STUDY TITLE: Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura (MAYARI)
CLINICALTRIALS.GOV IDENTIFIER: NCT05468320
PARTICIPATING CENTERS: International study with 53 participating centers across the United States and Europe
SPONSOR: Sanofi
ACCRUAL GOAL: 61 participants
STUDY DESIGN: MAYARI is an open-label, single-group, phase III multicenter trial of caplacizumab with immunosuppressive therapy (IST) without frontline use of therapeutic plasma exchange (TPE) for immune-mediated thrombotic thrombocytopenic purpura (iTTP). Eligible participants include adults presenting with de novo or recurrent iTTP confirmed by low ADAMTS13 activity and absence of signs or symptoms consistent with other thrombotic microangiopathy (TMA) syndromes such as atypical hemolytic uremia syndrome (aHUS). Participants will receive caplacizumab, a humanized monoclonal antibody targeting von Willebrand factor (vWF), and immunosuppressive therapy (IST) (corticosteroids and rituximab). The primary outcome measure is the proportion of participants achieving remission without TPE. To achieve remission, participants must achieve normalization of platelet count; reduction in hemolysis (lactate dehydrogenase [LDH] <1.5 x upper limit normal [ULN]); and no new or progressive ischemic organ injury for ≥30 days after completion of initial therapy, or recovery of ADAMTS13 activity above 50%.
| . | NCT05468320 (MAYARI) . | NCT05714969 . |
|---|---|---|
| Study type | Phase III, single-group, multicenter | Phase IIb, multicenter, randomized, double-blinded |
| Planned enrollment | 61 | 40 |
| Eligibility | Adults aged 18-80 with de novo or relapsed iTTP, French TMA score of 1 or 2, and other TMA syndromes ruled out | Adults aged 18 and above with de novo or relapsed iTTP, other TMA syndromes ruled out, and no TPE or caplacizumab prior to enrollment |
| Treatment | • Caplacizumab and IST (corticosteroid +/ rituximab) for all participants • No TPE | • IST and randomized to two different doses of rADAMTS13 for the acute phase (until clinical response) • Same dose of rADAMTS13 in either group for post-acute phase up to six weeks |
| Study period | 24 weeks | 12 weeks |
| Primary outcome | Sustained clinical response, defined by: • platelet count ≥150 x 10^9/L • LDH <1.5 x ULN • no new or progressive ischemic organ injury • no TPE and no anti-vWF therapy for ≥30 days (CR), or ADAMTS13 activity ≥50%, whichever occurs first | Incidence of adverse events |
| Key secondary outcomes | • Proportion achieving remission • Proportion requiring TPE • Occurrence of adverse events • Time to platelet count response • Relapse • iTTP-related mortality | • Clinical response (normalization of platelets and no new ischemic events) • TPE use • Time to response • iTTP-related mortality |
| . | NCT05468320 (MAYARI) . | NCT05714969 . |
|---|---|---|
| Study type | Phase III, single-group, multicenter | Phase IIb, multicenter, randomized, double-blinded |
| Planned enrollment | 61 | 40 |
| Eligibility | Adults aged 18-80 with de novo or relapsed iTTP, French TMA score of 1 or 2, and other TMA syndromes ruled out | Adults aged 18 and above with de novo or relapsed iTTP, other TMA syndromes ruled out, and no TPE or caplacizumab prior to enrollment |
| Treatment | • Caplacizumab and IST (corticosteroid +/ rituximab) for all participants • No TPE | • IST and randomized to two different doses of rADAMTS13 for the acute phase (until clinical response) • Same dose of rADAMTS13 in either group for post-acute phase up to six weeks |
| Study period | 24 weeks | 12 weeks |
| Primary outcome | Sustained clinical response, defined by: • platelet count ≥150 x 10^9/L • LDH <1.5 x ULN • no new or progressive ischemic organ injury • no TPE and no anti-vWF therapy for ≥30 days (CR), or ADAMTS13 activity ≥50%, whichever occurs first | Incidence of adverse events |
| Key secondary outcomes | • Proportion achieving remission • Proportion requiring TPE • Occurrence of adverse events • Time to platelet count response • Relapse • iTTP-related mortality | • Clinical response (normalization of platelets and no new ischemic events) • TPE use • Time to response • iTTP-related mortality |
Abbreviations: CR, clinical remission; IST, immunosuppressive therapy; iTTP, immune-mediated thrombotic thrombocytopenic purpura; LDH, lactate dehydrogenase; rADAMTS13, recombinant ADAMTS13; TMA, thrombotic microangiopathy; TPE, therapeutic plasma exchange; ULN, upper limit normal; vWF, von Willebrand factor.
