Ocriplasmin
Status - U.S. BLA approved in Oct. 2012; EU MAA approval in March 2013
Organizations involved:
ThromboGenics NV – R&D; Tech.; World mark
Alcon Inc. – Intl. mark.
Novartis AG – Parent..
Fuji Diosynth Biotechnologies – Manuf.
Katholieke Universiteit Leuven – R&D; Tech.
Description: Ocriplasmin is a formulation of a truncated, stable form of the natural human protein microplasmin, a thrombolytic (blood clot break-down) enzyme, apparently expressed in Pichia pastoris yeast cells. ThomboGenics claims this is "the first stabilized and readily manufactured form of this molecule." Microplasmin consists of two polypeptide chains connected by disulfide bonds. One polypeptide is the B-chain of plasmin consisting of 230 amino acids, and the other peptide is the COOH-terminal portion of the A chain of plasmin consisting of 31 amino acid residues. Microplasmin has a molecular weight of 28.635 kDa, calculated from its primary sequence. It is slightly more positively charged than plasminogen and is a more hydrophobic molecule.
Microplasmin is a trypsin-line serine protease enzyme known to degrade various proteins in blood clots, including fibrin, thrombospondin, laminin, won Willebrand's Factor. and alpha2-antiplasmin.
Jetrea is the first therapeutic for treatment of vitreomacular adhesion (VMA).
Biological.: Microplasmin is a naturally occurring enzyme that dissolves protein formations that are crucial to blood clot (thrombus) formation. Similar protein formations are also seen linking the vitreous to the retina in the eye. Thus, microplasmin has the potential to be used in the treatment of a number of important ophthalmic indications.
The autocatalytic hydrolysis (serves as substrate and enzyme) of native human plasmin leads to the formation of microplasmin.
Microplasmin is a small molecule designed specifically for use in the eye for the treatment of symptomatic vitreomacular adhesion. Ocriplasmin (microplasmin) is believed to primarily target the fibronectin, laminin, and type IV collagen fibers that adhere the vitreous to the retina. Ocriplasmin is delivered via an intravitreal injection.
Vitreomacular adhesion (VMA) occurs when the vitreous humor, the gelled fluid within the eyes liqifies and contracts. This can result in damage to the macula, part of the retina, with degradation of vision. Microplasmin degrades residual fibronectin and laminin fibril that connect the the gel and the retina. This can improve surgical outcomes, and in many cases may fix the problem, allowing avoidance of surgery. Vitrectomy, a surgical procedure, was the only treatment option for VMA prior to Jetrea.
The goal of any pharmacologic separation of the vitreoretinal interface is to create a clean separation of the posterior vitreous cortex and the inner limiting membrane (ILM) of the retina. Compared to mechanical separation by vitrectomy surgery, pharmacologic options may provide a bare ILM with no residual vitreous, adhesions, or collagen remnants.
ThromboGenics is developing microplasmin as a non-surgical treatment for focal vitreomacular adhesion (or traction), a condition in which the vitreous gel has an abnormally strong adhesion to the retina. Over time, the gel tends to pull forward and can cause vessel and retinal distortion causing decreased vision. Microplasmin, as a proteolytic enzyme, may be able to facilitate and in some cases replace vitrectomy (surgery) and induce posterior vitreous detachment (PVD) by breaking down the protein structures which join the vitreous to the retina. Microplasmin could offer a well tolerated and lower cost solution as compared to vitrectomy. In addition to treat focal vitreomacular adhesion, microplasmin might also have the potential to treat Diabetic Retinopathy (DR) and Age-related Macular Degeneration (AMD) specifically in patients where vitreomacular adhesion might play an important role in their condition.
Nomenclature: microplasmin, rDNA [BIO]; Jetrea [TR]; Ocriplasmin [SY]
Companies.: ThromboGenics has exclusively in-licensed microplasmin from the Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven. Microplasmin was commercially developed by ThromboGenics NV. Presumably, Thrombogenics, a small company with no established sales force, will license marketing rights to one or more companies.
