Immunoglobulin (IG) drives the blood-plasma therapeutics market

Human blood—which consists primarily of red blood cells (roughly 45% by volume) and plasma (roughly 55% by volume)—has unparalleled healing properties. With the help of plasma-fractionation techniques and several innovative processes, human blood is used to produce plasma-derived therapies that are being used to treat an expanding list of debilitating, chronic and life-threatening disorders.

• Immunoglobulin (IG) is used to help patients suffering from primary and secondary immunodeficiency disorders and to combat viral and bacterial infections. Today, intravenous IG (IVIG) is also being considered for a range of neurological diseases including multiple sclerosis, neuropathic pain, chronic fatigue syndrome and post-polio syndrome. Last fall, the Sutter Institute of Medical Research (Sacramento, CA) published a study indicating value in IVIG for Alzheimer’s; if that study is confirmed, a huge new therapeutic market could open up.
• Albumin is used to treat patients who have experienced trauma (such as surgery), to address some liver conditions and cardiopulmonary disease; albumin is also being studied to treat stroke, cirrhosis, Alzheimer’s disease, malaria and sepsis.
• Coagulation factor concentrates (specifically known as clotting factors, such as factor VIIa, factor VIII, factor IX and others) save lives by stopping or preventing internal and external bleeding in patients with rare coagulation-related disorders such as hemophilia A, hemophilia B, von Willebrand disease and others.

Today, the global plasma industry has annual sales of more than $14 billion, according to Patrick Robert, president of The Marketing Research Bureau, Inc. (MRB). Worldwide demand for the primary plasma-derived therapies is on a steady growth path, with projections of 10+% annual growth according to several market-research firms. In past years, demand for albumin was the driver; this was succeeded by factor VIII, but recombinant-DNA production techniques have met most of that demand. Now, IG is the driver.

“Currently, nine products have FDA approval for approximately six indications; however, the medical community has identified more than 200 indications that benefit from IVIG, so it’s obvious that off-label use is increasing,” says Neil Herson, president of ASD Healthcare, an AmerisourceBergen company.

Several trends continue to shape the landscape in blood/plasma-derived therapies, creating new distribution and reimbursement challenges and opportunities for all stakeholders: (1) The shift away from IVIG to subcutaneous infusion of immunoglobulin (SCIG); and (2) the commercialization of recombinant coagulation factors for the treatment of hemophilia. Similarly, volatility in the supply of human blood and plasma, bottlenecks in the manufacturing industry, supply disruptions in both source materials and finished products, and growing worldwide demand are a constant backdrop in this specialty pharmaceutical sector.

“With the plasma market, we’ve traditionally seen some type of supply disruption every three to five years,” says Travis Poe, VP and GM of specialty distributor, McKesson Plasma and Biologics. “Due to the small number of manufacturers and the long lead time between plasma collection and getting product on the market, any manufacturing issue or recall hits the marketplace hard.” He adds, “Demand can shift quickly to other manufacturers, however they may not be able to necessarily ramp up production.” This is exacerbated by the fact that for some therapies, the duration between collection of plasma and shipment of plasma-derived products can take up to 12 months.

“In previous decades, blood-borne diseases and manufacturing challenges created supply disruptions. Today, the market has largely stabilized. Patients typically receive their lifesaving therapeutics when and where they need it,” adds Herson of ASD Healthcare. A major factor for this stability in the US is paid donors at plasmapheresis centers in the US (“source” plasma); in Europe, plasma supply is evenly split between donated source plasma and “recovered” plasma from blood donations. US source plasma supply nearly doubled between 2004 and 2012 while recovered plasma was relatively flat, according to MRB.

Nonetheless, some in the industry are waiting for the proverbial shoe to drop. “Despite the fact that the industry has been relatively stable for the past six or seven years, many feel we are due for some type of supply disruption because it’s been so long,” says Poe of McKesson.

