September 29, 2020 PAP-Q3-20-CL-029
Plasma is the largest component of human blood, comprising about 55% of the volume, with the remainder comprising red blood cells (44%) and white blood cells and platelets (1%). Consisting primarily of water (92%), along with enzymes, antibodies, and other proteins (~7%), and salts and other solutions (1%), plasma transports cells and important nutrients and other compounds needed by cells. It thus plays an important role in many important physiological functions, such as blood clotting and immune responses.
While there are thousands of proteins found within human blood plasma, some of the key therapeutic proteins include immunoglobulins, albumin, clotting factors (including FVIII, FIX, fibrinogen, prothrombin, and others), C-1 esterase inhibitor (C1-INH), and alpha-1-proteinase inhibitor.
Given their role in many important physiological functions, the isolation and use of plasma proteins as therapeutics for the treatment of various diseases has been pursued for decades. Both source (collected via plasmapheresis) and recovered (collected through whole blood donation) plasma are used to produce therapies that treat a range of diseases, including immune deficiencies, autoimmune and neurological disorders, hemophilia, infectious diseases, trauma, burns, and shock. Many of these diseases treated with plasma-derived therapeutics are considered rare diseases that do not respond adequately to other treatment options.
In general, plasma-derived therapeutics replace missing or deficient proteins found in patients or act to modulate the disease process. In many cases, these plasma-derived therapeutics must be administered chronically via intravenous or subcutaneous infusion or injection. Because these proteins are isolated from donated plasma, and no generics or substitutes exist, they are defined by regulatory authorities as human biologic products.
Three of the most important plasma proteins from a global market utilization perspective are immunoglobulins (IgGs), human serum albumin (HSA), and plasma-derived factor VIII (pdFVIII). In 2019, immunoglobulins captured the leading position, comprising $8.1 billion of the $12.2 billion U.S. plasma-derived therapeutics market, according to the Marketing Research Bureau (MRB).1 Other plasma proteins of importance from a therapeutic perspective include alpha-1-antitrypsin (AAT), hyperimmune globulins (HIG), other coagulation factors, fibrinogen, and C1-INH.
Immunoglobulins are antibodies in the immune system that neutralize foreign agents, such as bacteria and viruses. As therapies, they are used as replacement therapy in patients with low levels of antibodies due to primary immune deficiencies or genetic disorders or to treat secondary immune deficiencies due to exposure to drugs or toxins that attack the immune system. Immunoglobulins are also used extensively in treatment of autoimmune disorders, where the body’s immune system malfunctions and attacks the skin, muscle, heart, and other organs. Its function here is considered immunomodulatory. Examples of autoimmune disorders include chronic inflammatory demyelinating polyneuropathy (CIDP), a rare disorder of the peripheral nerves; idiopathic thrombocytopenic purpura (ITP), a bleeding disorder in which the immune system destroys platelets; and Kawasaki disease, a condition that primarily affects the blood vessels of the heart in children under the age of five and is the leading cause of acquired heart disease in children.
Albumin is the major plasma protein. It regulates blood volume and provides many essential functions and thus has been developed as a treatment for cardiac surgery patients and people suffering from liver disease, severe infections, shock, and severe burns.
Coagulation factors are essential for blood clotting and are used to treat genetic bleeding disorders (hemophilia A and B, von Willebrand disease, and antithrombin III deficiency), surgical bleeding, overdoses of anticoagulants, and some liver diseases.
Alpha-1 proteinase inhibitors protect lung tissues from enzymes produced by inflammatory cells and serve as a treatment for AAT deficiency, a genetic disorder that can potentially result in life-threatening lung disease in adults and/or liver disease in people of any age and is one of the most common serious hereditary disorders in the world.
HIGs are immunoglobulin treatments high in specific antibodies developed to fight certain infections and other foreign bodies, including rabies, tetanus, hepatitis, Rh-negative pregnancies, and issues that occur during liver transplants and other surgeries. Several companies are currently collaborating on the development of HIG-based treatments to treat COVID-19 infection.
Finally, C1-INH controls the C1 protein, which is part of the complement system. It is used to treat hereditary angioedema, a rare, potentially life-threatening condition characterized by acute attacks of swelling of the face, larynx, abdomen, and extremities.
