Immune Globulin Therapy: The Investigational Frontier

Despite immune globulin (IG) being approved by the U.S. Food and Drug Administration (FDA) to treat only five diseases, the number of diseases treated off label by IG (those not FDA-approved) continues to grow. According to the Medscape Reference website, that number exceeds 60 disease states. A few of these off-label treatments have become accepted use, while many others are under investigation and are relatively new to the IG treatment frontier.

For all off-label uses, IG is currently considered a second line of treatment after first-line treatments have proved ineffective. Because this is often the case, IG is a lifesaving therapy that offers hope for so many. However, the beneficial effects of IG for many conditions are under debate in the medical community, and growing demand for IG poses challenges regarding both reimbursement and supply.

On-Label and Accepted Off-Label Uses

Currently,IG is FDA-approved to treat primary immunodeficiency, chronic lymphocytic leukemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome and chronic inflammatory demyelinating polyneuropathy.

Beyond these approved therapies,IG has become an accepted treatment for some other diseases in which preliminary studies and medical literature have shown the drug’s effectiveness as a second-line treatment. According to the FDA (as noted in a 1982 policy guidance): “Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such ‘unapproved’ or, more precisely, ‘unlabeled’ uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.”

Of course,some of these diseases have more extensive medical literature to back the use of IG as an accepted treatment. These include, but are not limited to, Guillain-Barré syndrome, multifocal motor neuropathy and inflammatory myopathies. And, because IG is considered an accepted treatment for these diseases, it is often easier for a patient to be approved for reimbursement, although that is certainly not always the case.

Guillain Barré syndrome (GBS). GBS is an acute inflammatory demyelinating polyneuropathy characterized by progressive symmetric ascending muscle weakness, paralysis and hyporeflexia with or without sensory or autonomic symptoms; however, variants involving the cranial nerves or pure motor involvement are not uncommon. Both plasma exchange (PE) and intravenous IG (IVIG) have proved effective for GBS because they may decrease autoantibody production and increase solubilization and removal of immune complexes, and both have been shown to shorten recovery time by as much as 50 percent.

Randomized trials in severe disease show that IVIG started within four weeks from onset hastens recovery as much as PE. However, combining PE and IVIG neither improved outcomes nor shortened illness duration. IVIG also has been found safe and effective in the treatment of pediatric GBS, and it is the preferential treatment in hemodynamically unstable patients and in those unable to ambulate independently.¹

Multifocal motor neuropathy (MMN). MMN is a rare autoimmune disorder characterized by progressive weakness in the limbs, leading to significant difficulty with simple manual tasks. If left untreated, MMN often progresses to more severe weakness, including muscle atrophy or involuntary twitching.

It is caused by malfunctions in the conduction pathway of motor nerves, limiting transmission of electrical impulses. Of the one in 100,000 people it affects, 80 percent are between 20 and 65 years of age at the onset of disease, with men more frequently affected than women.

In June 2011, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) gave Baxter International marketing authorization for KIOVIG, the first centrally licensed indication for an immunoglobulin preparation for MMN. The authorization was based on two studies, both of which showed maintenance of muscle strength and improved functionality. Adverse events were reversible and consistent with those seen in other KIOVIG indications, with no serious adverse events. In 2008, Baxter initiated a Phase III clinical trial in the U.S. and Canada for Gammagard Liquid (marketed as KIOVIG outside the U.S.) for the treatment of MMN, and is currently seeking FDA approval.²

Inflammatory myopathies. Inflammatory myopathies include polymyositis(PM), dermatomyositis(DM) and inclusion body myositis (IBM). Patients with PM and DM typically experience weakness in muscles involved in lifting the arms above the head, getting up from a chair or walking up stairs. In DM, there is skin involvement characterized by a rash either on the eyelids, hands or trunk of the body. Because DM can sometimes be associated with malignancies, screening is conducted for this as well. IBM can affect some of the same muscles as PM and DM, but also often affects the hand muscles and the quadriceps muscles. IBM usually affects people who are over 50 who do not respond well to medication.³