‘Vein-to-vein’ therapies

“Today, the annual cost of therapy using a plasma-derived therapeutic protein product can easily exceed $200,000,” says Robert of MRB, due to several factors that are emblematic of this sector:

• The cost to process plasma is high—much higher, comparatively speaking, than the cost of raw materials and compounds used to produce traditional pharma products. Significant costs arise from both the collection of plasma and the manufacturing processes involved, both of which are highly regulated at every step to safeguard the purity of plasma-derived products against transfusion-transmittable pathogens
• Plasma-derived therapies are mainly used to treat rare (orphan) disorders, with patient populations that typically number from the hundreds to the hundreds of thousands—but not into the millions. This means that the therapies must be priced accordingly to help manufacturers recoup costs; and, opportunities for economies of scale are often not available.

Today, the lion’s share of plasma fractionation in the US is carried out by three companies: CSL Behring, Grifols and Baxalta (which was recently spun off from Baxter and has agreed to be purchased by Shire), and to a lesser extent by Kedrion, Biotest and Octapharma Plasma, which, collectively, operate close to 500 plasma-collection centers across the US. According to the latest data published by MRB, in 2013, the collective production of the largest plasma fractionators was nearly 42 million liters. By 2020, production is expected to reach nearly 47 million liters (with nameplate capacity of around 55 million liters). Demand for plasma is expected to grow from 2013 levels of around 36 million liters, to 50 million liters by 2020.

Managing volatility

“Because of the inherent volatility in this market, products must be allocated, as needed, to help hospital and other treatment sites manage inventory fluctuations,” notes Poe of McKesson. “Many hospitals—which typically don’t have a regularly scheduled base of hemophilia patients—still need to keep 40–60 days of plasma inventory on hand at all times (in all assay sizes). But the cost to maintain an inventory of hemophilia therapies is very high, so keeping that much inventory on hand poses risks, in terms of potential wasted costs and expiration issues related to the limited shelf life of the product.” He continues, “Nonetheless, they must have these lifesaving products on hand, to support surgeries and patients with hemophilia who may show up at any time.”

Because of the small size of the overall plasma-production infrastructure, and the volatile nature of demand, specialty distributors play a big part in ensuring access to not just individual patients, but to hospitals, outpatient clinics and physicians’ offices. “Appropriate allocation of products among facilities is essential, yet remains challenging due to the various discrete entities that regulate plasma around the world,” says Herson of ASD Healthcare.

“Advocacy groups have noted that only about a third of pharmacy and therapeutics committees had developed locally defined protocols for prioritizing IVIG indications, which essentially means more than 100 different protocols exist across the nation,” says Herson. To rectify this, ASD Healthcare has sponsored an advisory board comprised of globally recognized specialists across multiple medical disciplines. The advisory board has created a set of guidelines that aim to build consensus—across the country and at any facility or provider level—for IVIG prioritization, especially in event of supply disruption.

McKesson, through its consignment program, is able to help healthcare facilities reduce risk by providing a certain amount of hemophilia therapies to the hospital. “They don’t pay for it until they actually use it. We partner with each facility to manage their consignment inventory, and we swap out these products on a regular basis, typically staying six to nine months ahead of the expiration dates.”

Repro Med Systems’ infusion pump for subcutaneous immunoglobulin.

The rise of recombinant factors

“To obtain enough raw materials for the commercial-scale production of plasma products, millions of liters of plasma must be collected annually from donors,” adds Robert of MRB. By way of example, one liter of plasma is required to produce just 4.5 grams of IVIG and 150–180 international units of coagulation factor VIII.

“One patient with hemophilia may require up to 1,200 plasma donations to produce one year’s supply of factor products—and that’s just one patient’s need,” adds Herson of ASD Healthcare. “When you consider the global need, it creates a completely new perspective on demand.”

