Vincent T. Ho, MD: Transplant-associated TMA [thrombotic microangiopathy] is a major problem after transplantation. The survival rates in these patients after development of this disease varies in the literature. But in general, for patients whose TMA does not respond, does not improve after stopping the calcium inhibitor or reducing the immune prophylaxis agents, this type of TMA tends to have a very bad outcome, and survival rates have been reported to be as low as 10% to 20% in this population.
Factors associated with poor survival include patients who have concurrent significant graft-vs-host disease as well as concurrent infections. It seems as though it really depends on the trigger. If the trigger is just a calcineurin inhibitor and it gets better, these patients might do OK. But if its trigger is something beyond that and includes an infection of graft-vs-host disease, those patients do a lot worse.
In pediatrics, the literature also suggests that presence of renal damage in the form of proteinuria, as well as presence of high levels of complements in MAC [membrane attack complex] soluble C5b-9, a marker of the terminal complement cascade is associated with poor outcomes. At least in the pediatric literature, it’s suggested that patients who have proteinuria or elevations of the soluble C5b-9 are considered high risk and that, therefore, those patients should be treated promptly.
The historical management of transplant-associated TMA has been with the use of total plasma exchange. Unfortunately, this approach, while it’s been used for many years, has been of limited utility.
While some patients respond well, it is certainly not a very good approach.
In contrast, the patients with TTP [thrombotic thrombocytopenic purpura], where total plasma exchange is extremely effective, in TA [transplant-associated]—TMA, the rate of improvement with plasma exchange has been relatively low across the literature, and survival remains very poor. There might be a role for plasma exchange in TMA that develops in the setting of a known antibody against the endothelium or against complement factors. But outside this setting, I think total plasma exchange is unlikely to be very effective.
The current management of TMA has primarily focused on the use of 2 drugs. One is a complement blockade with eculizumab where the literature would suggest about 60% to 70% response rate, especially in patients for whom there are measurable levels of C5b-9 in their blood.
The other potential therapeutic approach is to use a drug such as defibrotide, which has brought endothelial-protecting properties and prevents platelet aggregation and platelet activation in the small microendothelial vasculature.
Rituxan [rituximab] has also been used in some cases for the treatment of TMA, especially in cases where we think there’s an antibody component that’s driving the TMA process. Other than that, there remains a great need for effective treatment in this disease. That’s where narsoplimab may come in as a potential new agent in this space.
The mechanism of action for narsoplimab is that inhibits the lectin pathway for complement activation. The antibody is targeted against a protein called MBL-associated serine protease 2, or MASP2. MASP2 binds to mannose-binding lectin, and this combination basically is present on the surfaces of certain bacteria. This is a mechanism for activating the complement cascade to attack certain types of bacteria that invade our bodies. Without the need for an antibody, these complements will actually stick to the surface of the bacteria, and then this combination of MBL with the MASP2 will trigger the conversion of C2 and C4 to C3 convertase, which then triggers the entire downstream cascade leading to the formation of the C5b-9, ultimately the MAC attack complex that would destroy the pathogen. So MASP2 is much higher up in the complement pathway compared with toeculizumab, which targets the terminal attack complex.
Transcript Edited for Clarity