Glybera
alipogene tiparvovec
Sources:EMA assessment report ↗
Species
MouseRabbit
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Wild-type mouse only for GLP tox; PD in LPL-/- mice and LPL-deficient cats; biodistribution in cats, mice, rabbits
“All toxicity studies were performed in wild type mice in accordance with GLP.”
Why that species
Single species accepted per EU gene therapy guidelines; LPL-deficient mice and cats used as disease models
“The use of a single species for toxicity evaluation is in accordance with the guideline for gene therapy medicinal products EMEA/CHMP/GTWP/587488/2007 and the guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products (EMEA/CHMP/GTWP/12459/2006).”
Surrogate molecule
No surrogate; clinical vector AMT-011 (baculovirus) and earlier plasmid-derived AMT-010 tested in mice
“Studies were conducted with AMT-010 (plasmid derived) and several different batches of AMT-011 (baculovirus derived) and doses ranged from 1x1011 – 1x1013 gc/kg.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Moreover, the long-term expression of the therapeutic gene has been taken into account by including an extended follow-up period of 6 months in one of the single dose toxicity studies performed with AMT-011.”
Pivotal GLP studies
Single-dose IM mouse studies: AMT-010 (90-day), AMT-011 (180-day, 105-day with immunosuppression); combined repro/breeding study
“The non-clinical toxicology programme of Glybera included one single dose toxicity study performed with AMT-010 with a 90-day observation period, two single dose toxicity studies performed with AMT-011 with a 180-day and 105-day observation period, respectively, and a combined reproductive toxicology and breeding study performed with AMT-011.”
Route in tox
Intramuscular (clinical route); intravenous as worst case
“The single dose toxicity studies reflect the clinical dosing situation by addressing the toxic effects following either IM (clinical use) or IV (worst case scenario) administration of AMT-011 at a single occasion.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (standard tests not relevant); integration studies (LAM-PCR, nrLAM-PCR) instead
“Standard genotoxicity studies, as applied to a conventional chemical drug, are not relevant for this type of product and were not performed.”
Carcinogenicity
Not conducted; integration analyses argued sufficient (97% episomal, <2% near-random integration)
“Carcinogenicity studies have not been conducted. The applicant argues that the studies conducted to assess integration are sufficient to address risk of carcinogenicity.”
Reproductive & developmental
Mouse repro study: no effects on female reproduction or fetal development; male breeding study showed no paternal germline transmission
“Reproductive toxicity was studied in pregnant mice in whom no effects of female reproduction or fetal development were detected.”
Safety pharmacology
Not stated in public reviews
First doseopen answer page →
First-in-human starting dose
Not explicitly justified; clinical 1x10^12 gc/kg lies within active range in LPL-/- mice (10^11-10^13); tox covered 10x
“Activity was demonstrated in the dose range 1011-1013 gc/kg compared to the proposed human dose of 1x1012 gc/kg.”
NOAEL / key findings
NOAEL 1x10^11 gc/kg IM (mouse); dose-related injection-site myodegeneration and sub-acute inflammation, reversible; no systemic toxicity
“At the injection sites, histopathological findings including myodegenerative changes and sub-acute inflammation were consistently found in all three single dose toxicity studies upon IM administration of either 1x 1012 or 1 x1013 gc/kg AMT-010 and AMT-011, respectively.”
Risksopen answer page →
Immune & cytokine safety
Neutralising anti-AAV1 capsid antibodies blocked readministration; no CD8+ T cells in infiltrates; no anti-LPL antibodies
“on readministration, the second dose was not able to elicit a response, an effect attributable to formation of neutralising antibodies to AAV1 capsid.”
Biodistribution & persistence
Injected muscle, liver, spleen, inguinal lymph nodes; gonads/semen positive; incomplete clearance by 180 days in mice
“The main tissues where vector DNA was detected were the injected muscle, liver, spleen and inguinal lymph nodes.”
Modality-specific risk
Tumourigenicity via rAAV integration and WPRE (WHV X protein); local muscle toxicity from LPL overexpression; germline transmission
“The consensus view is that rAAV vector genomes remain episomal with minimal integration into the mammalian genome with no association with oncogenicity.”