The MASP2 gene is a component of the lectin pathway of complement activation of the innate immune defense. MASP2 is expressed exclusively in hepatocytes and, as such, is an excellent target for inhibition using a GalNac-conjugated siRNA. The target is fully validated in human with neutralizing monoclonal antibodies. Inhibition of the lectin pathway not only may represent a therapeutic solution for COVID-19 patients but also for a remarkable variety of pathological conditions, both orphan and non-orphan.
The Company is developing a siRNA drug targeting MASP2 with convenient (such as subcutaneous self-administration) with infrequent (once in 5-6 months) dosing regimen.
- Lepton has the know-how and the technology to target siRNA to the liver
- Single subcutaneous injection
- Duration of effect up to 6 months
- High knockdown efficiency
- Favorable safety profile
Lepton’s approach for prevention of severe COVID-19 complications focuses, initially, on the inhibition lectin pathway (LP) components, overactivation of which is responsible for the cytokine storm and related vasculitis, hypercoagulation and long-term cardiovascular complications of the Covid-19 disease. This is accomplished by development of a proprietary GalNac-conjugated siRNA compound targeting MASP2 of the lectin pathway to be administered essentially as a prophylactic early following diagnosis, to prevent severe disease and long-term complications of the disease, in particular in high-risk patients. Based on CDC data over 90 million US adults are at high risk for serious disease due to older age and/or underlying medical conditions[i].
Lepton plans to initiate clinical trials with the MASP2 siRNA within approximately one year under the Coronavirus Treatment Acceleration Program (CTAP) of the FDA Emergency Use Authorization (EUA) authority. The clinical development is expected to require relatively small clinical trials (few hundred patients).
MASP2 siRNA for post-infection prophylaxis of severe COVID-19 disease in high-risk population has many advantages over other potential alternatives.
- Lepton’s injected siRNA will knock down the complement MASP2 in the liver. This will prevent virus-induced activation of only the lectin complement pathway and the eruption of uncontrolled systemic inflammatory response, without, however disrupting other complement pathways that provide anti-infective and/or anti-tumor defense mechanisms. [ii].
- Lepton’s drug will protect high risk patients independently of the virus variants of SARS-CoV-2 and indeed it is expected to be efficient against all coronaviral strains, novel and mutated.
- The drug has a long duration of activity, hence will have convenient dosing schedule.
- The synthetic nature of siRNAs and their chemically modified nature significantly simplifies large-scale production and thus makes siRNAs more economical than antibodies and markedly simplifies the supply chain and use-under a wide variety of thermal conditions.
Remarkable Additional Indications
The expected accelerated review of the LN 008 IND application and Phase 1 clinical study for treating COVID19 patients, would create a regulatory springboard ready for fast development of several remarkable indications for the same molecule some of which are illustrated below.
A vast amount of literature [iii], [iv] and clinical trials[v] data with anti MASP2 monoclonal antibody indicates that additional indications could be selected from a variety of rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS), IgA nephropathy (Berger’s disease), lupus nephritis. The Company has selected to pursue IgA nephropathy, an autoimmune, slowly progressive rare kidney disease[vi]; and lupus nephritis, one of the most serious complications occurring in a large percentage of people who have systemic lupus erythematosus (SLE)[vii]. Both diseases lead to kidney failure. There’s no cure for either disease and sure way of predicting progression; the goal of treatment is to avoid the need for kidney dialysis or kidney transplantation for as long as possible[viii],[ix].
In addition non-orphan and orphan indications associated with ischemia-reperfusion injury of various organs and systems, inflammatory vascular pathology including various types of vasculitis and atherosclerosis, rheumatoid heart disease, arthritis and others. A selected future indication is ischemia reperfusion injury (I/R) following acute myocardial infarction (AMI), a leading cause of morbidity and mortality worldwide. It has been shown that MASP-2 dependent activation of the lectin pathway is critically involved in mediating myocardial I/R injury, contributes to continued myocardial injury during reperfusion following AMI[x],[xi] making the inhibition of the lectin pathway, a promising future therapeutic approach in AMI.
Java et al. The complement system in COVID-19: friend and foe? JCI Insight. 2020;5(15):e140711
[iii] Alghadban, Samy et al. “Absence of the Lectin Activation Pathway of Complement Ameliorates Proteinuria-Induced Renal Injury.” Frontiers in immunology vol. 10 2238. 23 Sep. 2019, doi:10.3389/fimmu.2019.02238
[iv] Mariana Gaya da Costa, Felix Poppelaars, Stefan P Berger, Mohamed R Daha, Marc A Seelen, The lectin pathway in renal disease: old concept and new insights, Nephrology Dialysis Transplantation, Volume 33, Issue 12, December 2018, Pages 2073–2079, https://doi.org/10.1093/ndt/gfy073
[v] Clinical trials.gov for Narsoplimab
[vi] Jennifer C. Rodrigues, Mark Haas and Heather N. Reich, CJASN April 2017, 12 (4) 677-686; DOI: https://doi.org/10.2215/CJN.07420716
[vii] Saxena, Ramesh et al. “Lupus nephritis: current update.” Arthritis research & therapy vol. 13,5 (2011): 240. doi:10.1186/ar3378
[x] Clark JE, Dudler T, Marber MS, et alCardioprotection by an anti-MASP-2 antibody in a murine model of myocardial infarctionOpen Heart 2018;5:e000652. doi: 10.1136/openhrt-2017-000652
[xi] Panagiotou Anneza, Trendelenburg Marten, Osthoff Michael, The Lectin Pathway of Complement in Myocardial Ischemia/Reperfusion Injury—Review of Its Significance and the Potential Impact of Therapeutic Interference by C1 Esterase Inhibitor, Frontiers in Immunology . Vol 9, 2018, page 1151, https://www.frontiersin.org/article/10.3389/fimmu.2018.01151, DOI=10.3389/fimmu.2018.01151, ISSN=1664-3224