Since the first recombinant forms of therapeutic human plasma proteins were introduced in the early 1990s, a growing number of recombinant plasma protein therapies have come to market. These include recombinant factor VIIa, albumin, antithrombin-III, C1 esterase inhibitor (C1-1NH) and thrombin. Additional recombinant proteins are being pursued, including recombinant von Willebrand factor, factor Xa, factor XIII, fibrinogen, alpha-1 antitrypsin, plasmin and others. In addition to eliminating the need for donated human plasma, “recombinant factor concentrates have never been known to transmit pathogens of any kind,” according to the Hemophilia Federation of America (see sidebar article at the bottom of this page).

“We are already seeing this trend drive down demand for human-plasma-derived coagulation factors in the US,” says MRB’s Robert, adding that he expects to see traditional plasma-derived coagulation factors continue to dominate the scene in developing nations, because they are cheaper than their recombinant alternatives.

Supporting the patient journey

“From the time of diagnosis, a patient requiring plasma-based therapies will be on a life-long infusible or injectable therapy that requires a number of support mechanisms for both patients and caregivers, to give them the best chance of a normal life,” says Rich Gaton, cofounder and president of specialty distributor BDI Pharma, Inc. (Columbia, SC).

In particular, there are many psychological challenges associated with having to infuse on a daily, weekly or monthly basis, and this can be especially daunting for pediatric patients and their parents. “These families require psycho/social support as well as financial assistance in order to access and continue therapy throughout the patient’s lifetime,” says Gaton.

As with so many other specialty drugs for chronic conditions, “having a fully integrated hub is essential to assist patients with benefits investigation, payer support, copay support, patient assistance (especially for indigent patients) and advocacy support,” notes Biju Chorinchath, senior director, immunology marketing for pharmaceutical manufacturer CSL Behring.

“Patients who fill the prescription with US Bioservices receive clinical assessments from the pharmacist and nurses, to ensure appropriate usage and adherence to the prescribed regimen,” adds says Joy Gilbert, VP of operations for US Bioservices, a part of AmerisourceBergen. “We’ve also found that our US Bioservices nurses who infuse IG patients in their homes or offer telephonic support help patients adapt quickly and stay adherent.”

Distribution is another important aspect of the commercialization success of any plasma-based product. “Traditional pick-pack-and-ship models are not effective due to just-in-time inventory demand and the level of detail and communication that is required for the dosing needs of the patient—especially when dealing with hemophilic factors,” says Gaton of BDI Pharma.

Site of care

For many plasma-derived therapies, patients must receive infusions on a regular basis, monthly or even weekly, throughout their entire lives, so the site of care is a critical component when it comes to managing cost, access and adherence. When it’s a clinically appropriate option, the ability to receive infusions of IG or other plasma-derived therapies at home—using either traditional IVIG products with the help of an IV infusion nurse, or via self-administration using today’s newer subcutaneous IG products has obvious advantages.

Today, in the US, roughly 50% all IVIG is administered in hospitals, about 30% administered in doctors’ offices, and the remaining 20% is distributed by home care companies and administered at home. “Receiving infusions at home helps to reduce costs compared to hospital administration, and is often more convenient for the patient,” adds Chorinchath of CSL Behring.

Reimbursement will be different for home care than other settings, and whether the medication is covered under a medical or pharmacy benefit can also impact the patient’s options, says Gilbert of US Bioservices.

Under the medical benefit, the cost of the medication is bundled with the total care including nurses, the diagnostics, hospital costs and more. Coverage under the medical benefit includes the cost of the medication, nursing services, diagnostics and hospital costs. “This structure allows the health plan to better manage the total cost of care.” By contrast, “When the therapy is covered under the patient’s pharmacy benefit, PBMs are able to manage the drug costs at the NDC [drug cost] level, but this approach may limit the payer’s ability to integrate the utilization data to see the overall cost of these episodes of care and tie it to the overall cost management of the disease.”

As a result, Gilbert says, “Many commercial payers will drive patients to payer-owned providers, such as infusion clinics or specialty pharmacies, or will impose restrictions related to who might qualify for home care.” Additionally, she notes that Medicare has different requirements related to home care, which may limit Medicare patients from being served in the home setting.

