Provenge
sipuleucel-T
Species
no relevantRatMouse
Longest study
6 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
No conventional tox species; rat and mouse proof-of-concept studies with rodent surrogate products
“The immunogenicity and anti-tumour properties of these surrogate products were evaluated in rats and mice.”
Why that species
Autologous human product cannot be tested in animals; species-specific rodent equivalents used (rat/mouse PAP and GM-CSF)
“Animal models using species-specific variations of the human cell therapy product have been used.”
Surrogate molecule
Yes: rat APCs loaded with rPAP-rGM-CSF or hPAP-mGM-CSF fusion proteins; mouse hPAP-hGM-CSF loaded APCs
“The equivalent of sipuleucel-T has been prepared from rat APCs loaded with PAP•GM-CSF fusion proteins”
Species: general tox
None (no conventional toxicology studies submitted)
“The general battery of non-clinical toxicology studies were not submitted by the applicant.”
Species: DART
Not conducted (not considered relevant for an autologous cell therapy product)
“Conventional reproductive and development toxicity studies were not considered relevant given the nature and the intended clinical use of this autologous cell therapy product.”
Species: carcinogenicity
Not conducted (absence considered acceptable given the nature of sipuleucel-T)
“The absence of genotoxicity, mutagenicity and carcinogenicity studies was considered acceptable taking into account the nature of sipuleucel-T.”
Surrogate used in
Yes: rat APCs loaded with rPAP-rGM-CSF or hPAP-mGM-CSF fusion proteins used as sipuleucel-T equivalents for pharmacology
“The equivalent of sipuleucel-T has been prepared from rat APCs loaded with PAP•GM-CSF fusion proteins composed of rat or human PAP (rPAP and hPAP, respectively) fused to the rat or murine GM-CSF homologues (rPAP•rGM–CSF and hPAP•mGM-CSF, respectively).”
Study lengthopen answer page →
Longest pivotal study
6 weeks
“On day 42, 4 rats from the control (unimmunised)”
Pivotal GLP studies
None; non-GLP proof-of-concept rat prostatitis and mouse tumor-challenge studies only (rat observation to day 42)
“All pharmacological experiments were proof of concept studies that were non-GLP compliant.”
Route in tox
Intravenous (rat cell infusions); intraperitoneal in mice
“Copenhagen male rats, 10 weeks old, were immunised with three separate intravenous (IV) infusions”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (autologous nature of product)
“Toxicology studies, as described in the International Conference on Harmonization (ICH) Safety (‘S’) guidelines”
Carcinogenicity
Not conducted (autologous nature of product)
“No genotoxicity, reproductive toxicity, mutagenicity and carcinogenicity studies were provided”
Instead of genotoxicity
Not applicable: cells not genetically modified
“Toxicology studies, as described in the International Conference on Harmonization (ICH) Safety (‘S’) guidelines”
Reproductive & developmental
Not conducted
“No genotoxicity, reproductive toxicity, mutagenicity and carcinogenicity studies were provided”
Safety pharmacology
Not conducted as ICH battery; safety observations collected in pharmacodynamic rat and mouse studies
“The general battery of safety pharmacology studies as outlined in the International Conference of Harmonization (ICH) guidelines were not submitted by the applicant.”
Genotox: Ames
Not conducted
“No genotoxicity, reproductive toxicity, mutagenicity and carcinogenicity studies were provided”
Genotox: in vitro mammalian
Not conducted
“No genotoxicity, reproductive toxicity, mutagenicity and carcinogenicity studies were provided”
Genotox: in vivo
Not conducted
“No genotoxicity, reproductive toxicity, mutagenicity and carcinogenicity studies were provided”
Carcinogenicity model
Not conducted; no such effects expected given the nature of sipuleucel-T
“The absence of genotoxicity, mutagenicity and carcinogenicity studies was considered acceptable taking into account the nature of sipuleucel-T. No such effects are expected to be associated with Provenge.”
