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Pharmaceutical Approval Update May 2011

Marvin M. Goldenberg PhD, RPh, MS

Belimumab (Benlysta) Intravenous Injection

Manufacturer: Human Genome Sciences, Inc., licensed by GlaxoSmithKline, Rockville, Md.

Indication: This B-lymphocyte stimulator (BLyS)-specific inhibitor is designed to treat adults with active, auto-antibody-positive systemic lupus erythematosus (SLE) who are receiving standard therapy.

Biologic Class: Belimumab is a human immunoglobulin G1-lambda-1 (IgG1-λ) monoclonal antibody that is specific for soluble BLyS human protein, also known as B-cell activating factor (BAFF) and tumor necrosis factor ligand superfamily member 13B (TNFSF13B). The molecular weight is approximately 147 kilodaltons. Belimumab is produced by recombinant DNA technology in a mammalian cell expression system.

Uniqueness of Biologic Agent: Belimumab blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells; however, the drug does not bind to B cells directly. By blocking the binding of BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

Warnings and Precautions:

Mortality. During controlled clinical trials, more deaths were reported with belimumab than with placebo. No single cause of death predominated. Etiologic factors included infection, cardiovascular disease, and suicide.

Serious infections. Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including belimumab. Physicians should exercise caution when considering belimumab in patients with chronic infections. Patients receiving any therapy for a chronic infection should not receive belimumab. If a new infection develops while a patient is receiving belimumab, therapy should be interrupted and the patient should be monitored closely.

In controlled clinical trials, overall incidence rates of infections were 71% with belimumab and 67% with placebo. The most common infections occurring in more than 5% of patients receiving belimumab were upper respiratory tract infections, urinary tract infections, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6% of belimumab patients and in 5.2% of placebo patients. Infections leading to discontinuation of treatment occurred in 0.7% of treated patients and in 1% of placebo patients. Infections resulting in death occurred in four of 1,458 patients (0.3%) treated with belimumab and in one of 675 patients (0.1%) receiving placebo.

Malignancy. The effect of belimumab on the development of malignancies is not known. In clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving the study drug and in 0.4% of patients receiving placebo. Malignancies, excluding non-melanoma skin cancers, were observed in 0.2% of patients receiving belimumab and in 0.3% of those receiving placebo. As with other immunomodulating agents, the drug’s mechanism of action may increase the risk of malignancy.

Hypersensitivity reactions and anaphylaxis. In controlled clinical trials, hypersensitivity reactions occurring on the same day of infusion were reported in 13% of patients receiving belimumab and in 11% of those receiving placebo. Anaphylaxis was observed in 0.6% of belimumab patients and in 0.4% of placebo patients. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Because of an overlap in signs and symptoms, it was not always possible to distinguish between hypersensitivity reactions and infusion reactions. If a serious reaction occurs, belimumab must be discontinued immediately and appropriate medical therapy should be given.

Infusion reactions. Serious infusion reactions, excluding hypersensitivity reactions, were reported in 0.5% of patients receiving belimumab and in 0.4% of patients receiving placebo. Reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. Common infusion reactions in 3% or more patients receiving belimumab included headache, nausea, and skin problems.

Depression. In controlled clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with belimumab (16%) than with placebo (12%). Serious psychiatric events were reported in 0.8% of treated patients and in 0.4% of placebo patients. Serious depression was reported in 0.4% of treated patients and in 0.1% receiving placebo. Two suicides were reported in the treated patients (0.1%).

Immunization. Because clinical safety has not been established, live vaccines should not be given for 30 days before or during therapy with belimumab.

Use with other biologics. Belimumab has not been studied in combination with other biologics, including B-cell targeted therapies and IV cyclophosphamide; therefore, it should not be given concomitantly with these products.

Dosage and Administration: The recommended dose of belimumab is 10 mg/kg at two-week intervals for the first three doses and at four-week intervals thereafter. The product should be reconstituted, diluted, and administered as an IV infusion only, over a period of one hour. Premedication for prophylaxis against infusion reactions and hypersensitivity reactions can be considered. Belimumab is available as single-use vials of lyophilized powder (120 mg and 400 mg per vial).

Commentary: Systemic lupus erythematosus (SLE) is a chronic, debilitating, and usually progressive autoimmune disease in which the body’s immune cells secrete antibodies that attack its own tissues. The illness causes skin rashes, joint pain, psychiatric symptoms, inflammation, and damage to the heart, lung, kidney, and other organs. Between 300,000 and 1.5 million Americans have lupus, and women are nine times more likely than men to be affected.

As the first new lupus drug in 56 years, belimumab was approved only as an addition to ongoing treatment with previously approved drugs, such as corticosteroids (prednisone), nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarial agents (hydroxychloroquine), and immunosuppressive drugs.

In assessing the benefits and risks of the drug, the FDA concluded that belimumab met the criteria for approval, showing superior efficacy over placebo in at least two clinical trials, but only at 10 mg/kg. In light of several other findings, the agency cautioned that the limitations should be considered. For instance, the drug’s efficacy resulted largely from improved muscle and skin organ systems, not organ systems that are more critical. Efficacy was reduced in patients of African-American or African heritage, and the drug’s benefits were inconsistent in various geographical regions. In addition, the onset of response was slow and a durable response was lacking.