US Bioservices is working with several health plans to manage patient site of care and optimize patient experience, adherence, and reduce costs. “We believe these actions will impact how coverage for home infusion of IVIG can be more effectively managed and potentially expanded,” says Gilbert. “We hope that expanded coverage for home infusion will become a reality for patients in the near future.”

Meanwhile, when IVIG is administered monthly (whether in a clinical setting or at home), it typically takes several hours to infuse the therapy. “Putting a tremendous volume of IG into the patient at a single time raises the IG serum levels very high, and then over the course of the month, the levels fall off and break through the infection threshold,” explains Andrew Sealfon, CEO of Repro Med Systems (Chester, NY), one of several manufacturers of infusion pumps for SCIG (see photo). “As a result, patients on IVIG often experience a predictable roller coaster of feeling good when IG levels are near a peak shortly after a monthly infusion, but then feeling tired and less energetic, and getting sick, as the serum levels fall through the breakthrough infection threshold.”

These peaks and valleys in IG serum concentration are to blame for a variety of adverse effects, ranging from serious conditions such as aseptic meningitis, thrombosis, and hemolysis, to less serious (but no less burdensome) side effects, such as muscle aches or exhaustion. These side effects often contribute to poor adherence levels, especially for patients who rely on the therapy for prophylaxis (rather than for acute treatment).

Using the right infusion needles is also essential to optimize the SCIG experience for the patient. “In the early days of SCIG, healthcare providers routinely reached for standard insulin needles,” says Sealfon, “but they are not ideal for pumping IG, which involves a larger volume of a thick, viscous drug.” The pumps from Repro Med Systems include specially designed longer needles that have low fluid resistance. “During the early years of development efforts related to SCIG, whenever problems arose in the clinical trials, researchers immediately assumed the drug was to blame, but it turns out the need to optimize the pump and needles and peripherals was critical in the success of SCIG use,” he adds.

Enter subcutaneous IG

Today, as an alternative to IV infusion, some patients are able to self-administer their IG at home, typically on a weekly basis, using subcutaneous infusion IG (SCIG). Today, there are at least five approved SCIG products on the market (from CSL Behring, Baxalta, Grifols and Kedrion Biopharma), and several others in development. “Studies are underway that could allow factor products to be infused subcutaneously, as well,” says Gaton of BDI Pharma.

Unlike the monthly administration schedule of IVIG, SCIG is typically administered in smaller doses throughout the month. “SCIG has been very good at eliminating the highs and lows in terms of IG levels and systemic side effects associated with IV administration, and has definitely eliminated the breakthrough level,” says Sealfon. As such, the availability of the SCIG option is considered to be a game changer for many patients. For instance, CSL Behring’s SCIG product Hizentra “enables patients to maintain steady-state IG levels with lower peaks and higher trough serum levels than monthly IVIG,” says Chorinchath.

In addition to these clinical benefits, SCIG allows patients to administer their therapy independently at home (using a programmable infusion pump, after some initial training) thereby eliminating the need for home infusion nursing support and the need for transportation to a hospital or office for treatment. Home infusion also helps to reduce the risk of nosocomial (hospital-acquired) infections for these immune-compromised patients, and benefits patients in rural areas.

Self-administration of SCIG also provides some safety and psychological advantages. “Visiting the hospital each month when their IG levels are at their lowest may predispose these individuals to infection and illnesses, and they are often sharing treatment rooms with seriously ill patients, which can be emotionally challenging,” says Amar Pabla, VP, nursing, clinics and pharmacovigilance for Innomar Strategies, a part of AmerisourceBergen. “We are often told by our patients that they feel that they have been given their life back with SC administration.”