IVIG’s immunomodulatory effect can be used to treat DM and PM where other treatments have not proved effective.In a double-blind placebo-controlled crossover trial in patients with DM resistant to other treatments, IVIG produced a significant increase of muscle strength, as well as a marked improvement in immunopathological parameters in repeated muscle biopsies (before and after IVIG). No randomized trials have been undertaken with IVIG for PM. For IBM, three controlled trials showed some muscle strength improvement, although the changes did not reach statistical significance. However, improvement in swallowing was repeatedly observed, suggesting that some patients with severe dysphagia may derive a modest benefit from IVIG therapy.⁴

Other Diseases Treated with IG

According to the Advocacy for Patients with Chronic Illness website: “Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by wellplanned and executed clinical investigations.” But, even when this occurs, that doesn’t mean the drug will ever be FDAapproved to treat a disease. Therefore, accepted medical practice often includes drug use that is not reflected in approved drug labeling.

Right now, many different diseases are being treated with IG other than those that are FDA-approved or accepted usage. These fall under such medical categories as hematology, infectious diseases, neurology, obstetrics, pulmonology and rheumatology, as well as a host of other miscellaneous conditions. Some of the specific diseases being treated with IG include pure red cell aplasia, hemolytic disease of the newborn, epilepsy, multiple sclerosis, Sjögren’s syndrome, recurrent pregnancy loss, asthma, systemic lupus erythematosus, narcolepsy and Alzheimer’s.

Pure red cell aplasia (PRCA). PRCA is a condition in which red blood cell precursors in bone marrow are nearly absent, while megakaryocytes and white blood cell precursors are usually present at normal levels. PRCA exists in several forms, the most common of which is an acute self-limited condition. It is often chronic and is associated with underlying disorders such as thymomas (tumors originating in the thymus) and autoimmune diseases. There is sufficient evidence that IVIG, which regulates immune function, is effective. In fact, a recent guideline recommends IVIG for red cell aplasia. Most studies show a response to high-dose IVIG, followed by low doses initially to monitor for anaphylaxis and other complications (doses mentioned in the package insert are followed later).⁵

In 2007, specific recommendations were made for routine use of IVIG for seven conditions: acquired red cell aplasia, acquired hypogammaglobulinemia (secondary to malignancy), fetal-neonatal alloimmune thrombocytopenia, hemolytic disease of the newborn, HIV-associated thrombocytopenia, idiopathic thrombocytopenic purpura (an FDA-approved indication) and post-transfusion purpura — all of which are hematologic conditions.⁶

Epilepsy. Epilepsy is characterized by recurrent, unprovoked, spontaneous seizure activities and affects 0.5 percent to 1.5 percent of the world’s population. Over the years, it has been suggested that inflammation plays a role in epilepsy, evoked by pro-inflammatory modulators that are meant to protect from and heal injuries to the body. Because inflammation is known to cause several neurological disorders such as Parkinson’s disease, meningitis and encephalitis, it has recently been acknowledged and is the subject of discussion, abstracts and publications at professional epilepsy meetings worldwide.

Since 1977, IVIG has been implicated for treatment of epilepsy, although it has been reported that IVIG responds differently in different forms of epilepsy. Improvement has been seen in children with severe epilepsy being treated for respiratory infections with IVIG, and there are good response rates in patients with West syndrome and Lennox-Gastaut syndrome. How IVIG decreases seizure frequency and severity is not yet fully understood. And, there have not been many large or double-blind, placebo-controlled studies regarding the efficacy of IVIG to treat epilepsy.⁷

