Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Partner Therapeutics Ltd., 28 - 32 Pembroke Street Upper, Dublin 2, Ireland., D02NT28, Tel: +353.1264.1754, e-mail: info@partnertx.com
Pharmacotherapeutic group: Immunostimulants, Colony-stimulating factors
ATC code: L03AA09
Sargramostim is a recombinant human GM-CSF. The binding to GM-CSF receptors expressed on the surface of target cells (haematopoietic progenitors and mature immune cells), initiates an intracellular signalling cascade which induces the cellular responses (i.e., division, maturation, activation). GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, it can promote the proliferation and maturation of megakaryocytic and erythroid progenitors.
Efficacy studies of sargramostim for the H-ARS indication could not be conducted in humans because the conduct of such studies is contrary to generally accepted principals of medical ethics and field studies after accidental or deliberate exposure to life-threatening doses of ionising radiation are not feasible. Therefore, 3 adequate and well-controlled studies (i.e., randomised, blinded, placebo-controlled) were conducted in a well-characterised Rhesus monkey model of total body irradiation (TBI)-induced H-ARS.
These studies provided minimal supportive care, mimicking the limited resource environment following a radiological and/or nuclear mass casualty incident. No whole blood, blood products, or individualised antibiotics were provided.
In all studies, Rhesus monkeys were administered with 7 mcg/kg as a single daily subcutaneous injection, which is the clinical recommended dose for adults exposed to myelosuppressive doses of radiation (see section 4.2).
The primary evidence of efficacy of sargramostim is summarised in Tables below.
Table 2. Randomised, blinded, placebo-controlled study in Rhesus monkey:
| Design | Randomised, blinded, placebo-controlled efficacy study conducted in Rhesus monkey |
| Number of animals | 108 Non-Human Primates (NHP, 54 male, 54 female). Animals exposed to 6.55 Gy (36 male:36 female) or 7.13 Gy (18 male:18 female) |
| Randomisation | NHPs randomised to receive sargramostim (7 mcg/kg/day) or placebo (water for injections). Treatment began 48 ± 1 hours post-TBI and continued daily until ANC ≥1 000 cells/μL for 3 consecutive days or ANC ≥10 000 cells/μL |
| Radiation dose | 6.55 and 7.13 Gy |
| Primary endpoint | 60-day survival post-radiation |
| Results | |
| Primary endpoint results (6.55 Gy TBI) | Sargramostim significantly increased 60-day survival: 28/36 (77.8%) survived compared to 15/36 (41.7%) in the control group (p=0.0018, Fisher's exact one-sided) |
| Primary endpoint results (7.13 Gy TBI) | Sargramostim improved 60-day survival: 11/18 (61.1%) survived compared to 3/18 (16.7%) in the control group (p=0.0076, Fisher's exact one-sided) |
| Secondary endpoint results | Sargramostim improved recovery rates of leukocytes, neutrophils and platelets at both radiation doses (6.55 and 7.13 Gy). A reduction in incidence of bacterial infections was also noted. |
| Mean duration of exposure to Imreplys | 17.6 days (range 12 to 23) [6.55 Gy group] 16.8 days (range 12 to 23*) [7.13 Gy group] |
Abbreviations: ANC: absolute neutrophil count; NHP: non-human primate; TBI: total body irradiation
* Study report Table 32 lists range of duration as 12 to 24, however 1 day was missed on day 16 for the animal that received treatment days 2-25.
Table 3. Time to recovery for neutrophils (ANC) and platelets, and incidence of infection in Rhesus monkey (Study 1):
| Study 1 | TBI Dose | Sargramostim (N=36) | Vehicle control (N=36) | Statistical significance (log-rank test) |
| Time to recovery (days), median days (95% CI) | ||||
| ANC ≥500/μL | 6.55 Gy | 17 (16, 18) | 19 (18, 20) | p<0.0001 |
| ANC ≥1 000/μL | 18 (17, 18) | 20 (19, 20) | p<0.0001 | |
| Platelet count ≥20 000/μL | 16 (NE, NE) | 18 (18, NE) | p=0.0008 | |
| ANC ≥500/μL | 7.13 Gy | 17 (16, 18) | 19 (19, 20) | p=0.2076 |
| ANC ≥1 000/μL | 17 (17, 18) | 19 (18, 20) | p=0.0206 | |
| Platelet count ≥20 000/μL | 16 (15, 17) | 20 (17, NE) | p=0.0002 | |
| Incidence of infection | ||||
| Incidence % of bacterial infection (95% CI) | 6.55 Gy | 32 (27, 38) | 63 (58, 69) | p<0.0001 |
| Incidence % of positive haemoculture | 6.55 Gy | 18% | 45% | NA |
Abbreviations: ANC: absolute neutrophil count; CI: confidence interval; NE: not estimated
Table 4. Randomised, placebo-controlled efficacy study in the Rhesus monkey model of TBI-induced H-ARS (Study 2):
| Design | Efficacy study, specifically the survival benefit and delayed response (expectant haematopoietic recovery response) of sargramostim 60 days following lethal TBI at the LD50/60 dose with minimal supportive care (antibiotics and fluids) in Rhesus monkey |
| Number of animals | 105 male NHPs randomised into 3 groups (n=35 per group) |
| Treatment | Daily until ANC count ≥1 000 cells/μL |
| Radiation dose | 6.80 Gy TBI |
| Primary endpoint | 60-day survival |
| Results | |
| 60-day survival 24-hours 48-hours | Number of sargramostim-treated NHPs survived 17 of 35 (49%) (p=0.11, log-rank test) 21 of 35 (60%) (p=0.03, log-rank test) |
| 60-day survival Control | Number of control NHPs survived 10 of 34 (29%) |
| Mean duration of exposure to Imreplys | 18 days or until ANC increased above 1 000 cells/μL |
Abbreviations: ANC: absolute neutrophil count; LD: lethal dose: NHP: non-human primate; TBI: total body irradiation
The adequate and well-controlled (AWC) efficacy and confirmatory AWC efficacy non-human primate (NHP) studies are summarised in Table 5.