Despite these benefits, at-home self-administration is not for everyone. “In addition to clinical considerations, some patients prefer the IV route because they value their nursing support team and often benefit from the social aspect of seeing friends they’ve made at each infusion,” says Gaton of BDI Pharma. “Patients who are anxious, aren’t willing or able to learn the proper self-infusion technique, or enjoy interacting with medical are not strong candidates for SCIG,” adds Gilbert of US Bioservices.

Self-administration has another potential downside. “To evaluate adherence and outcomes, the prescriber may have to depend on lab values to validate whether a patient is being compliant to therapy, since SC administration eliminates the need for regular nursing supervision and support,” says Gaton of BDI Pharma. “And payers ultimately want to see patients remain adherent to their therapy to lower the overall cost of care. While SC administration can reduce nursing costs, IV administration requires more observation, which can translate to a higher level of adherence, improved outcomes and reduce costs over the long term. From a payer perspective, we have yet to see a push toward SC over IV.”

Reimbursement issues

When it comes to infused plasma-based therapies, the medication will either be covered under either the patient’s medical benefit or pharmacy benefit. “Specific pharmacy benefit managers (PBMs) often require the use of a particular infusion provider (carve-out). However, many times, this designated provider does not have a nursing team with infusion expertise, and may not service certain rural areas (thereby essentially ruling out home infusion of IVIG). “This poses access-related problems because the patient’s health condition may not allow for travel to a physician’s office,” says Gaton of BDI Pharma.

“When a patient’s insurance only covers treatment under the medical benefit, this requires providers to have the expertise to access payer policies specific to the particular treatment/drug, and to understand the proper authorizations and medical documentation required to determine whether the patient meets the outlined clinical criteria for the claim to be accepted as medical necessity,” says Gaton of BDI Pharma.

BDI operates a subsidiary patient-support service, Radius Specialty Solutions, which provides reimbursement guidance and ongoing patient support for specialty pharmaceuticals, including its range of IG products. Radius recently reviewed the reimbursement inequality between specialty drug reimbursement under the patient’s medical benefit versus pharmacy benefit for immunoglobulin and hemophilia factors for the top 10 diagnoses (figure). The data suggest that a patient’s out-of-pocket costs were much lower when the therapy was covered under the pharmacy benefit (which tends to rely on fixed-dollar copays), as opposed to coverage under the medical benefit (where coinsurance requirements tend to result in higher out-of-pocket expenses). In some cases, “A patient’s ability to pay directly impacts their adherence to therapy,” says Gaton.

Safeguarding the blood and plasma supply

To safeguard blood and plasma supplies against infectious agents and pathogens that could be transmitted to recipients, today’s blood-donation infrastructure and specialty pharmaceutical manufacturers employ a variety of tactics and technologies. Screening methods are in place for blood and plasma donors (including the routine use of Hep-C antibody testing and HIV antibody testing in blood- and plasma-collection facilities), and registries of ineligible donors are maintained. Drug manufacturers routinely use a variety of processes to kill viruses, such as dry heat, solvent-detergent treatment and pasteurization to kill pathogens, according to the American Society of Hematology, and then nanofiltration to clear inactivated viruses from the plasma or final manufactured product.

In late 2014, Cerus Corp. (Concord, CA) gained FDA approval for its Intercept Blood System; outside the US, more than 100 centers in 20 countries already employ it. Last month, it struck a multiyear agreement with American Red Cross to use this system for blood platelets and plasma; American Red Cross collects 40% of all blood donations in the US.

The Intercept Blood System uses a proprietary photochemical process involving ultraviolet light and a proprietary chemical, amotosalen, which interferes with nucleic acid synthesis in infectious pathogens and residual white blood cells found in blood components; the treated plasma is then purified to remove the chemical additive and its byproducts.

Global blood supply is under stress from a variety of endemic or epidemic viruses, such as Ebola, dengue fever and now Zika virus. Blood banks are required to continually prevent contamination of blood supplies. The key attribute of the Intercept system, according to the Cerus, is that it provides proactive inactivation of susceptible pathogens—whether or not there are current screening tests available at the time of blood collection.