Relapsing-remitting multiple sclerosis (RRMS). One of four internationally recognized forms of MS, RRMS is characterized by relapses (also known as exacerbations) during which time new symptoms can appear and old ones resurface or worsen. The relapses, which can last for days, weeks or months, are followed by periods of remission,when the person fully or partially recovers from the deficits acquired during the relapse. During relapses, myelin, a protective insulating sheath around the nerve fibers (neurons) in the white matter regions of the central nervous system (CNS), is damaged in an inflammatory response by the body’s own immune system. This causes a wide variety of neurological symptoms that vary considerably depending on which areas of the CNS are damaged.⁸

Treatment of RRMS with IVIG has had mixed results. The American Academy of Neurology Report of the Therapeutics and Technology Assessment Subcommittee from 2001 refers to three studies conducted in the 1990s. According to the report, the first study showed treatment with IVIG reduced the clinical attack rate, the second reduced the total number of enhancing lesions and new lesions when treated with IVIG, and the third showed significant reductions in clinical attack rate. However, the report also states that those studies “have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned.”⁹

Yet, a recently published paper summarizing four doubleblind IVIG studies of RRMS cites two more recent studies with positive results. In one study, published in the October 2004 issue of Neurology, 91 patients were studied after their first neurological event suggestive of demyelinative disease. That study showed that IVIG treatment for the first year of these patients significantly lowered the incidence of a second attack and reduced disease activity as measured by brain MRI. Another study published in June 2006 in Review of Neurology found that IVIG is “thought to exert a twofold effect: an immunomodulating action and a positive action on remyelization.”⁹

Sjögren’s syndrome. Sjögren’s syndrome is a chronic autoimmune disease in which people’s white blood cells attack their moisture-producing glands. It is one of the most prevalent autoimmune diseases, affecting as many as four million Americans, nine out of 10 of whom are women. Symptoms are dry eyes, dry mouth, extreme fatigue and joint pain. And, Sjögren’s also may cause dysfunction of other organs such as the kidneys, gastrointestinal system, blood vessels, lungs, liver, pancreas and the central nervous system.¹⁰

A 2011 study evaluated 19 patients with Sjögren’s syndromerelated presumed non-necrotizing vasculitic neuropathy who had been treated with one or more doses of IVIG. The patients’ mean age was 60 years old and 58 percent were women. They had a variety of neuropathies classified as sensorimotor, ataxic, nonataxic sensory polyneuropathy and conduction block neuropathy. IVIG was administered in monthly infusions of 2 g/kg over either two or five days, and the median duration of IVIG treatment was seven months with follow-up ranging from three to 84 months. A variety of other immunosuppressive agents were used either prior to or along with the IVIG.

Results were measured using the patient-completed Modified Rankin Score (MRS). In eight patients, the MRS improved; in 10 patients, the MRS was stable; and in one patient, the MRS worsened. All patients with sensorimotor, nonataxic sensory neuropathy and conduction block improved; however, of the nine patients with ataxic neuropathy, only two improved, four worsened and three remained stable. Ten of 13 patients treated with steroids were able to lower their doses, presumably as a result of the effects of IVIG. The researchers concluded that IVIG may be useful in the treatment of some neuropathic manifestations of Sjögren’s syndrome, but because of the small sample, conclusions are limited.¹¹

Recurrent pregnancy loss. Recurrent pregnancy loss, also known as recurrent spontaneous abortion (RSA), is a disease distinct from infertility, defined by two or more failed pregnancies. Any of these pregnancy losses, though unexplained, have an immunologic basis.

