Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Gentium S.r.l, Piazza XX Settembre, 2, 22079 Villa Guardia (Como), Italy
Pharmacotherapeutic group: other antithrombotic agents
ATC code: B01AX01
Defibrotide is an oligonucleotide mixture with demonstrated antithrombotic, fibrinolytic, anti-adhesive and anti-inflammatory actions. The mechanism of action is multifactorial. It primarily acts through reducing excessive endothelial cell (EC) activation (endothelial dysfunction), modulating endothelial homeostasis as well as restoring thrombo-fibrinolytic balance. However, the exact mechanism of action of defibrotide is not fully elucidated.
Defibrotide has demonstrated antithrombotic and fibrinolytic effects in vitro and in vivo by: increasing systemic tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA) and thrombomodulin ™ expression; decreasing von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression; and enhancing the enzymatic activity of plasmin to hydrolyse fibrin clots.
In vitro and in vivo studies have demonstrated that defibrotide inhibits leukocyte and platelet adhesion to endothelium by: suppressing P-selectin and vascular cell adhesion molecule-1 (VCAM)-1; interfering with lymphocyte function-associated antigen 1-intercell adhesion molecule (LFA-1-ICAM) mediated leukocyte transmigration; and increasing nitric oxide (NO), Prostaglandin I2 (PGI2) and Prostaglandin E2 (PGE2).
In vitro defibrotide demonstrates anti-inflammatory effects that attenuate the release and production of reactive oxygen species and inflammatory mediators such as interleukin 6, thromboxane A2, leukotriene B4 and tumour necrosis factor-α (TNF-α).
Defibrotide protects ECs from damage and promotes tissue homeostasis by decreasing fludarabine-mediated apoptosis of EC while maintaining its anti-leukemic effect and by inhibiting the expression of heparanase, shown in in vitro and in vivo studies respectively.
The efficacy and safety of defibrotide in the treatment of severe VOD were studied in a pivotal Phase 3 historical-controlled study (2005-01). Forty-four children and 58 adult patients with severe VOD post-HSCT, were treated with Defitelio 25 mg/kg/day intravenous by infusion, and compared with 32 historical control patients. Median length of therapy in those treated with Defitelio was 22 days.
A significantly higher proportion of patients in the Defitelio treated group achieved a complete response defined as total bilirubin less than 2 mg/dL and resolution of MOF (multiple organ failure); Day+100 complete response was 23.5% (24/102) with Defitelio versus 9.4% (3/32) in the historical control (p=0.013). In addition, Day+100 survival rate was improved in the Defitelio group with 38.2% (39/102) of the patients surviving versus 25.0% (8/32) in the historical control group (p=0.034). The efficacy data from this pivotal study are supported and confirmed with data from a dose-finding study (25 mg/kg arm) and the Open Label Treatment-IND study, as presented in Tables 1.
Table 1. Treatment study results: Complete response and survival rate of severe VOD at day+100:
| Individual studies | ||||
|---|---|---|---|---|
| Dose-finding (25 mg/kg/day arm) | Open label treatment IND (25 mg/kg/day) | Historically controlled trial (25 mg/kg/day) | ||
| Defibrotide treated group | Historical control | |||
| Complete response by Day+100 | 43% (32/75) | 39.3% (201/512) | 23.5% (24/102) | 9.4% (3/32) |
| p=0.0131 | ||||
| Survival by Day+100 | 43.9%* | 49.5%* | 38.2%* | 25.0%* |
| p=0.0341 | ||||
* = Kaplan Meier estimates for time-to-event analysis by Day 100
Outcome data available from 611 patients treated with Defitelio on a compassionate use basis for non-severe and severe VOD post-transplant, are consistent with the controlled clinical studies, with complete response rate 24% (51/212) and survival 37% (78/212) in the subset of patients with severe VOD.
Coppell et al in 2010 reported data from a large meta-analysis of 235 patients with severe VOD showing a background mortality rate of severe VOD of 84.3% and that this mortality rate has remained constant over several decades.
Data derived from an independent US registry have shown a beneficial effect of Defitelio in routine clinical practice. At an interim analysis of the on-going registry, data from 96 patients with severe VOD were available.
The Day+100 all-cause mortality in patients with severe VOD who were not treated with defibrotide was 69%, and 61% in those patients who received defibrotide. These data are from an open label registry and the subjects were not randomised.
Additional information is shown in the following Table 2.
Table 2. US Registry data:
| Non-defibrotide treated | Defibrotide treated | |
|---|---|---|
| 55 | 41 | |
| Alive at Day +100 | 17 (31%) | 16 (39%) |
| VOD resolved by Day +100 | 16 (29%) | 21 (51%) |
A controlled randomised prophylaxis study (Study 2004-000592-33) was conducted in the paediatric patients undergoing HSCT. Patients (n=356) were randomised to receive 25 mg/kg/day from the start of conditioning or were randomised to receive no prophylaxis.
A 40% reduction in the overall incidence of VOD in the Defitelio prophylaxis arm (from 19.9% in the control arm to 12.2% in the Defitelio arm), has been shown. The use of Defitelio rescue treatment for all patients who developed VOD meant that the study was not designed to assess any survival advantage and none was seen in this study.
In secondary analyses on the subset of patients undergoing allogeneic transplants, Defitelio prophylaxis was also associated with a lower incidence and less Grade 2 to 4 severity of acute graft versus host disease (aGvHD) by Day+100.