Table 5. Randomised, placebo-controlled efficacy study in the Rhesus monkey model of TBI-induced H-ARS (Study 3):
| Design | Randomised, placebo-controlled efficacy study in the NHP model of TBI-induced H-ARS |
| Number of animals | 308 NHPs (154 male: 154 female) |
| Treatment | Daily starting 48-, 72-, 96-, or 120-hours post-irradiation until ANC returned to ≥1 000/μL for 3 consecutive days. Treatment was stopped if the ANC was ≥10 000/μL |
| Radiation dose | 7.13 Gy TBI |
| Primary objective | Evaluate the efficacy of sargramostim (7 mcg/kg/day) versus placebo when initiated at 48, 72, 96, or 120 hours post-TBI in NHPs exposed to 7.13 Gy TBI |
| Primary endpoint | 60-day survival |
| Secondary objectives | Assess efficacy on haematology parameters and incidence of infection |
| Results | |
| 60-day survival 48-hours 72-hours 96-hours 120-hours | Number of sargramostim-treated NHPs survived 30 of 44 (68%) 33 of 44 (75%) 30 of 44 (68%) 37 of 44 (84%) |
| 60-day survival Control | Number of control NHPs survived 38 of 44 (86%) |
| Mean duration of exposure to Imreplys | Approximately 16 days until ANC ≥1 000 cells/μL for 3 consecutive days or ANC ≥10 000 cells/μL |
* The 60-day survival results have not been statistically controlled for multiplicity. As a result, the strength of the evidence is limited, and findings should be interpreted with caution.
Abbreviations: ANC: absolute neutrophil count; NHP: non-human primate; TBI: total body irradiation
As with all therapeutic proteins, there is the potential for immunogenicity with sargramostim. In Rhesus monkeys exposed to radiation lower than 2 Gy and treated with 7 mcg/kg/day of sargramostim via subcutaneous injection for 14-days, no anti-drug antibodies were observed. It is expected that the effect of radiation impairs the ability of human body developing anti-drug antibodies.
No clinical safety signals have been associated with anti-drug or neutralising anti-drug antibodies in non-myelosuppressed patients, to date.
The European Medicines Agency has deferred the obligation to submit the results of studies with Imreplys in one or more subsets of the paediatric population in treatment of acute radiation syndrome (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under 'exceptional circumstances'. This means that due to the rarity of the disease and for scientific and ethical reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The pharmacokinetics of sargramostim are not available in patients acutely exposed to myelosuppressive doses of radiation.
Modelling and simulation of the healthy human adult pharmacokinetic data indicate that sargramostim Cmax and area under the curve (AUC) exposures at dose of 7 mcg/kg in healthy adults are expected to exceed sargramostim Cmax (97.6% of patients) and AUC (100% of patients) exposures at the same dose of 7 mcg/kg in Rhesus monkeys.
The pharmacokinetics of sargramostim in healthy paediatric patients were estimated by scaling the adult population pharmacokinetic model to the paediatric population. The model-predicted mean AUC0-24 values at 7, 10, and 12 mcg/kg doses of sargramostim in paediatric patients weighing greater than 40 kg (~adolescents), 15 to 40 kg (~young children), and 0 to less than 15 kg (~newborns to toddlers), respectively, were similar to AUC values in adults after a 7 mcg/kg dose.
Based on a population pharmacokinetics analysis of lyophilised sargramostim data, the mean Cmax after a 7 mcg/kg subcutaneous dose (equivalent to a 250 mcg/m² dose in a 70 kg human with a body surface area of 1.96 m²) was 3.03 ng/mL and mean AUC024 was 21.3 ng•h/mL. There is no accumulation of sargramostim after repeated subcutaneous dosing and steady state conditions are met after a single subcutaneous dose.
After subcutaneous administration, sargramostim was detected in the serum early (15 min) and reached maximum serum concentrations between 2.5 and 4 h.