Belimumab is expected to cost $35,000 per year per patient. Although African-Americans did not appear to respond to the drug, the number of these patients in trials was not sufficient to confirm this finding. Investigators plan to undertake a new trial of African-American patients as a condition of the approval (about one-third of all lupus patients are African-American). The FDA will allow the use of belimumab in all patients, including African-Americans, even though they did not respond to the biologic agent in clinical studies.

This drug should not be administered with live vaccines.


Ipilimumab (Yervoy) Intravenous Injection

Manufacturer: Bristol-Myers Squibb, Princeton, N.J.

Indication: Ipilimumab is used to treat patients with unresectable or metastatic melanoma.

Biologic Class: A recombinant, human monoclonal antibody, ipilimumab binds to the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4). This immunoglobulin G1-kappa (IgG1-κ) has an approximate molecular weight of 148 kilodaltons and is produced in mammalian (Chinese hamster ovary) cell culture.

Uniqueness of Biologic Agent: CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80 and CD86. Blockade of CTLA-4 augments T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell–mediated antitumor immune responses.

Boxed Warning: Ipilimumab can result in severe and fatal immune-mediated adverse reactions resulting from T-cell activation and proliferation. These reactions may involve any organ system, but the most common severe reactions are enterocolitis; hepatitis; neuropathy; endocrinopathy; and dermatitis, including toxic epidermal necrolysis (TEN). Most of these reactions are first manifested during treatment; however, a few reactions have occurred weeks to months after therapy was discontinued. Ipilimumab should be permanently withdrawn, and systemic high-dose corticosteroids should be initiated for severe immune-mediated reactions. Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy. Liver and thyroid function tests should be evaluated at baseline and before each dose.

Warnings and Precautions:

Immune-mediated enterocolitis. Severe, life-threatening, or fatal immune-mediated enterocolitis (diarrhea, fever, ileus, peritoneal signs) occurred in 7% of the ipilimumab-treated patients. Moderate enterocolitis (diarrhea, abdominal pain, mucus, or blood in stool) occurred in 5% of patients. Of all 511 treated subjects, five patients (1%) experienced intestinal perforation, four patients (0.8%) died as a result of complications, and 26 patients (5%) were hospitalized for severe enterocolitis. The median time to onset after the initiation of ipilimumab was 7.4 weeks for patients with grade 3 to 5 enterocolitis and 6.3 weeks for those with grade 2 enterocolitis.

Twenty-nine patients (85%) with grade 3 to 5 enterocolitis received high-dose corticosteroids (prednisone 40 mg or more, or equivalent, daily), with a median dose of prednisone 80 mg/day or equivalent. The median duration of treatment was 2.3 weeks (lasting up to 13.9 weeks), followed by tapering of the corticosteroid dose.

Ipilimumab should be withheld if the patient has moderate enterocolitis, and antidiarrheal treatment should be given. If enterocolitis persists for more than one week, systemic corticosteroids (prednisone 0.5 mg/kg daily or equivalent) should be initiated.

Immune-mediated hepatitis. Severe, life-threatening, or fatal hepatotoxicity—defined as elevated liver enzymes at more than five times the upper limit of normal (ULN) or total bilirubin elevations at more than three times the ULN—occurred in eight ipilimumab patients (2%). Of these treated patients, 0.2% experienced fatal hepatic failure and 0.4% had to be hospitalized. An additional 13 patients (2.5%) experienced moderate hepatotoxicity, with liver enzymes elevated at between 2.5 and five times the ULN or with total bilirubin elevated at between 1.5 and three times the ULN.

The underlying pathology, although not determined in all patients, sometimes included immune-mediated hepatitis. Liver function tests (transaminase and bilirubin levels) should be monitored, and patients should be evaluated for signs and symptoms of hepatotoxicity before they receive each dose of ipilimumab. The drug should be permanently discontinued in patients with grades 3 to 5 hepatotoxicity, and systemic corticosteroids should be given. In the clinical development program for ipilimumab, mycophenolate (CellCept, Roche) was given to patients with persistent, severe hepatitis even though they had received high-dose corticosteroids. Standard therapy for autoimmune hepatitis consists of steroids plus mycophenolate. These drugs are safe and effective as a first-line therapy in inducing and maintaining remission in treatment-naive patients with autoimmune hepatitis. Ipilimumab should be withheld in patients with grade 2 hepatotoxicity.

Immune-mediated dermatitis. Severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens–Johnson syndrome, TEN, or rash complicated by full-thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations) occurred in 13 ipilimumab patients (2.5%). One patient died as a result of TEN, and one patient required hospitalization for severe dermatitis. Moderate dermatitis developed in 63 patients (12%). Seven ipilimumab-treated patients (54%) with severe dermatitis received high-dose corticosteroids for up to 14.9 weeks, followed by tapering of the corticosteroid dose. Of these seven patients, six experienced complete resolution. The time to resolution varied for up to 15.6 weeks.

