Heplisav-B (hepatitis B vaccine (recombinant), adjuvanted): how was the first human dose set?

Atlas/Oligonucleotides/Heplisav-B/First dose

Heplisav-B: how was the first human dose set?

hepatitis B vaccine (recombinant), adjuvanted · TLR9 (CpG 1018 adjuvant)

First-in-human starting dose

Not stated in public reviews

Why it's blank

The public FDA and EMA reviews of Heplisav-B 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.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

This product's starting point

NOAEL / key findings: Monkey NOAEL 0.5 mg/kg CpG 1018 (>10-fold clinical) for systemic immunostimulation; spleen and lymph node hyperplasia, liver inflammation at higher doses (EMA assessment report, p. 28)

Full method, every step sourced →

NOAEL / key findings

Monkey NOAEL 0.5 mg/kg CpG 1018 (>10-fold clinical) for systemic immunostimulation; spleen and lymph node hyperplasia, liver inflammation at higher doses

“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”

✓ VerifiedEMA assessment report, p. 28Source ↗

Summary across all 28 oligonucleotides →

Heplisav-B: how was the first human dose set?

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