In Sept. 2010, ThromboGenics concluded a 10-year supply agreement with MSD Biologics (UK) Ltd. (fomerly Avecia Biologics), later part of the Merck BioManufacturing Network, Merck & Co., Inc., now Fuji Diosynth, for the production of microplasmin at its Billingham facility (UK). ThromboGenics anticipates that this will meet its long-term commercial needs for bulk drug substance.
In March 2012, ThromboGenics signed a strategic partnership with Alcon (Novartis) for the commercialization of ocriplasmin outside the United States. Under this agreement, ThromboGenics received an initial €75 million could receive up to a total of €375 million in up-front and milestone payments, plus "an attractive level of royalties" on Alcon’s net sales of ocriplasmin. ThromboGenics and Alcon share the costs equally of developing ocriplasmin for a number of new vitreoretinal indications.
Upon approval, there was much discussion that it made considerable strategic and business sense for Novartis to acquire ThromboGenics or otherwise procure U.S. marketing rights (i.e., secure worldwide rights).
FDA class: BLA Biologic
Status: On Dec. 23, 2011, a BLA was filed for ocriplasmin intravitreal injection, 2.5 mg/mL, for the treatment of symptomatic vitreomacular adhesion (VMA) including macular hole. In Feb. 2012, the FDA indicated to ThromboGenics that it intended to assign a Priority Review designation to the original BLA submission. On April 17, 2012, ThromboGenics resubmitted its BLA to facilitate FDA assigning priority review designation. On July 3, 2012, FDA accepted the BLA for filing.
An EU MAA is also pending for the same indication - the treatment of symptomatic vitreomacular adhesion (VMA) including macular hole.
Ocriplasmin has received orphan designation from FDA.
On Oct. 17, FDA granted the BLA for Jetrea. Product launch was then planned for Jan. 2013.
The EU granted an MAA in March 2013.
Tech. transfer: U.S. 7,547,435 and 7,803,368, "Pharmacological vitreolysis," claim methods of liquefying a vitreous and/or inducing posterior vitreous detachment of an eye of a subject by contacting the vitreous and/or aqueous humor in the eye of the subject with microplasmin, resulting in liquefying a vitreous and/or inducing posterior vitreous detachment of the eye of a subject; and recombinant microplasmin constructs..
Two Pichia clones, X33-KMPLG1 #6 and X33-KMPLG1 #25, showing the highest miniplasmin activity, were selected for large scale production. Presumably, one of these exemplifies the commercial product. These clones were deposited with the Belgian Coordinated Collections of Microorganisms as Accession Number MUCL 45309 (clone X33-KMPLG1 #6) and Accession Number MUCL 45308 (clone X33-KMPLG1 #25).
Other related U.S. applications apparently include "Pharmacological vitreolysis," 20050118158, 20090081187 , 20090074739, 20080095753 and 20080050356, assigned to Thromb-X NV (Leuven, Belgium). U.S. 20040071676, "Yeast expression vector and a method of making a recombinant protein by expression in a yeast cell," covers aspects of yeast expression of microplasmin and related plasminogen derivatives.
Dr. Desire Collen, Chairman and Founder, ThromoboGenics, is widely attributed as the developer of Jetrea. She is also attributed as having been the primary developer of tissue plasminogen activator (Activase) while at Genentech.
Trials: The microplasmin Phase III program, referred to as MIVI-TRUST (Microplasmin for IntraVitreous Injection-Traction Release without Surgical Treatment), consists of two multi-center, randomized, placebo controlled, double-masked trials. These trials are designed to evaluate 125 µg of microplasmin versus placebo in the intravitreal treatment of patients with symptomatic focal vitreomacular adhesion (VMA). The MIVI-TRUST program is the largest interventional clinical program ever performed to specifically evaluate the vitreoretinal interface in patients with retinal disorders. In total, over 650 patients were enrolled in these trials at 90 centers in 7 countries.