A number of studies have looked at the effects of IVIG to prevent RSA, with many of the most recent studies having positive results. In one clinical trial of 47 women with a history of RSA, IVIG was given at a dose of 0.2 g/kg within two weeks of attempted conception. Once conception was achieved, IVIG was given once every four weeks at the same dose through 26 to 30 weeks of gestation. Thirty-six women received IVIG and 11 women refused IVIG. Of the 36 women who received IVIG, 24 became pregnant and 20 of those received IVIG through 26 to 30 weeks of gestation. Nineteen of these patients had a term pregnancy and one miscarried at eight weeks. Four women stopped IVIG therapy at 10 to 12 weeks gestation, and three of these women had term pregnancies.The fourth miscarried at 15 weeks gestation. Seven of the 11 women who refused IVIG became pregnant and all had first trimester miscarriages. The conclusion: The difference in successful pregnancies was significantly higher in the women treated with IVIG. Other studies have not found statistically significant differences between groups of women who were treated with IVIG versus a placebo.¹²

Steroid-dependent asthma. Individuals with difficult-tocontrol asthma typically have daily or nearly daily asthmatic symptoms, functional limitations due to asthma that interrupt work, school or recreational schedules, and a requirement for daily or every-other-day corticosteroids. While the mechanism of action is unknown, IVIG is one of the newer types of experimental treatments for severe steroid-dependent asthma. And, because permanent side effects are rare, some specialists view IVIG as a reasonable alternative to continuing treatment with high-dose, daily oral corticosteroids with their associated risks of significant side effects.¹³

In one study, seven patients with severe steroid-dependent asthma were given IVIG at a dose of 1 g/kg each month for six months. Baseline pulmonary function tests and immunoglobulin levels were obtained, and at the end of six months, lung function and the degree of reduction in the dose of oral steroids were observed. The number of hospital admissions during the 12 months following commencement of IVIG also was compared with the preceding 12 months. Results showed a significant reduction in daily prednisolone dose and a decrease in the number of hospital admissions. No significant improvement occurred in lung function. From this, the researchers concluded that IVIG provides a potentially important adjunctive therapy in severe steroid-dependent asthma, reducing steroid requirement and decreasing hospital admissions, but not improving lung function.¹⁴

Systemic lupus erythematosus (SLE). SLE is a multisystemic autoimmune disease with clinical manifestations ranging from mild to life-threatening, and the course of the disease is unpredictable, with periods of illness (called flares) alternating with remissions. SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system. The disease occurs nine times more often in women than in men, especially in women in child-bearing years ages 15 to 35, and is also more common in those of non-European descent. Most deaths due to SLE are caused by kidney failure.

Several studies have demonstrated a significant effect of IVIG on overall disease activity. While the first study on the beneficial effect of IVIG advocated it for acute exacerbation only, several later studies showed significant improvement in chronic refractory SLE. The general efficacy in several small case series involving three to 12 patients ranged between 33 percent and 100 percent. In the largest study reported recently, which included 20 SLE patients with an 85 percent response rate, the authors advocate using IVIG as a useful steroid-sparing agent in SLE patients requiring high doses of steroids. However, that study’s authors recommended confirming the recommendation in a double-blind placebo-controlled study. Unfortunately, because of the small number of patients and the conflicting results presented in the literature, it is not possible to ascertain which signs or symptoms will usually respond to IVIG.¹⁵

Narcolepsy with cataplexy (NC). NC affects 0.02 percent of adults worldwide. It is a disabling sleep disorder characterized by severe, irresistible daytime sleepiness and sudden loss of muscle tone (cataplexy), and can be associated with sleeponset or sleep-offset paralysis and hallucinations, frequent movement and awakening during sleep, and weight gain. The onset of NC is usually during teenage and young adulthood and persists throughout the lifetime. Pathophysiological studies have shown that the disease is caused by the early loss of neurons in the hypothalamus that produce hypocretin, a wakefulness-associated neurotransmitter present in cerebrospinal fluid. The cause of neural loss could be autoimmune since most patients have the HLA DQB1*0602 allele that predisposes individuals to the disorder.¹⁶

In one study that tested IVIG treatment in early onset NC, two NC children received 1 g/kg/day of IVIG two days per month, five times, at three and six months disease duration, respectively. Cataplexy improved in both children, but only temporarily in one patient. Subjective sleepiness temporarily improved, sleep paralysis emerged and hypnagogic hallucinations and REM sleep behavior disorder worsened in one child. The researchers concluded that IVIG treatment initiated before nine months disease duration has some clinical efficacy. However, they recommended that the final IVIG effect be investigated in a placebo-controlled study.¹⁷

