Lynozyfic
linvoseltamab
Species
Monkey
Longest study
14 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Overall, data indicate that linvoseltamab bound human and Cynomolgus monkey BCMA, but not rat or mouse BCMA.”
Why that species
Binds human and monkey BCMA (monkey lower affinity, KD 24.6 nM vs 437 pM human) and CD3 on both; no rat/mouse BCMA binding
“Overall, data indicate that linvoseltamab bound human and Cynomolgus monkey BCMA, but not rat or mouse BCMA.”
Surrogate molecule
No surrogate; clinical molecule (REGN5458) tested in cynomolgus monkey
“Two repeat dose toxicology studies were performed by the applicant, (Study R5458-TX-17179 and Study r5458-tx-20118).”
Species: general tox
Cynomolgus monkey only
“The first study was conducted in male and female monkeys once weekly for 5 weeks at doses of 0.1, 1, or 10 mg/kg IV infusion with a subsequent recovery period of 12.”
Species: DART
Not conducted (weight-of-evidence risk assessment)
“No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab.”
Species: carcinogenicity
Not conducted (ICH S9, advanced malignancies)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Surrogate used in
No surrogate used; clinical molecule tested in cynomolgus monkey
“Safety pharmacology evaluations were integrated into a GLP-compliant repeat-dose toxicology study conducted in Cynomolgus monkeys using linvoseltamab”
Study lengthopen answer page →
Longest pivotal study
14 weeks
“The subsequent toxicology study was initially programmed for 26 weeks of treatment but due to declining clinical condition that necessitated early sacrifice of a number of animals for welfare reasons, the study was stopped after 9 (total of 9 doses; 20 mg/kg group) or 14 weeks”
Pivotal GLP studies
GLP cynomolgus 5-week IV (0.1/1/10 mg/kg, 12-wk recovery) and 9- or 14-week IV (1/5/20 mg/kg, 13-wk recovery) studies
“Study R5458-TX-17179: A 5-Week Intravenous Infusion Toxicity and Toxicokinetic Study in Cynomolgus Monkeys With a 12-Week Dose-Free Recovery Phase”
Route in tox
IV (infusion/bolus)
“Male and female Cynomolgus monkeys, assigned to 4 groups, were administered once weekly for 5 weeks via intravenous infusion”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (antibody not expected to interact with DNA)
“No genotoxicity studies were conducted with linvoseltamab as antibodies are not expected to interact directly with DNA or other chromosomal material.”
Carcinogenicity
Not conducted (ICH S9, advanced malignancy)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Reproductive & developmental
Not conducted; weight-of-evidence (T-cell activation, cytokine release, B-cell depletion, placental IgG transfer)
“The Applicant provided a weight of evidence (WOE)-based risk assessment to assess the potential for reproductive and developmental toxicities.”
Safety pharmacology
Incorporated into 5-week GLP monkey study (telemetry ECG, BP, respiration, CNS); no effects to 10 mg/kg/week
“Safety pharmacology evaluations were integrated into a GLP-compliant repeat-dose toxicology study conducted in Cynomolgus monkeys using linvoseltamab (R5458-TX-17179, also see Repeat dose toxicity).”
Genotox: Ames
Not conducted (antibody not expected to interact with DNA)
“No genotoxicity studies were conducted with linvoseltamab as antibodies are not expected to interact directly with DNA or other chromosomal material.”
Genotox: in vitro mammalian
Not conducted (antibody not expected to interact with DNA)
“No genotoxicity studies were conducted with linvoseltamab as antibodies are not expected to interact directly with DNA or other chromosomal material.”
Genotox: in vivo
Not conducted (antibody not expected to interact with DNA)
“No genotoxicity studies were conducted with linvoseltamab as antibodies are not expected to interact directly with DNA or other chromosomal material.”
Carcinogenicity model
Not conducted (ICH S9, advanced malignancies)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Carcinogenicity timing
Not required (ICH S9)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
hERG / QT
No hERG assay; no cardiovascular, respiratory or neurological changes in monkeys up to 10 mg/kg/week
“At dosages up to 10 mg/kg/week (IV), the highest dose administered for 5 consecutive weeks, there were no drug-related respiratory, neurological, or cardiovascular changes evident.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Lynozyfic 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 multispecifics
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.”
This product's starting point
NOAEL / key findings: 5-week: HNSTD 10 mg/kg/wk; 9/14-week: NOAEL not determined (early sacrifice at all doses; multi-organ inflammation, peritonitis/pleuritis, body weight loss) (EMA assessment report, p. 36)
NOAEL / key findings
5-week: HNSTD 10 mg/kg/wk; 9/14-week: NOAEL not determined (early sacrifice at all doses; multi-organ inflammation, peritonitis/pleuritis, body weight loss)
“In the 9- or 14-week study, a NOAEL could not be determined.”
Risksopen answer page →
Immune & cytokine safety
Transient emesis with CRP/cytokine increase; sustained CRP, IL-2, IL-6, MCP-1 inflammation; ADA in 36-47% of monkeys reduced exposure
“the most severely impacted animals showed a dose-dependent induction of CRP that correlated with increased IL-2, IL-6, and MCP-1.”