In Aug. 2012, results from two Phase III trials were published in the New England Journal of Medicine, showing that 26.5% of patients who received treatment had their vitreomacular adhesion (VMA) resolved compared with 10.1% in patients on placebo. Among the 652 total patients, 40.6% treated had closure of macular holes compared with 10.6% of placebo patients. Ocriplasmin was linked with more side effects, but these were temporary.
Disease: There are an estimated quarter million VMAP patients in the U.S.
Focal vitreomacular adhesion is a condition in which the vitreous gel, in the center of the eye, has an abnormally strong adhesion to the macula, the center of the retina at the back of the eye. Vitreomacular adhesion plays a key role in numerous back of the eye conditions, such as macular hole and some forms of macular edema. Vitreomacular adhesion is also associated with a worse prognosis in certain major eye conditions, including Diabetic Retinopathy and Age-related Macular Degeneration (AMD).
Focal vitreomacular adhesion can lead to macular hole, where the traction from the vitreomacular adhesion actually pulls off a piece of the macula (the part of the retina responsible for central vision). If not treated with major eye surgery called a vitrectomy, which involves using suction to remove the vitreous from the eye, macular hole can lead to irreversible, central blindness. While vitrectomy is generally effective in closing macular holes, it is an invasive procedure and a proportion of patients experience side-effects. These include alteration of vision, bleeding, retinal detachment and development of glaucoma and cataracts. Therefore, a nonsurgical treatment option for such patients could be an important breakthrough in the way macular hole patients are treated.
Neovascular age-related macular degeneration (nAMD) is a degenerative condition of the macula. It is the most common cause of vision loss in the age group 50 years or older, in the westernized world, with the disease affecting approximately 1.2 million Americans. It has been estimated that as many as approximately one-third of subjects with nAMD have VMA. Additionally, it has been hypothesized that posterior vitreous detachment (PVD) can prevent subjects from progressing to the neovascular form of AMD. Data has shown that subjects that have the dry form of AMD also have higher incidence of PVD.
Market: Some analysts project 2016 sales over $400 million. Others are more optimistic. For example, Jeffries (stock brokerage) projected peak sales of $875 million, and KBC Securities projected sales over $950 million for VMA alone.
Jetrea has considerable market potential beyond it initial FDA-approved VMA indication. This includes treatment of retinal venous occlusion, age-related macular degeneration (adjuvant therapy) and in many patients with diabetic macular edema, with VMA affecting about half of these patients. Although the FDA approval is broad, specific approvals are expected to be required inorder to allow marketing for these VMA-associated indications.
In Oct. 2013, the U.K. National Institute for Health and Clinical Excellence (NICE) recommended Novartis-unit Alcon's Jetrea (ocriplasmin) injection as an option for patients with the disease, deeming it both clinically and cost effective.
But the Institute stipulated that Jetrea should only be considered if an epiretinal membrane is not present, and patients have a stage II macular hole (full thickness with a diameter of 400 micrometres or less) and/or severe symptoms.
The treatment was found to offer an important alternative to the current standard approach of ‘watch and wait’, where patients undergo a period of observation before they become eligible for eye surgery due to worsening of their condition, so the availability of Jetrea means that those unsuited to a surgical procedure now have the opportunity for treatment before their condition deteriorates.
Jetrea costs £2,500 per injection (just one of which is needed for treatment), and NICE concluded that the cost per QALY gained for patients with a stage II macular hole was likely to be under £30,500, and therefore a cost effective use of NHS resources.
Companies involvement:
Full monograph
230.1 Microplasmin, rDNA
Nomenclature:
Microplasmin, rDNA [BIO]
Jetrea [TR]
Ocriplasmin [SY]
molecular weight (kDa) = 28.635
FDA Class: BLA Biologic
Year of approval (FDA) = 2012
Date of 1st FDA approval = 20121017
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
enzymes
enzymes
exempt from CBER lot release requirements
fibrinolysin
MRC5 cellular proteins
MRC5 cellular proteins
pHuLTAC plasmid
pHuLTAC plasmid
x-linked immunodeficiency
x-linked immunodeficiency
orphan status
PrefGel
EU002 EU application pending
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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