The global market for plasma-derived therapeutics continues to grow significantly, increasing from approximately $7 billion in 20052 to just over $24 billion in 2018 and expanding at a compound annual growth rate (CAGR) of approximately 10.0%, according to MRB.1 The U.S. market is growing even more quickly, with a CAGR of approximately 12%.1
This strong growth has been driven by greater diagnosis and expanded use in patients requiring treatments such as IgG, which includes the more recent introduction of subcutaneous IgG (SCIG), in addition to C1 INH and AAT.4 The U.S. immunoglobulin market was valued at over $8.1 billion in 2019, accounting for nearly 66% of the U.S. plasma products market.3
Continued growth will also be driven largely by increasing demand for IgG in both the treatment of conditions where it is known to be efficacious and new indications that are discovered. There is also expected be an increase due to continued geographic expansion.4 Demand for albumin is also expected to rise, owing to improved diagnosis of hypoalbuminemia caused by liver cirrhosis and hepatitis B, potential new indications, and growing use in China,1 as well increasing use as a drug formulation agent, sealant in surgeries, vaccine ingredient, and coating for medical devices.
Plasma proteins have traditionally been isolated from pooled, collected plasma using cold ethanol fractionation, a method initially developed in the 1940s by Harvard University professor Edwin Cohn to provide albumin to treat soldiers injured during World War II.
Acid, alcohol, and salts are employed at cold temperatures to precipitate proteins into fractions containing many proteins in their non-native forms. Specific proteins are purified using various methods after re-solubilizing the precipitated fractions. They are also subjected to viral inactivation and removal processes. The process generally takes several months from the time plasma is donated until a final product is released for distribution.
Notably, because cold ethanol fractionation was originally developed to extract albumin and not any of the numerous other proteins now approved as therapeutics, the process conditions are not fully optimized for these other proteins. Some, for instance, are not fully stable in ethanol. The use of ethanol also poses challenges, because it is a flammable solvent with specific and extensive storage, handling, and use requirements to ensure safe operations. The fractionation process also consumes significant energy to run at a low temperature and produce product, thereby contributing to greenhouse gas emissions. As such, there is a need for modern, safer, more sustainable, and more efficient/productive methods for the production of plasma-derived therapeutics.
Evolve Biologics was created specifically to commercialize an alternative plasma protein production technology that eliminates the need for cold ethanol fractionation and could isolate plasma proteins in their native forms and in higher yields, thereby capturing as many proteins as possible from every liter of plasma.
Patented PlasmaCap EBA® technology has been under development for plasma extraction since 2012. It uses proprietary affinity adsorbents in expanded bed adsorption (EBA) chromatography to capture plasma proteins directly from plasma without the use of precipitating solvents. The plasma is passed through a series of chromatography columns arranged in a particular sequence and designed to capture the proteins in their native form with a higher degree of efficiency and selectivity.
Each column contains proprietary adsorbent composed of tungsten carbide beads coated with agarose modified with ligands that are chemical substances with specific protein binding sites. The expanded bed columns provide more space between the beads than in traditional packed-bed chromatography, allowing the viscous plasma to flow through more quickly and without clogging.
A fluidizer rotates gently as the plasma passes through the column, generating optimal conditions for binding the target protein and allowing the remaining proteins to flow through without any structural alterations. In addition, because EBA columns operate via upward flow, plasma can be processed without aggressive cleaning, sanitizing, and conditioning agents and with little risk of plugging.
The key to the process is the creation of a stable fluidized bed that is not affected by variability in lipid, lipoprotein, micelle, or soluble aggregate concentrations. This design enables the extraction of many valuable proteins at higher yields from each liter of precious donor plasma compared with legacy techniques. PlasmaCap EBA® technology has also been shown in many cases to enable capture of proteins at a higher yield per liter of plasma compared with published industry norms using traditional cold ethanol fractionation.5 Furthermore, because precipitation is avoided, more consistent quality and purity can potentially be achieved than is possible with conventional fractionation methods.
As important as the results obtained with the new PlasmaCap EBA® technology is the fact that the expanded bed chromatography approach to plasma protein purification is readily scalable. It can be scaled both up and down in response to market demand, making it possible for plasma protein manufacturers to operate at scales not generally considered economically viable using cold ethanol fractionation.
