Tecentriq (atezolizumab): what was done before first-in-human, and what came after?

Precedia/Monoclonal antibodies/Tecentriq/Tox package

Tecentriq: what was done before first-in-human, and what came after?

atezolizumab · PD-L1

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Before first-in-human

First-in-human: where

Country not stated; first-in-human dose-escalation study in patients with solid tumours (PCD4989g)

“Multicenter, first-in-human, dose-escalation, open-label study”

✓ VerifiedEMA assessment report, p. 37Source ↗

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 Tecentriq 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 monoclonal antibodies

ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.

“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”

✓ VerifiedICH 2018: ICH S9 Guideline: Nonclinical Evaluation for Anticancer…, p. 15Source ↗

This product's starting point

NOAEL / key findings: Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response (EMA assessment report, p. 36)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week IV cynomolgus monkey study (13-3278) with recovery groups; recovery length not stated

“13-3278 3/sex (main) 2/sex (recovery) IV: 0, 5, 15, 50 26 weeks Q1W”

✓ VerifiedEMA assessment report, p. 31Source ↗

Pivotal GLP studies

GLP cynomolgus monkey studies: 8-week SC and IV, and 26-week IV, weekly up to 50 mg/kg

“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”

✓ VerifiedFDA pharmacology/toxicology review, p. 55Source ↗

DART package

Species: DART

Not conducted; reproductive organs assessed in chronic monkey study (irregular cycles, no new corpora lutea)

“Reproductive and developmental toxicity studies have not been conducted with atezolizumab. However, in the chronic toxicity study in sexually mature monkeys, atezolizumab treatment at the high-dose resulted in irregular menstrual cycles and a lack of newly formed corpora lutea in the ovaries.”

✓ VerifiedEMA assessment report, p. 36Source ↗

Reproductive & developmental

No dedicated studies; chronic monkey study: irregular menstrual cycles and no new corpora lutea at high dose

✓ VerifiedEMA assessment report, p. 36Source ↗

PPND / ePPND: when

Not conducted; literature-based assessment of reproductive and developmental risk instead (oncology, ICH S9)

“The Applicant did not conduct reproductive and developmental toxicology studies with atezolizumab.”

✓ VerifiedFDA pharmacology/toxicology review, p. 49Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (ICH S6(R1), ICH S9)

“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9.”

✓ VerifiedEMA assessment report, p. 36Source ↗

Carcinogenicity model

Not conducted (ICH S6(R1), ICH S9); no increased carcinogenic risk expected from mechanism

“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9. Furthermore, due to its mechanism of action, atezolizumab is not expected to be associated with an increased carcinogenic risk.”

✓ VerifiedEMA assessment report, p. 36Source ↗

Carcinogenicity timing

Not required (ICH S6(R1) and ICH S9)

“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9.”

✓ VerifiedEMA assessment report, p. 36Source ↗

Summary across all 117 monoclonal antibodies →

Tecentriq: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other monoclonal antibodies