Ipilimumab should be permanently discontinued in patients with Stevens–Johnson syndrome, TEN, or severe rash with dermal ulceration or necrotic, bullous, or hemorrhagic manifestations. Systemic corticosteroids (prednisone or its equivalent) should be given in these instances. Ipilimumab should be withheld in patients with moderate-to-severe signs and symptoms. For patients with mild-to-moderate dermatitis, consisting of localized rash or pruritus, treatment can be symptomatic.

Immune-mediated neuropathies. One case of fatal Guillain-Barré syndrome and one case of severe peripheral motor neuropathy were reported. Myasthenia gravis and additional cases of Guillain-Barré syndrome have also been documented. Ipilimumab should be permanently withdrawn in patients with severe neuropathy such as Guillain-Barré-like syndromes. Medical intervention designed to manage severe neuropathy should be instituted. Systemic corticosteroids (prednisone or equivalent) should be considered if severe neuropathy develops.

Immune-mediated endocrinopathies. Severe to life-threatening immune-mediated endocrinopathies occurred in 1.8% of patients receiving ipilimumab. All of these patients had hypopituitarism, and some had concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Moderate endocrinopathy (hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism, and Cushing’s syndrome) occurred in 2.3% of patients. Ipilimumab should be withheld in symptomatic patients. Systemic corticosteroids (prednisone or equivalent), as well as appropriate hormone replacement therapy, should be initiated.

Other immune-mediated adverse reactions. Clinically significant immune-mediated reactions (e.g., nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia) have been noted in fewer than 1% of ipilimumab-treated patients. Ipilimumab should be permanently discontinued if significant or severe immune-mediated adverse reactions occur. Patients should receive corticosteroid eye-drops if uveitis, iritis, or episcleritis develops.

Dosage and Administration: The recommended dose of ipilimumab is 3 mg/kg, given intravenously over 90 minutes every three weeks, for a total of four doses. The scheduled dose should be withheld if a moderate immune-mediated adverse reaction or symptomatic endocrinopathy occurs. For patients receiving less than 7.5 mg of prednisone or equivalent each day and who have a grade 0 or 1 adverse reaction that resolves partially or completely, ipilimumab can be resumed at a dose of 3 mg/kg every three weeks until all four planned doses are given or until 16 weeks from the first dose has elapsed, whichever occurs earlier.

Ipilimumab should be discontinued permanently if (1) moderate adverse reactions persist, (2) the corticosteroid dose cannot be reduced to 7.5 mg of prednisone or equivalent per day, (3) the full treatment course cannot be completed within 16 weeks from administration of first dose, and (4) any severe or life-threatening adverse reaction occurs. Examples of a severe or life-threatening reaction include:

  • colitis with abdominal pain, fever, ileus, or peritoneal signs.
  • increased stool frequency or stool incontinence.
  • a need for IV hydration for more than 24 hours.
  • gastrointestinal (GI) hemorrhage or GI perforation.
  • elevated liver enzyme levels exceeding five times the ULN.
  • total bilirubin levels exceeding three times the ULN.
  • Stevens–Johnson syndrome, TEN, or severe rash with dermatological complications.
  • severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis.
  • severe immune-mediated reactions involving any organ system (e.g., nephritis, pneumonitis, pancreatitis, or non-infectious myocarditis).
  • immune-mediated ocular disease that has not responded to topical immunosuppressive therapy.

Commentary: By 1996, the lifetime risk of malignant melanoma in the U.S. had reached one in 87 persons and one in 70 for white men; this was an increase of more than 1,800% since the 1930s, according to the Wiley Library. Based on 2005–2007 rates provided by the National Cancer Institute, the risk has been updated to 1 in 52 men and women. Late-stage melanoma is devastating, with few treatment options, none of which prolongs life. Ipilimumab is the first therapy approved by the FDA to show prolonged survival in patients with unresectable or metastatic melanoma.

In a randomized, double-blind, double-dummy study, patients receiving a combination of ipilimumab and an investigational tumor vaccine were able to extend life by an average of 10 months; by contrast, those receiving only the vaccine survived for an average of 6.5 months. Ipilimumab is being approved with a Risk Evaluation and Mitigation Strategy (REMS) and a medication guide to inform health care professionals and patients of potential risks.

Severe and fatal autoimmune reactions were seen in 12.9% of treated patients. When severe side effects occurred, the drug was stopped and corticosteroids were given. However, not all patients responded to this treatment, and many who did respond did not experience improvement until several weeks had passed.

Ipilimumab is priced at $30,000 per dose, or $120,000 for a four-dose course of treatment. More than 20% of subjects receiving ipilimumab in the trial survived for at least two years and some survived much longer. The high price of ipilimumab has created a controversy with the public and with insurance companies. Government leaders, concerned about spiraling health care costs, might have a different reaction, because drugs used for cancer treatment are usually costly even when cures are unpredictable.