The flexibility in scale also makes it possible to construct small, modular facilities that leverage the PlasmaCap EBA® technology in countries and regions where smaller quantities of plasma (150,000–200,000 liters annually) are collected. This ability could potentially boost the effectiveness of certain plasma-derived therapeutics, because dosing populations with indigenous proteins is thought to lead to improved performance, particularly for plasma-derived therapeutics intended to treat immune diseases. As an example, the composition and quantity of IgG in plasma has been shown to vary greatly with the local environment and exposure to different infective agents.
Domestic regional production of plasma-derived therapeutics would also reduce the dependence of many countries on products derived from U.S.-sourced plasma. PlasmaCap EBA® technology should also allow purifying and producing plasma-derived therapeutics other than those that are already on the market much more effectively than can be achieved with cold ethanol fractionation. Obtaining sufficient quantities of proteins present in donated plasma at very low levels has been difficult to date, thus limiting the development of additional plasma protein therapies beyond the compounds that are present and readily accessible in the highest concentrations.
As a result, no new plasma-derived therapeutics have been introduced into the major markets in the last decade. Despite expected production challenges, however, researchers are evaluating several products in clinical trials, including plasminogen and reconstituted high-density lipoprotein (HDL).2 Several companies are also at the early stages of investigating the potential therapeutic effects of novel proteins not yet isolated from plasma with the hope that an effective means of production will be developed.
It is also worth noting that existing plasma-derived therapeutics are under investigation for the treatment of expanded indications, such as IVIG for neurological diseases, AAT for type 1 diabetes, fibrinogen for aortic aneurysm surgery, and C1 INH for antibody-mediated rejection in organ transplantation.4 All of these proteins under development and others yet to be fully explored are being investigated as potential candidates for production using PlasmaCap EBA® technology.
Evolve has two lead candidates in clinical trials that have been produced using our novel human plasma protein purification platform. The adult portion of a phase III trial conducted in the United States for a 10% liquid formulation intravenous immunoglobulin (IVIG) product manufactured from U.S.-source plasma as a replacement therapy in primary immunodeficiency disease (PIDD) was completed in 2019.
The preliminary data analysis for adults appears to indicate that the product is efficacious, safe, and well-tolerated in the treatment of patients with PIDD. The pediatric portion of the study was also recently completed, and analysis of the data is underway, with similar results expected. Regulatory submissions for both IVIG and albumin are currently being prepared.
Evolve has a three-pronged approach to the development and commercialization of plasma-derived therapeutics using our PlasmaCap EBA® technology. Our first priority is the commercialization of IVIG and albumin, through the establishment of a commercial facility for the manufacture of these products, and we expect growth to be driven by increased demand.
Secondly, we intend to continue adding additional capacity to process larger volumes of plasma, creating products for major developed markets, complemented in the future by geographic expansion using a modular approach for countries that collect plasma domestically at volumes not generally addressed by current manufacturers.
Our third focus area will be on mining human plasma for other proteins using Evolve’s PlasmaCap EBA® technology as a means for establishing a more robust future pipeline. Our ability to improve the quality and reliability of supply for plasma-derived therapeutics and achieve the cost-effective production of novel proteins present in small concentrations in human plasma will benefit patients, healthcare providers, and the pharmaceutical industry as a whole.
We will also be taking advantage of the opportunities afforded by our PlasmaCap EBA® technology and our many years of experience working in this space. Partnerships and collaborations with healthcare providers, patients, and other market partners will enable us to innovate further to improve the way that plasma-derived therapeutics are developed and ultimately administered.
Worldwide Plasma Proteins Market 2018. Rep. Marketing Research Bureau. 2020.
The Worldwide Plasma Proteins Market 2018. Rep. Marketing Research Bureau. Dec. 2019.
The Plasma Proteins Market in the United States 2019. Rep. Marketing Research Bureau. 2020.
“The Plasma Industry: A Look to the Future.” Marketing Research Bureau. 2017. Web.
Radosevich, M. and T. Burnouf. “Intravenous Immunoglobulin G: Trends in Production Methods, Quality Control and Quality Assurance.” Vox Sanguinis. 98: 12–28 (2009).
With over 30 years of pharmaceutical and biologics experience, David has held progressively senior commercial roles in both private and public companies. He has successfully launched and commercialized a number of key biologics in the UK, United States, and other international markets, most recently, as VP Commercial Operations for Octapharma US. Prior to this, he was Global Vice President of Marketing Operations and Hemophilia for Baxter and also led their UK Bioscience business, following a 17-year career with Novartis. David holds a DMS from Kingston University in London.