikrein / KLKB1 (ASO)
Not stated in public reviews

Defitelio

defibrotide · Fragmented DNA oligonucleotides
Not stated in public reviews

Exondys 51

eteplirsen · DMD exon 51 (PMO)
Not stated in public reviews

Givlaari

givosiran · ALAS1 (siRNA)
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

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

Oxlumo

lumasiran · HAO1 (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

Summary across all 27 oligonucleotides →