STUDY TITLE: A Study of TAK-755 (rADAMTS13) With Little to No Plasma Exchange (PEX) Treatment in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP)
CLINICALTRIALS.GOV IDENTIFIER: NCT05714969
PARTICIPATING CENTERS: International study with 28 participating centers across North America, South America, and Europe
SPONSOR: Takeda
ACCRUAL GOAL: 40 participants
STUDY DESIGN: The study is a phase IIb, randomized, double-blind trial of recombinant ADAMTS13 (rADAMTS13) for iTTP. Similar to MAYARI, adults presenting with de novo or recurrent iTTP are eligible after ruling out other TMA syndromes. The use of caplacizumab is a key exclusion criterion. Participants are randomized two dose levels of intravenous rADAMTS13 for the acute treatment period combined with IST. Participants on either arm who achieve clinical response continue treatment with rADAMTS13 for up to six weeks. The primary outcome in this trial is incidence of adverse events over a 12-week period. Key secondary outcome measures include achievement of clinical response (normalization of platelet count, reduction of LDH to <1.5 ULN with no new or progressive end-organ ischemia) paired with no TPE; minimal TPE (1-3 rounds); and overall response (regardless of TPE use).
RATIONALE: Advancements in the management of iTTP over the past three decades have transformed this previously near-fatal TMA (with 90% mortality in the 1980s) to an acute illness with a 10% mortality rate.1 This dramatic improvement in survival is largely due to recognition of the benefits of TPE and its widespread adoption in the acute management of iTTP.2 Understanding the metalloprotease ADATMS13 and its deficiency in the development of iTTP provided mechanistic insight on why TPE was effective in these patients.3,4 The importance of TPE in iTTP cannot be overstated. TPE is routinely initiated in suspected iTTP while the diagnosis is being established, and continued until platelet recovery. The later addition of IST, principally with corticosteroids and rituximab, has reduced rates of refractory disease and relapse, as well as morbidity.1,5 However, despite these advances, as Spero R. Cataland, MD, reported in the May/June 2024 issue of The Hematologist,6 iTTP is far from benign, with 28.6% of survivors developing major adverse cardiovascular events over the 7.6 years following an iTTP episode.7
The most recent addition to the management of iTTP has been the development and approval of caplacizumab, an anti-vWF antibody. Caplacizumab blocks the platelet-vWF interaction caused by accumulation of ultralarge vWF multimers in the setting of ADAMTS13 deficiency, thereby preventing the widespread platelet adhesion, aggregation, and microvascular thrombosis that are the hallmark of iTTP. When added to the standard management of iTTP, caplacizumab more rapidly restores the platelet count, reduces the need for TPE, and — most importantly — reduces mortality.8-10 Despite persistent concerns about cost-effectiveness,11 these results have led to the systematic upfront use of caplacizumab in acute iTTP in most institutions.
In contrast, there is far less data on the use of rADAMTS13 in iTTP. The objectives of TPE in iTTP are twofold: 1) restoration of ADAMTS13 activity and 2) removal of autoantibodies against ADAMTS13. Indeed, rADAMTS13 can fulfill the first objective and has been successfully used in the management of congenital TTP, where autoimmunity is less of a concern.12 In iTTP, in vitro data, using plasma samples from patients with iTTP, suggests that autoimmune inhibition can be overcome with rADAMTS13 supplementation.13 In vivo assessment of the safety and efficacy of rADAMTS13 for treatment of iTTP, which is the next step, is the objective of the Takeda study.
The efficacy of caplacizumab and development of rADAMTS13 have raised some tantalizing questions: Is TPE, the cornerstone therapy for iTTP for the past three decades, still necessary to maintain the current outcomes in iTTP? Can iTTP patients, particularly those who are diagnosed early or considered low risk, be managed in the ambulatory setting?
In our experience, urgent TPE requires careful coordination between multiple subspecialists, including critical care, proceduralists (for central line placement), and readily available transfusion medicine and apheresis nursing. Smaller hospitals often lack access to around-the-clock TPE, necessitating tertiary hospital transfer and contributing to unnecessary treatment delays. Linus A. Völker, MD, and colleagues have shown some success in treating iTTP with caplacizumab while omitting TPE in a small number of patients.9,14 Both of these trials will shed some light on the safety and efficacy of substituting TPE with caplacizumab or rADATMS13.
COMMENT: Morbidity and mortality in iTTP have improved over the past three decades, largely due to the timely use of TPE. These two clinical trials challenge this foundational practice. The benefits of omitting TPE for iTTP are clear — eliminating the need for resource-intensive apheresis and central access. Nevertheless, in consideration of the long-term cardiovascular morbidity associated with iTTP despite TPE use, long-term follow-up will be needed to confirm the safety of TPE omission, which these trials are arguably not designed to determine. Troublingly, the high cost of caplacizumab and rADAMTS13 will limit availability to larger centers, contributing to treatment delays and negating their key potential benefit over TPE. It is therefore likely that this debate will continue, even if these studies are favorable, until we have long-term follow-up data on safety and outcomes.