Carcinogenicity timing
Not required: absence of carcinogenicity studies accepted given the nature of sipuleucel-T
“The absence of genotoxicity, mutagenicity and carcinogenicity studies was considered acceptable taking into account the nature of sipuleucel-T.”
hERG / QT
Not conducted (no conventional safety pharmacology studies)
“Conventional safety pharmacology studies were not submitted by the applicant.”
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 Provenge 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 cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; cell dose not limited by toxicity; highest feasible dose used in animal studies; no obvious adverse effects in mice (EMA assessment report, p. 34)
NOAEL / key findings
No NOAEL; cell dose not limited by toxicity; highest feasible dose used in animal studies; no obvious adverse effects in mice
“It was agreed that the cell dose is apparently not limited by toxicity.”
Risksopen answer page →
Immune & cytokine safety
Autoimmune prostatitis induced in rats (mild to moderate); non-prostate PAP-expressing tissues not fully examined; no robust data on autoimmunity risk
“Mild to severe interstitial inflammation was observed in Groups 4-6 rats.”
Biodistribution & persistence
No conventional ADME/biodistribution studies submitted
“No conventional ADME studies were submitted by the applicant”
Modality-specific risk
Autoimmunity against PAP-expressing tissues (prostatitis, non-prostatic tissues); tolerance breaking by design
“The likelihood of auto-immune reactions in non-prostatic tissues expressing PAP cannot be excluded in the clinical setting”
Anti-drug antibodies: animals
Humoral and cellular anti-PAP responses in mice immunized with hPAP-mGM-CSF (intended immune response); no product ADA assessment
“The purpose of the first study (Report TR30508) was to assess the immunogenicity of human PAP when fused to murine GM-CSF. Humoral and cellular anti PAP responses were observed.”
Anti-drug antibodies: patients
Anti-GM-CSF neutralizing activity (treatment-related) in 22.7% (10/44) of sipuleucel-T vs 6.3% placebo subjects
“anti-GM-CSF neutralizing activity was observed for 10 of 44 evaluated subjects in the sipuleucel-T arm (22.7%) and for 1 of 16 evaluated subjects in the placebo arm (6.3%).”
Label warnings
- Acute Infusion Reactions
- Thromboembolic Events
- Vascular Disorders
- Handling Precautions for Control of Infectious Disease
- Concomitant Chemotherapy or Immunosuppressive Therapy
- Product Safety Testing
Hypersensitivity & infusion reactionsThrombosis & embolismInfections
US prescribing information, 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 Provenge 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 cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; cell dose not limited by toxicity; highest feasible dose used in animal studies; no obvious adverse effects in mice (EMA assessment report, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose toxicity study (autologous product)
“consisting of pharmacokinetics, acute toxicology, chronic toxicology, genotoxicity, carcinogenicity, reproductive and developmental toxicity, safety pharmacology, and immunotoxicity (http://www.ich.org/cache/compo/276-254 1.html) were not conducted due to the autologous nature of Sipuleucel-T”
Pivotal GLP studies
None; non-GLP proof-of-concept rat prostatitis and mouse tumor-challenge studies only (rat observation to day 42)
“All pharmacological experiments were proof of concept studies that were non-GLP compliant.”
DART package
Species: DART
Not conducted (not considered relevant for an autologous cell therapy product)
“Conventional reproductive and development toxicity studies were not considered relevant given the nature and the intended clinical use of this autologous cell therapy product.”
Reproductive & developmental
Not conducted
“No genotoxicity, reproductive toxicity, mutagenicity and carcinogenicity studies were provided”
PPND / ePPND: when
Not conducted: not considered relevant for an autologous cell therapy
“Conventional reproductive and development toxicity studies were not considered relevant given the nature and the intended clinical use of this autologous cell therapy product.”
