Role of Leptin in the MASP-2 Pathway

Video

Jeffrey Laurence, MD, discusses the role of leptin in the MASP-2 pathway as well as coagulation and complement pathways.

Samer Khaled, MD: We’ll move on to our next segment and talk about an evolving novel therapy that’s being introduced by Omeros. This is a MASP-2 [mannan-binding lectin serine protease] inhibitor that inhibits the lectin pathway. Just to start with, [let’s] talk about the role of MASP-2 and the TMA [thrombotic microangiopathy] development and the rationale behind targeting that.

Jeffrey Laurence, MD: In terms of the MASP-2 pathway, virtually every intervention that’s used in the transplant setting from the calcineurin and mTOR [mechanistic target of rapamycin] inhibitors, to total body radiation, to the infections, the graft-versus-host disease; all of it damages microvascular endothelium. All of it exposes these sites for binding of mannan-binding lectin, which then activates MASP-2, and MASP-2 then activates the lectin pathway complement.

The rationale for suggesting use of narsoplimab in transplant-associated TMA is 2-fold. It’s to try to put a brake early on in the complement pathway. We published a case series in January in clinical experimental immunology that looked at levels of MASP-2 in our transplant patients with and without TMAs, and also typical patients with HUS [hemolytic uremic syndrome], where we found really high levels in those patients. There is a reason to document the involvement of the MASP-2 lectin pathway in the disorder. You’d want to treat with a MASP-2 inhibitor, not only to block that early activation of the lectin pathway [but also to] prevent the activation of the alternate pathway.

Also, coagulation is an issue in this disorder. It’s the microvascular thrombi that we’re interested in, not the other coagulation pathway factors. If you can inhibit MASP-2, which activates prothrombin to thrombin, you’re getting 2 hits; you’re not only disabling a specific part of the complement pathway, but you’re also affecting the prothrombotic condition related to thrombin activation.

Then another advantage here, there’s this black box warning on eculizumab. As we all know, in inhibiting C5, which is further down in the complement cascade from where a MASP-2 is acting, you’re in danger of developing infections in adults: meningococci, meningococcal meningitis; [and in children,] Neisseria gonorrhoeae, also other encapsulated organisms, including [Haemophilus influenzae] and [Streptococcus pneumoniae].

There is no black box warning in the clinical trials that are being run with narsoplimab, but there is no requirement for taking prophylactic antibiotics to try to prevent those kinds of infections the way there are with eculizumab. This offers a kind of advantage, not only blocking 2 different pathways, but also [not appearing] to require prophylactic antibiotics.

Samer Khaled, MD: This is a very important point, because narsoplimab inhibits upstream complement activation and doesn’t interact with a classical pathway; it didn’t require that infectious prophylaxis.

There was also a retrospective study in Europe that shows patients with a rare D120G homozygous mutation that leads to a MASP-2 deficiency didn’t have increased risk of infection as opposed to other patients.

Transcript edited for clarity.

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