In another study, IVIG treatment was tested in four children with NC with an early diagnosis and extreme disease severity. One of four patients showed an objective and persistent improvement in clinical features during and after IVIG treatment. The researchers concluded that their data partially support the recent report of the efficacy of IVIG treatment in early diagnosed NC and support the need for a controlled multicenter clinical trial on IVIG in narcolepsy.¹⁸

Alzheimer’s. Alzheimer’s is a type of dementia that causes problems with memory, thinking and behavior. It is caused by a buildup of proteins in the brain. The buildup manifests in two ways: plaques (deposits of the protein beta-amyloid that accumulate in the spaces between nerve cells) and tangles (deposits of the protein tau that accumulate inside nerve cells). Alzheimer’s symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks. In its early stages, memory loss is mild, but with late-stage Alzheimer’s, individuals lose the ability to carry on a conversation and respond to their environment. Alzheimer’s is the sixthleading cause of death in the U.S. Those with the disease live an average of eight years after their symptoms become noticeable to others, but survival can range from four to 20 years, depending on age and other health conditions.^19,20

Since the late 1990s, there has been increasing evidence that immunotherapy targeting the amyloid beta peptide can be used to treat Alzheimer’s disease. Because IVIG contains antiamyloid antibodies, many studies have been conducted to determine its treatment efficacy. In a Phase I safety and preliminary efficacy study, eight Alzheimer’s patients were treated with IVIG (Gammagard S/D Immune Globulin Intravenous Human). Seven patients completed the study and were evaluated by cognitive testing after six months of therapy. Cognitive function stopped declining in all seven patients and improved in six of the seven patients. Results from a Phase II clinical trial testing of Gammagard showed that IVIG slowed clinical decline, as well as reduced brain atrophy to the rate of agematched normal control subjects.²¹

Currently, a Phase III double-blind placebo-controlled study, called the GAP (Gammaglobulin Alzheimer’s Partnership) Study, is examining whether IVIG treatment will slow the rate or prevent the decline of dementia symptoms in individuals with mild to moderate Alzheimer’s patients. The study includes 360 patients and will last 82 weeks. Two-thirds of the participants will receive IVIG, while one-third will get a placebo every two weeks for 18 months.²²

Challenges of Off-Label Use

The two biggest challenges with using IVIG treatment for off-label indications include reimbursement and supply. Just because the use of a drug is not indicated and, therefore, off label does not mean it is not covered. Nonetheless, reimbursement for off-label uses can be more cumbersome and require more documentation to prove it is medically necessary. The more expensive the therapy is, the more attention a payer is likely to give it. Documentation must be provided to prove a patient’s symptoms fit the diagnosis. If a patient’s medical profile fits the diagnostic criteria, many payers still require the patient to first fail other forms of treatment; this is known as step therapy or a fail-first policy. Payers also may limit the quantity and/or interval that a drug is given.

With the growing number of indications being researched for IVIG treatment, should some of them gain FDA approval, there is concern that the demand for IG could outweigh the supply. Manufacturing IG differs significantly from traditional pharmaceutical manufacturing processes.IG is a plasma product that relies solely on the proteins present in human blood rather than on chemical processes that can be developed and/or improved for traditional pharmaceuticals. Manufacturing plasma is a lengthy and expensive process; manufacturing costs are about 65 percent of the price of IG, compared with 20 percent to 25 percent for traditional pharmaceutical processes.

A Promising Future?

The next frontier for IG looks extremely promising as this lifesaving therapy proves successful in treating more and more diseases. However, while much attention is being given to researching new indications for IG, an equal amount of attention will need to be devoted to the issues of supply and demand.