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Omeros' Lead mAb Granted Breakthrough Therapy Designation for IgA Nephropathy

The FDA granted breakthrough therapy designation to Omeros’ lead human monoclonal antibody (mAb) OMS721 for the treatment of immunoglobulin A (IgA) nephropathy. The antibody targets mannan-binding lectin-associated serine protease-2 (MASP-2). Omeros holds glob

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The FDA granted breakthrough therapy designation to Omeros’ lead human monoclonal antibody (mAb) OMS721 for the treatment of immunoglobulin A (IgA) nephropathy. The antibody targets mannan-binding lectin-associated serine protease-2 (MASP-2). Omeros holds global rights to MASP-2 and therapeutics targeting the lectin pathway effector enzyme.

Breakthrough therapy designation for OMS721 for the IgA nephropathy indication was based on data from Omeros’ Phase II study in patients with kidney diseases including IgA nephropahy, which showed that administering OMS721 therapy for 12 weeks led to a 77% mean reduction in urine albumin-to-creatinine ratios, and a 73% mean reduction in 24-hour urine protein levels. The study data were presented at the recent 54th European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress. A Phase III study with OMS721 in patients with IgA nephropathy is now being planned. Seattle-based Omeros has established a compassionate-use program for OMS721 in both the U.S. and Europe.

There is no currently approved therapy for IgA nephropathy, Omeros points out. “We are pleased that FDA has granted breakthrough designation to OMS721 for IgA nephropathy and appreciate the Agency’s recognition of the potential importance of OMS721 in the treatment of this disease,” stated Gregory A. Demopulos, M.D., Omeros chairman and CEO. “OMS721 appears to be helping IgA nephropathy patients with a rapidity and magnitude not previously seen with any other therapy, and we look forward to working closely with the FDA to accelerate its development.”

OMS721 is separately undergoing Phase III evaluation for treating atypical hemolytic uremic syndrome (aHUS), and a separate Phase II trial is assessing the antibody against hematopoietic stem cell transplant-associated thrombotic microangiopathy (TMA). Phase III programs for the stem cell transplant-associated TMA indication are also being planned. OMS721 has been granted FDA orphan drug status for preventing complement-mediated TMAs, and fast track designation for the aHUS indication.

Omeros’ clinical pipeline includes a PDE10-targeting candidate (OMS824), which is in Phase II development for treating central nervous system disorders including Huntington’s and Schizophrenia, and a PPARγ candidate OMS405, which is also in Phase II development for treating opioid drug and nicotine addiction. The firm has a broad small-molecule and preclinical pipeline, and is exploiting its PharmacoSurgery, G protein-coupled receptor, and antibody platforms.

Omeros’s first marketed drug product, Omidria® (phenylephrine and ketorolac injection) is approved in the U.S. and in Europe for specified indications including the prevention of intraoperative miosis (pupil size reduction), and maintaining mydriasis (pupil dilation) during cataract surgery or lens replacement procedures. The firm reported global Omidria revenues of $12.3 million in the first quarter of 2017, up 69.2% on Q1 2016 figures.

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Related questions

01How stable is the antibody?

A crucial question often addressed during preclinical development focuses on the in vivo stability of therapeutic antibodies. Increasing the half-life of a therapeutic antibody has several benefits ranging from higher treatment efficacy to increased advantages for the patients who will have a fewer number of therapy sessions and a reduced cost. Given these compelling benefits, following the identification of therapeutic antibodies with the desired specificity, developers usually subject them to a refinement step to increase their stability. This process is often hindered by the lack of reliable experimental tools to predict the half-life of antibodies in patients. The major hurdle of using mouse models to predict antibody stability in the serum lies in the way immunoglobulin proteins are processed by the organism. In mammals, most proteins circulating in the serum undergo constant uptake by endothelial cells and are routed through the endosomes to the lysosomal compartment for degradation. In the endosomes, immunoglobulin G (IgG) proteins are recognized and bound by a transmembrane protein, called the neonatal Fc receptor (FcRn), which mediates their recycling to the plasma membrane and subsequent release back into the serum. As a result, the half-life of IgGs are significantly extended by this mechanism. Since most therapeutic antibodies belong to the IgG class, this recycling system is very relevant for their relative stability in the body. Remarkably, the relative affinity between IgGs and FcRn is extremely disparate between different species, with the mouse receptor showing a much higher affinity than its human counterpart.

Source: www.genengnews.com ↗
02Undruggable or unscreenable?

Another obstacle to discovering new PPI inhibitors is the lack of libraries designed to hunt for them, points out Philippe Roche, PhD, senior scientist at the Integrative Structural and Chemical Biology team at the Cancer Research Center of Marseilles, France. “If you screen PPIs using libraries that were designed for kinases or GPCRs, that’s why you don’t get a lot of good results,” he says. To that end, his group began assembling a library focused on orthosteric inhibitors of PPIs. The result was 2P2Idb, a hand-curated, structural database cataloguing orthosteric inhibitors of PPIs for which the interface had been 3D characterized. From analyzing these known PPI inhibitors, and what structures they had in common, Roche and his colleagues developed a model to predict whether compounds would likely inhibit PPIs. Using this method, 2P2Idb creates an enriched screening library that dramatically increases the hit rate compared to standard libraries. Having proven their success with a small library of 1600 compounds, they are in the process of expanding the library to 10,000 compounds. Once that’s published, “the idea is to make this library available to labs around the world,” Roche says. “We will provide the library free of charge for people to be able to screen PPI targets.”

Source: www.genengnews.com ↗
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