Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura

2011 ◽  
Vol 105 (03) ◽  
pp. 545-552 ◽  
Author(s):  
Bernd Jilma ◽  
Jolanta Siller-Matula ◽  
James Gilbert ◽  
Paul Knöbl ◽  
Petra Jilma-Stohlawetz ◽  
...  
Keyword(s):  
Steady State ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Plasma Concentrations ◽  
Prospective Trial ◽  
Organ Damage ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Baseline Activity ◽  
Von Willebrand

SummaryThrombotic thrombocytopenic purpura (TTP) can cause severe organ damage due to enhanced platelet aggregation by ultra-large von Wille-brand factor (VWF) multimers. Thus inhibition of VWF by the anti-VWF ARC1779 might potentially be beneficial for TTP patients. This prospective trial tested the safety, pharmacokinetics and pharmacodynamics of the anti-VWF aptamer ARC1779 added to plasma exchange therapy (PEX) in patients with acute TTP. Seven patients received bolus primed continuous i.v. infusions of ARC1779 (1–2 μg/kg/min) in addition to PEX until remission of TTP was induced or for 14 days. Mean steady state ARC1779 plasma concentrations of 9.9 μg/ml reduced VWF activity to 5% (mean baseline activity was 125% in TTP patients compared to a reference plasma). PEX reduced ARC1779 levels by 50%, but steady state concentrations were restored rapidly with a mini-bolus. After discontinuation of PEX, ARC1779 alone further increased platelet counts in one patient. Stopping ARC1779 was associated with an immediate drop of platelet counts in this patient. This suggests that ARC1779 can block the progression of TTP in patients with severe ADAMTS13 is deficiency. ARC1779 was generally well tolerated without any signs of bleeding. Pharmacokinetics and pharmacodynamics of ARC1779 were well predictable and in agreement with those observed in a previous trial with healthy volunteers. Based on its mechanism of action and the observed effect on platelet counts, ARC1779 used as an adjunctive to PEX may help accelerate recovery from organ dysfunction.

scholarly journals Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura

Blood ◽  
2020 ◽  
Author(s):  
George Goshua ◽  
Pranay Sinha ◽  
Jeanne Elise Hendrickson ◽  
Christopher A Tormey ◽  
Pavan Bendapudi ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Organ Damage ◽  
Hospital Length Of Stay ◽  
Sensitivity Analyses ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Relapse Rates

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab +/- other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery and reduce TPE treatments and hospital length of stay in TTP patients treated in the TITAN and HERCULES trials. The addition of caplacizumab to SOC also led to increased bleeding due to transient reductions in von Willebrand factor and increased relapse rates. Using data from TITAN and HERCULES on caplacizumab, we performed the first-ever cost effectiveness analysis in TTP. Over a 5-year period, the projected incremental cost effectiveness ratio (ICER) in our Markov model was $1,482,260, significantly above the accepted 2019 US willingness-to-pay of $195,300. One-way sensitivity analyses showed the utility of the well state and the cost of caplacizumab to have the largest effects on ICER, with a reduction in caplacizumab cost demonstrating the greatest impact on lowering the ICER. In a probabilistic sensitivity analysis, SOC was favored over caplacizumab in 100% of 10,000 iterations. Our data indicate that the addition of caplacizumab to SOC in treatment of acquired TTP is not cost effective due to the high cost of the medication and its failure to improve relapse rates. The potential impact of caplacizumab on health system cost using longer-term follow-up data merits further study.