Carcinogenicity
Species: carcinogenicity
Not conducted (absence considered acceptable given the nature of sipuleucel-T)
“The absence of genotoxicity, mutagenicity and carcinogenicity studies was considered acceptable taking into account the nature of sipuleucel-T.”
Carcinogenicity model
Not conducted; no such effects expected given the nature of sipuleucel-T
“The absence of genotoxicity, mutagenicity and carcinogenicity studies was considered acceptable taking into account the nature of sipuleucel-T. No such effects are expected to be associated with Provenge.”
Carcinogenicity timing
Not required: absence of carcinogenicity studies accepted given the nature of sipuleucel-T
“The absence of genotoxicity, mutagenicity and carcinogenicity studies was considered acceptable taking into account the nature of sipuleucel-T.”
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
No NOAEL; cell dose not limited by toxicity; highest feasible dose used in animal studies; no obvious adverse effects in mice
“It was agreed that the cell dose is apparently not limited by toxicity.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent surrogates: rat APCs with rPAP-rGM-CSF inducing prostate-specific inflammation; antigen-loaded APCs protecting mice against tumour challenge
“ability of rat APCs loaded with rPAP•rGM-CSF fusion protein to stimulate prostate specific inflammation, and the ability of antigen loaded APCs to protect against tumour challenge in mice.”
Why that model
Appropriate prostate tumour models were not available at the time of the nonclinical studies
“It was acknowledged that the use of appropriate (prostate) tumour models was difficult if not impossible since such models were not available at the time of performing the non-clinical studies.”
Reviewer's view of the efficacy data
Pharmacology studies had some deficiencies but were sufficient to establish proof-of-concept
“Although the pharmacology studies presented some deficiencies, the pharmacological data were considered sufficient to establish a proof-of-concept for treatment of patients with Provenge in the proposed indication.”
Test articleopen answer page →
Test article vs clinical lot
Rat splenic cells loaded with PAP antigens instead of PBMCs, made by a process differing from sipuleucel-T
“However, splenic rat cells were loaded with PAP antigens instead of peripheral blood mononuclear cells and the manufacturing processes for the cellular products differed from the sipuleucel-T process.”
Genetically modified?
Autologous PBMCs including APCs activated ex vivo with PAP–GM-CSF fusion protein PA2024; not genetically modified
“Provenge (sipuleucel-T) consists of autologous peripheral blood mononuclear cells (PBMCs), including antigen presenting cells (APCs) that have been activated ex vivo with a recombinant fusion protein, PA2024, composed of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF).”
First approval
Flexibilityopen answer page →
Flexibility accepted
OtherCriticised but accepted
No conventional toxicology or pharmacokinetic studies; risk-based approach justification instead
Why: Considerable clinical efficacy and safety experience; risk-based approach under the ATMP framework · Human data · Within the guideline
“In line with Annex I, part IV of Directive 2001/83/EC applied to ATMP, a risk-based approach discussion was provided by the applicant to further justify the extent of non-clinical data provided in the dossier and particularly the lack of pharmacokinetic and toxicity studies.”
“Since considerable clinical experience is now available on the efficacy and safety of sipuleucel-T in the proposed indication, no additional studies in animals are needed.”
Safety pharmacologyAcceptedBeyond the letter
No conventional safety pharmacology studies; only non-GLP observations within rat pharmacodynamic studies
Why: Sufficient clinical safety data from clinical trials and US post-marketing experience · Human data
“Since sufficient clinical safety data are available from clinical trials and post-marketing experience in the USA, no dedicated non-clinical safety pharmacology studies with sipuleucel-T are deemed necessary at this stage.”
BiodistributionCriticised but acceptedBeyond the letter
No cell distribution or trafficking studies
Why: Available clinical efficacy and safety data · Human data
“Data on distribution and trafficking of cells would have been useful to know whether cells distribute to the prostate or non-prostate tissues expressing PAP antigen or to their draining lymph node. However, in view of the available clinical efficacy and safety data, such a study would not add relevant clinical information at this stage.”
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