Biodistribution & persistence
No distribution studies; GLP tissue cross-reactivity (human and monkey, incl. fetal) limited to mononuclear leukocytes, no unanticipated binding
“No unanticipated cross-reactivity of linvoseltamab was observed in either study.”
Modality-specific risk
Cytokine release/T-cell activation with multi-organ inflammation and infection risk from B-cell/plasma cell depletion
“Decreased B-cells and plasma cells likely contributed to decreased immunoglobulins causing secondary infections.”
Anti-drug antibodies: animals
ADA in both monkey studies; exposure maintained in 83% (5-week) and 92% (9/14-week) of animals
“Evidence of an anti-drug antibody (ADA) response was observed in both studies, but exposure was maintained in 83% (30/36) of the animals in the 5-week study and 92% (33/36) of the animals in the 9/14-week study.”
Anti-drug antibodies: patients
Treatment-emergent ADA 1.0% (2/195) overall; neutralizing antibodies not assessed
“1.8% (1/55) in patients in phase 1, 0.7% (1/140) in patients in phase 2, and 1.0% (2/195) overall. Neutralizing antibodies were not assessed in this study.”
Label warnings
Boxed warning: Cytokine release syndrome and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome
- Cytokine Release Syndrome (CRS)
- Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome
- Lynozyfic rems
- Infections
- Neutropenia
- Hepatotoxicity
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityInfectionsCytopeniasHepatotoxicityEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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 Lynozyfic 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 multispecifics
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.”
This product's starting point
NOAEL / key findings: 5-week: HNSTD 10 mg/kg/wk; 9/14-week: NOAEL not determined (early sacrifice at all doses; multi-organ inflammation, peritonitis/pleuritis, body weight loss) (EMA assessment report, p. 36)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9- or 14-week IV cynomolgus monkey study with 13-week recovery
“For the remaining animals the study was then divided into a 9-week (20 mg/kg group) or 14-week (1 and 5 mg/kg groups) repeat-dose study, each followed by a 13-week recovery phase.”
Pivotal GLP studies
GLP cynomolgus 5-week IV (0.1/1/10 mg/kg, 12-wk recovery) and 9- or 14-week IV (1/5/20 mg/kg, 13-wk recovery) studies
“Study R5458-TX-17179: A 5-Week Intravenous Infusion Toxicity and Toxicokinetic Study in Cynomolgus Monkeys With a 12-Week Dose-Free Recovery Phase”
DART package
Species: DART
Not conducted (weight-of-evidence risk assessment)
“No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab.”
Reproductive & developmental
Not conducted; weight-of-evidence (T-cell activation, cytokine release, B-cell depletion, placental IgG transfer)
“The Applicant provided a weight of evidence (WOE)-based risk assessment to assess the potential for reproductive and developmental toxicities.”
PPND / ePPND: when
Not conducted: no animal reproductive or developmental toxicity studies; immune activation may compromise pregnancy maintenance
“No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab. Linvoseltamab causes T cell activation and cytokine release; immune activation may compromise pregnancy maintenance.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced malignancies)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Carcinogenicity model
Not conducted (ICH S9, advanced malignancies)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Carcinogenicity timing
Not required (ICH S9)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
5-week: HNSTD 10 mg/kg/wk; 9/14-week: NOAEL not determined (early sacrifice at all doses; multi-organ inflammation, peritonitis/pleuritis, body weight loss)
“In the 9- or 14-week study, a NOAEL could not be determined.”
Efficacy evidenceopen answer page →
Efficacy evidence
NSG mice co-implanted with human PBMC and NCI-H929 or MOLP-8 myeloma xenografts
“In vivo studies were performed to evaluate the anti-tumor efficacy and minimum effective dose of linvoseltamab in immunodeficient NSG mice SC co-implanted with human PBMC and either NCI-H929 (BCMA-high) or MOLP-8 (BCMA-low) MM cells.”
Why that model
Binds human and cynomolgus monkey BCMA but not rat or mouse BCMA
“Overall, data indicate that linvoseltamab bound human and Cynomolgus monkey BCMA, but not rat or mouse BCMA.”
Reviewer's view of the efficacy data
EMA: efficacy demonstrated in the xenograft models
“Overall, linvoseltamab efficacy was demonstrated in the above-described xenograft models.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
Planned 26-week monkey study shortened after declining body condition in all dose groups; no 26-week study
Why: FDA did not request a 26-week study
“A subsequent toxicology study was initially planned as a 26-week repeat-dose study with once weekly dosing at 1, 5, and 20 mg/kg; the FDA did not request the study to be 26 weeks in duration. The study protocol was amended due to the declining body conditions across all dose groups compared to control.”
DARTAcceptedBeyond the letter
No standalone fertility or embryo-fetal studies; fertility endpoints in the 5-week monkey study and weight-of-evidence assessment of developmental risk
Why: In vivo studies of limited value to understand or communicate the risk to patients with advanced cancer · Serious disease
“Standalone fertility studies were not conducted by the applicant as male and female fertility endpoints were evaluated in the 5-week study and specific immunotoxicology endpoints were evaluated in both the 5- and 9- or 14-week studies repeat dose toxicity studies.”
“Based on the above, in vivo studies are deemed not warranted because of the limited value to further understand or communicate the risk to patients with advanced cancer.”
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