Anti Von Willebrand Factor Aptamer ARC 1779 for Refractory Thrombotic Thrombocytopenic Purpura.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2298-2298 ◽  
Author(s):  
Chri sta Firbas ◽  
Bernd Jilma ◽  
Patricia G Wagner ◽  
Renta Hutabarat ◽  
Robert G Schaub ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Severe Thrombocytopenia ◽  
Proof Of Concept ◽  
Phase Ii Trials ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Neurologic Function ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: The investigational anti von Willebrand Factor (vWF) aptamer ARC1779 effectively inhibits vWF activity in blood samples of controls and of patients suffering from thrombotic thrombocytopenic purpura (TTP) (Jilma et al, Blood2007;110:279a, Gilbert et al. Circulation2007;116:2678–2686). Methods: A 39 year old comatose male patient with acute (TTP) was treated with daily plasma exchange. Further, the patient received rituximab (375mg/m2 first treatment on day 8, and weekly thereafter for 8 weeks) and was splenectomized on day 18. Due to the refractory nature of his TTP, the patient received a concomitant intravenous infusion of ARC1779 at a rate of 2 μg/kg/min beginning on day 30. Results: ARC1779 increased the platelet count slightly from 7 to a maximum of 30/nL; during this period septicaemia and DIC may have blunted the rise in platelet counts. However, platelet counts dropped to 5/nL by 16h after cessation of infusion (day 34). The infusion of ARC1779 was re-started on day 37, and platelet counts increased from 9 to 45/nL. (Figure) Due to a temporary lack of drug, the dose of ARC1779 was stopped at 78h, and platelet counts fell to 12/nL by 12 h after interruption of the infusion. (circle in the Figure) When ARC1779 was re-started, platelet counts increased to a maximum of 97/nL and the patient’s neurologic status improved to near normal under therapy with ARC1779 over the next week. Conclusions: ARC1779 was well-tolerated, and caused a reproducible rise in platelet counts, which alleviated severe thrombocytopenia, in an otherwise refractory TTP case. This effect was reproducible under serial “re-challenge”. Together with the observed improvement in neurologic function, the data provide clinical proof-of-concept and suggest that ARC1779 treatment might improve the organ dysfunction which typically occurs in acute TTP. These data provide a rational basis for ongoing and planned phase II trials of ARC1779. Figure Figure

Proof of Concept for the Anti Von Willebrand Factor Aptamer in Patients with Relapsing Thrombotic Thrombocytopenic Purpura (TTP).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2290-2290 ◽  
Author(s):  
Bernd Ji lma ◽  
Petra Jilma ◽  
Petra Paulinska ◽  
James C. Gilbert ◽  
Renta Hutabarat ◽  
...  
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Platelet Function ◽  
Von Willebrand Factor ◽  
Proof Of Concept ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
The Third ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) has a high morbidity and mortality rate despite current standard therapy comprising plasma exchange (PEX). Aim of this prospective clinical trial was to test the safety and efficacy of the anti von Willebrand Factor aptamer ARC1779 in patients with relapsing TTP, and to find possible proof of concept. Methods: Three patients with relapsing TTP (with detectable anti-ADAMTS13 autoantibodies) received bolus primed continuous intravenous infusions of ARC1779 (0.002 mg/kg/min) on top of standard PEX therapy until remission of TTP was induced, or for 14 days whatever came first. ARC1779 concentrations were quantified by a highperformance liquid chromatography/ultraviolet assay, the inhibitory effect of ARC1779 on vWF activity was evaluated with an ELISA kit (READDS vWF Activity ELISA Test Kit, Corgenix, Inc, Westminster, Colo), and platelet function was assessed with the platelet function analyzer (PFA-100). Results: ARC1779 was well tolerated without any evidence for bleeding in these patients. Median ARC1779 concentrations of approximately 10μg/mL in plasma were reached under steady state, and inhibited the collagen binding site of the vWF A1 domain by >95%. While plasma exchange (PEX) removed some 50% of the drug from the blood, ARC1779 concentrations could be restored by subsequent mini boluses. Platelet counts in all patients normalized with concurrent ARC1779 and PEX: 2 days after initiation of ARC1779 in two patients, and after 6 days in the third. In the third, the time course of response (see Figure) provides support for the concept that ARC1779 can restore platelet counts, and thus interferes with the disease process. While PEX was stopped when platelet counts reached 125/nL, 4 more days of therapy with ARC1779 increased platelet counts to 260/nL. Discontinuation of the ARC1779 infusion was associated with an immediate drop in platelet counts, so that PEX had to be restarted after 2 days (Figure). Conclusion: These data indicate that ARC1779 effectively inhibits VWF and thereby increases platelet counts in TTP patients. Addition of ARC1779 to PEX may have the potential to accelerate recovery from organ dysfunction in TTP and thereby decrease morbidity/mortality. Figure Figure

scholarly journals Characterization and treatment of congenital thrombotic thrombocytopenic purpura

Blood ◽  
2019 ◽  
Vol 133 (15) ◽  
pp. 1644-1651 ◽  
Author(s):  
Ferras Alwan ◽  
Chiara Vendramin ◽  
Ri Liesner ◽  
Amanda Clark ◽  
William Lester ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Age Of Onset ◽  
Organ Damage ◽  
Compound Heterozygous ◽  
Prophylactic Therapy ◽  
Thrombocytopenic Purpura ◽  
Stroke Incidence ◽  
End Organ Damage ◽  
Congenital Thrombotic Thrombocytopenic Purpura ◽  
Diagnosis Age

Abstract Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

Sign in / Sign up

Export Citation Format

Share Document