A separate prophylaxis study (Study 15-007) using the same dose of Defitelio 25 mg/kg/day by intravenous infusion was conducted in paediatrics (n=198) as well as adults (n=174) post HSCT. The most common primary diseases of patients were acute lymphoblastic leukemia (n=100) 26.9%, acute myelogenous leukemia (n=96) 25.8%, or neuroblastoma (n=57) 15.3%. Patients were randomised to Defitelio plus best supportive (BSC) care or BSC alone.
The primary endpoint of VOD-free survival by Day +30 post-HSCT was not met; there was no difference when Defitelio plus BSC was compared with BSC alone. The Kaplan-Meier estimates (95% CIs) of VOD-free survival by Day +30 post-HSCT were 66.8% in the Defitelio prophylaxis arm (57.8%, 74.4%) and 72.5% (62.3%, 80.4%) in the BSC alone. The p-value from the stratified log rank test that compared VOD-free survival over time between the two treatment arms was 0.8504. By Day +30 post-HSCT, there were 10/190 or 5.7% deaths in Defitelio plus BSC and 5/182 or 2.9% deaths in the BSC alone.
Similar proportions of participants in the Defitelio plus BSC against the those receiving BSC alone only experienced TEAEs (99.4% vs 100%, respectively), serious TEAEs (40.9% vs 35.1%, respectively).
In the clinical studies performed in the treatment of VOD, over 55% (780 patients) were under the age of 18 years. Safety and efficacy information in children are available from three clinical studies for the treatment of VOD: the Phase 3 pivotal treatment study (2005-01), the Treatment-IND study (2006-05) and the dose-finding study (99-118). Safety in paediatric patients was also investigated in two additional prophylaxis studies (Study 2004-000592-33 & 15-007) described in section ‘Prophylaxis’ above.
Safety and efficacy in children aged less than 1 month have not yet been established.
Based on the results of the QTc study, conducted in healthy subjects at therapeutic and supra-therapeutic doses, it can be concluded that Defitelio has no significant or clinically relevant QTc-prolonging potential at doses up to 2.4 times higher than therapeutically indicated. Defitelio might be considered free of proarrhythmic toxicity related to QT changes.
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease and for ethical reasons preventing to perform a placebo-controlled study, 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.
In 52 healthy volunteers, after a single 6.25 mg/kg dose of Defitelio given as a 2-hour infusion, the pharmacokinetic parameters were as follows:
Table 3. Defitelio pharmacokinetic parameters after intravenous infusion of 6.25 mg/kg to healthy subjects:
| Parameter | Defitelio PK Parameters Mean ± SD |
|---|---|
| Cmax (μg/mL) | 17.3 ± 3.83 |
| tmax (h)# | 2.00 (1.00-2.00) |
| AUCt (μg/mL*h) | 26.9 ± 8.53 |
| AUC (μg/mL*h) | 48.1 ± 6.49 |
| Vd (mL) | 9934 ± 3807 |
| CL (L/h) | 10.4 ± 1.77 |
| Kel (1/h) | 1.25 ± 0.66 |
| t1/2 (h) | 0.71 ± 0.35 |
# median (min-max)
Maximum plasma concentrations peaked at the end of the infusion period and declined thereafter with a rapid clearance and most of samples were undetectable 3.5 hours after the start of the infusion. Pharmacokinetic modelling simulation analysis showed that Defitelio plasma concentrations do not accumulate upon multiple dose administration and with doses up to 4-fold the therapeutic dose. Volume of distribution is around 10 L. In vitro studies demonstrate that 93% of Defitelio is bound to plasma proteins.
After administration of the therapeutic dose (6.25 mg/kg) to healthy subjects, an average of 9.48% of the total dose administered is excreted in urine as unchanged defibrotide in 24 hours, with the majority excreted during the first collection interval of 0-4 hours (approximately 98%).
Defibrotide does not inhibit or induce CYP450s.
Six patients with an estimated glomerular filtration rate <30 mL/min/1.73m² (calculated using the Modification of Diet in Renal Disease equation) and not currently on dialysis were compared to 6 healthy subjects with similar baseline demographics. Defitelio 6.25 mg/kg was administered intravenously over 2 hours to subjects every 6 hours. Compared to healthy controls, subjects with renal impairment demonstrated 1.6- and 1.4-fold increases in AUC and Cmax, respectively and a half-life of about twice that of healthy subjects.
The amount of defibrotide excreted in urine over 24 hrs was about 5% of the total dose administered in those with renal impairment versus about 12% in healthy subjects.
Almost all renal excretion occurs within the first 4 hours. Accumulation of defibrotide over 4 doses was not found. Difference in exposure is not considered clinically relevant and so dose adjustment is not advised for patients with renal impairment (see section 4.2).
In a sub-study it was shown that haemodialysis did not remove defibrotide (see section 4.2)
No formal pharmacokinetic studies have been performed in hepatic impaired patients. Defitelio has been used in clinical studies in patients with hepatic impairment without dose adjustment with no major safety issues identified (see section 4.2).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity.
In both species, the main findings were accumulation of vacuolated macrophages in liver of dogs and in liver, kidneys and lymph nodes of rats. Macrophages are considered the main target organ.
In the Segment II reproductive studies in rats and rabbits, defibrotide has shown maternal toxicity by inducing a high rate of haemorrhagic abortion when infused intravenously over two hours at all dose levels tested including doses close to the human dose. Due to this maternal toxicity, no conclusion can be drawn regarding the effects of defibrotide on embryo-foetal development. PAI-2 is known to be uniquely up-regulated in the placenta.
Repeated intravenous administration of defibrotide, at doses below and close to the human therapeutic dose, to juvenile rats resulted in a delay in the mean age of preputial separation, suggesting a delay in the onset of male puberty in rats. However, the clinical relevance of these findings is unknown.
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