A more than dose proportional increase in AUC was observed following a single subcutaneous administration of sargramostim across the 2 to 8 mcg/kg dose range in healthy male subjects.
In a study, healthy subjects were administered 250 mcg sargramostim by intravenous infusion over 2 hours. The observed volume of distribution (Vz) after intravenous administration was 14 L.
Specific metabolism studies were not conducted, because sargramostim is a protein and is expected to degrade to small peptides and individual amino acids.
When sargramostim was administered subcutaneously to healthy adult volunteers, it had a terminal elimination half-life of 1.4 h. The observed total body clearance/subcutaneous bioavailability (CL/F) was 23.9 l/h.
In a repeated-dose toxicity study, sargramostim was administered subcutaneously daily to cynomolgus monkeys at doses of 20 and 200 mcg/kg/day for 30 days. The lympho-haematopoietic system was identified as the primary target of toxicity: an increase in white blood cells and platelets as well as splenic inflammatory and lymphoid cell infiltration were observed at ≥20 mcg/kg/day.
Moderate to moderately severe bone marrow myeloid hyperplasia and mononuclear cell infiltrates in the heart and other organs were observed at 200 mcg/kg/day at terminal sacrifice, and moderate to moderately severe thymic atrophy was observed at 200 mcg/kg/day in both terminal and recovery animals. All findings were considered related to the pharmacology of sargramostim and therefore are potentially clinically relevant; however, the majority of the findings were observed at a dose that is approximately 17 to 29-fold greater than clinical exposure at the recommended human doses (7 to 12 mcg/kg/day) based on body weight scaling.
A similar pattern of toxicity but at a lower dose (20 mcg/kg/day) was observed in a 42-day repeated- dose toxicity study in which cynomolgus monkeys were subcutaneously administered 20, 63 and 200 mcg/kg/day with a sargramostim formulation containing ethylenediaminetetraacetic acid (EDTA), different from Imreplys. In this study, the systemic exposure (AUC) at 20 mcg/kg/day was approximately 2-fold greater than the clinical exposure at the recommended human doses (7 to 12 mcg/kg/day).
All reprotoxicity studies were carried out with a sargramostim formulation containing EDTA, different from Imreplys.
In the fertility and early embryonic development study, sargramostim was administered subcutaneously to rabbits at doses of 25, 70 and 200 mcg/kg/day from 6 days prior to artificial insemination and continuing through gestation day (GD) 7. Maternal toxicity was evident at ≥70 mcg/kg/day. A decrease in implantation sites and an increase in preimplantation loss and reduction in viable embryos was observed at 200 mcg/kg/day. The AUC at the no-observed-adverse-effect-level (NOAEL) for female reproductive and early embryonic developmental toxicity of 70 mcg/kg/day was initially (at the start of the dosing period) approximately 7.2-fold the clinical exposure at the recommended adult clinical dose (7 mcg/kg/day).
In the embryo-foetal developmental study, pregnant rabbits were administered subcutaneously doses of sargramostim during the period GD 6 to GD19 or GD19 to GD28 at 25, 70, and 200 mcg/kg/day.
Maternal toxicity was evident at ≥25 mcg/kg/day. An increase in late resorptions and reduced foetal weights were observed at ≥70 mcg/kg/day. An increase in spontaneous abortions and post-implantation loss, a reduction in viable foetuses and a reduced gravid uterine and placental weight were evident at 200 mcg/kg/day. The AUC at the NOAEL for embryo-foetal toxicity of 25 mcg/kg/day was initially (at the start of the dosing period) approximately 2.9-fold the clinical exposure at the recommended adult clinical dose (7 mcg/kg/day).
In the pre- and postnatal development study, rabbits were administered SC doses of sargramostim during GD6 to GD19, GD19 to parturition, or lactation day (LD)1 to LD14 at 25, 70, and 200 mcg/kg/day. Maternal toxicity was observed at ≥25 mcg/kg/day. At doses ≥25 mcg/kg/day, a reduction in postnatal offspring survival was observed when rabbits were dosed during lactation. The high-dose of 200 mcg/kg caused a decreased pup body weight when rabbits were dosed during lactation and from GD19 to parturition. Treatment from GD6-GD19 and GD19-parturition at 200 mcg/kg/day resulted in abortions, while after GD6-GD19 treatment with 200 mcg/kg/day total litter loss, early resorptions, reduced number of kits born and reduced live litter size on Post Natal Day 0 were also observed. There is no NOAEL for neonatal toxicity. The AUC of 25 mcg/kg/day dose was initially (at the start of the dosing period) approximately 2.6-fold the clinical exposure at the recommended adult clinical dose (7 mcg/kg/day).
By the end of the dosing periods, the systemic exposures decreased due to the production of anti-sargramostim antibodies reaching 1-fold, 0.2-fold and 0.2-fold the clinical exposure in the fertility and early embryonic development, embryo-foetal developmental and pre- and postnatal development studies, respectively.
Studies to evaluate the mutagenic and carcinogenic potential of sargramostim have not been conducted.
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