The plasma industry has experienced strong growth in the 21st century, going from just over $5 billion in global sales in 2000 to over $24 billion in 2018 (excluding recombinant products). The growth has mainly been caused by new patients diagnosed and starting therapy with IgG, C1-INH, AAT. Even though no new plasma proteins have been introduced in the past ten years, the plasma industry is expected to continue expanding due to higher usage of core plasma proteins such as IgG as well as geographic expansion. Some of the current research efforts with plasma-based products are described below.
New Products Fractionated from Plasma
After a decades-long hiatus, the industry is on the cusp of introducing new plasma proteins. Plasminogen has finally recently been approved and launched by Kedrion, CSL Behring is exploring reconstituted HDL from plasma, and companies seeking to commercialize novel proteins are exploring new business models. More than 2,000 proteins exist in plasma, with only 15-20 commercialized, leaving the vast majority of potential proteins unexploited for commercialization. It is unlikely that a new protein will supplant IgG as the plasma industry driver, but additional proteins will contribute to the industry’s economic viability and benefit new patients with safe and efficacious plasma therapies, unless superior biotechnology-derived drugs and gene therapy options can be developed. Until such time, donor plasma will continue to be needed in growing quantities.
New Indications for Plasma-based Products
Other plasma-based products are under investigation for additional diseases or indications, including:
- IVIG & SCIG in various diseases (Myasthenia Gravis, Neuropathic Pain, Secondary Immunodeficiencies, Dermatomyositis, etc.),
- Albumin in Cirrhosis, liver disease, Alzheimer’s Disease, Malaria and Sepsis,
- Alpha-1 antitrypsin in lung Graft-vs-Host Disease (GVHD), Lung injuries, and
- Fibrinogen in aortic aneurysm surgery with acquired fibrinogen deficiency,
- C1 INH for antibody-mediated rejection in organ transplantation
In addition to new proteins and indications, the plasma industry continues to investigate new formulations for plasma-based products. For example, the original intramuscular formulation of immune globulins was not able to provide the volume necessary for optimal dosing in disease treatment. The development of intravenous (IVIG) formulations at 5%, then 10% concentration allowed for larger quantities of immune globulin to be infused, expanding the scope of diseases which could be successfully be treated with the product. More recently, subcutaneous (SCIG) preparations have gained market acceptance. First, for low dose applications, and recently to additional diseases with higher dosage such as CIDP. A subcutaneous version C1-INH was approved in 2017, after decades of an intravenous version on the market. Smaller reconstitution vial sizes have made it possible to administer coagulation factors to small infants, avoiding the need for ports, and efforts are made to find ways to administer these products through different routes, such as subcutaneously. New formulations are in development for other plasma-derived products, such as inhaled A1PI, which may increase their usefulness and/or decrease dosing and thus costs.
Competition from new Technologies
In the past four years a number of new recombinant and non-factor products have been introduced in the area of hemophilia therapy, representing increased competition to plasma-derived coagulation factors.
In the early 1990’s, the first recombinant factor VIII was introduced. Since then, many recombinant proteins have been developed, including recombinant factor VIIa, factor IX, factor XIII, von Willebrand factor, albumin, antithrombin-III, C1 esterase inhibitor (C1-INH) and thrombin. Additional recombinant proteins are under development including recombinant fibrinogen, alpha-1 antitrypsin, and others.
In 2014, the first extended half-life recombinant factor VIII and IX products were approved in the U.S. With an improved bio-availability over their plasma-derived competitors, these products provided higher trough levels in hemophilia patients, allowing them to infuse the product less frequently, which enhanced the patients comfort, reducing their dependency on frequent factor infusions. The availability of these new recombinant products increased the number of products available for hemophilia A and B treatment, leading to price erosion of the less advanced products, including the plasma-derived, particularly outside the United States.
In late 2017, Roche’s Hemlibra, a bi-specific monoclonal antibody, was approved by the FDA and the EMA (February 2018) for the treatment of hemophilia A patients with inhibitors antibodies to Factor VIII. In October 2018, Hemlibra was approved in the U.S. for the treatment of all hemophilia A patients. As it only requires one subcutaneous drug infusion weekly bi-weekly, or monthly, depending on the patients severity. Since then, it has gained rapid acceptance, affecting the entire factor VIII sales levels in the U.S. In addition, gene therapy for hemophilia A and B is likely to be commercially available in the early 2020s, representing a “cure” for the disease after just one infusion. The average durability of gene therapy treatment is still unknown, but indications are that it will last at least a few years and possibly more than a decade. Gene therapy will eventually cause a disruption in the marketplace for hemophilia treatment, though its uptake will be initially be slow and be restricted to adults severe patients at first.
As coagulation factors made from plasma have now been relegated to a secondary position in the hemophilia care market, immunoglobulin has become ever more important to sustain the economic viability of the plasma industry, along with albumin. To this day, the market preeminence of intravenous and subcutaneous immune globulin (IgG) in treating a number of autoimmune diseases was unsurpassed. However, several biotechnology companies (Argenx, UCB, Momenta, etc.) have recently developed new monoclonal antibodies (anti-FcRn agents) or recombinant products (recombinant trivalent IgG1 Fc multimers) that mimic the immune modulatory mode of action of IgG in the treatment of some diseases, such as ITP, Pemphigus Vulgaris, MMN, CIDP and Myasthenia Gravis. These products will be entering the market soon, and could begin to impact the IgG market in the next few years if they prove to be safe, efficacious, and price competitive. The ultimate effect of these novel agents on IgG is fiercely debated and is the subject of several recent reports by the Marketing Research Bureau.
Recombinant albumin was only commercialized in Japan, and failed to gain significant market share because its prohibitive price and absence of clinical superiority compared to plasma-derived albumin. As a result, it was eventually withdrawn from the market and has not been re-introduced since. However, more recent efforts at recombinant albumin, including by using recombinant technology to produce human albumin in rice plants may result in new competition with plasma derived albumin. Non-plasma-based, non-biotech plasma volume replacement solutions, such as starches have been on the market for a number of decades at much lower prices than human albumin. While they represent inexpensive alternatives for budget-constrained customers, their efficacy and particularly their safety do not match human albumin in many clinical indications.
Monoclonal antibodies (mAB) to prevent Hereditary Angioedema (HAE) now compete strongly with plasma derived C1-INH products in this disease. Novel mAB and small molecules are in development for the treatment of Alpha-1 Antitrypsin Deficiency. As the pharmaceutical industry continues to innovate and evolve, the prospects and positioning of plasma derived products will change with it, and it is important to know the latest information to make informed decisions.
For more information…
Since 1974, the Marketing Research Bureau has been supplying market data and intelligence to the plasma industry. Its syndicated reports cover over 80 countries and provide quantitative and qualitative data. Other studies forecast the demand for the main plasma proteins in the future given the competitive threats and cover other topics. For more information, please contact us or give us a call.