Review of Selected NMEs 2012

ABSTRACT: New molecular entities (NMEs), as defined by the FDA, are drug products containing as their active ingredient a chemical substance marketed for the first time in the United States. The following descriptions of NMEs approved in 2011–2012 ( TABLE 1) detail the basic clinical and pharmacologic profiles for each new drug, as well as its pharmacokinetics, adverse reactions, drug interactions, and dosing data. Note that the information for each NME was obtained primarily from sources published prior to FDA approval; thus, it is essential that practitioners become aware of changes in a drug’s therapeutic profile as reported by their own patients and in the pharmaceutical literature, such as the emergence of additional adverse reactions and black box warnings.

Aflibercept (Eylea, Regeneron Pharmaceuticals, Inc.)

Indication and Clinical Profile^1,2: Aflibercept is approved to treat patients with wet (neovascular) age-related macular degeneration (AMD), a leading cause of vision loss and blindness in Americans aged 60 years and older. There are two forms of AMD, wet and dry. The wet form involves the growth of abnormal blood vessels, which can leak fluid into the central part of the retina, the macula. With this fluid leakage, the macula thickens and vision loss occurs. Other FDA-approved injectable treatment options for wet AMD include verteporfin (Visudyne), pegaptanib (Macugen), and ranibizumab (Lucentis).

Aflibercept’s efficacy was established in two clinical trials (VIEW1, VIEW2) enrolling 2,412 patients with wet AMD. Patients were randomly assigned to one of four dosing regimens: 1) aflibercept administered 2 mg every 8 weeks following 3 initial monthly doses; 2) aflibercept administered 2 mg every 4 weeks; 3) aflibercept 0.5 mg administered every 4 weeks; or 4) ranibizumab administered 0.5 mg every 4 weeks. In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Aflibercept doses of 2 mg every 4 and 8 weeks were found to be as efficacious and clinically equivalent to the ranibizumab regimen. In VIEW1, this endpoint was reached by 94%, 95%, and 94% of subjects in the aflibercept 2Q8, aflibercept 2Q4, and ranibizumab arms, respectively. In VIEW2, this endpoint was reached by 95% of subjects in all three treatment arms.

Pharmacology and Pharmacokinetics^1,2: Vascular endothelial growth factor-A (VEGF-A) is a member of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. Aflibercept, a recombinant fusion protein, is a selective VEGF-A antagonist. It acts as a decoy receptor by competing for binding and inhibiting the activation of VEGF-A and other receptors responsible for neovascularization and vascular permeability.

Some aflibercept bound to VEGF-A may be absorbed into the systemic circulation. In plasma, aflibercept exists in equilibrium between VEGF-bound and free form. The free form is digested by proteolysis and cleared. The terminal elimination half-life of free aflibercept in plasma was found to be 5 to 6 days after IV administration at doses of 2 to 4 mg/kg.

Adverse Reactions and Drug Interactions^1,2: The most commonly reported side effects in patients receiving aflibercept included conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure. Intravitreal injections have been associated with endophthalmitis and retinal detachment; therefore, proper injection techniques must be used. Patients should report any symptoms suggestive of endophthalmitis or retinal detachment immediately and managed them accordingly. Elevated intraocular pressure is common acutely following aflibercept injection. Sustained increase in pressure should be monitored to avoid perfusion to the optic nerve. Although uncommon (<2%) in clinical trials, arterial thromboembolic events did occur following intravitreal use of aflibercept.

Aflibercept is contraindicated in patients with ocular or periocular infections or active ocular inflammation. This drug has not been studied in pregnant women, so the treatment should be used only in pregnancy if the potential benefits outweigh any risks.

Dosage and Administration^1,2: Aflibercept is available as a 40 mg/mL solution for intravitreal injection in a single-use vial (FIGURE 1). Adequate anesthesia and topical broad-spectrum microbicide should be given prior to injection. The recommended dosage is 2 mg (0.05 mL) administered by intravitreal injection monthly for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal injection once every 2 months. Although aflibercept may be dosed as frequently as 2 mg every month, additional efficacy was not demonstrated when aflibercept was dosed every month compared to every 2 months.

Asparaginase Erwinia chrysanthemi (Erwinaze, EUSA Pharma [USA], Inc.)

Indication and Clinical Profile^3,4: Asparaginase Erwinia chrysanthemi has been approved for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to Escherichia coli–derived asparaginase and pegaspargase drugs used to treat ALL. ALL is the most common malignancy in children and is characterized by an overproduction of lymphocytes in bone marrow. Multidrug chemotherapy cures about 80% of children with ALL. Inclusion of an asparaginase in ALL regimens improves outcomes, but approximately 15% to 20% of patients treated with E coli–derived asparaginase develop hypersensitivity to the drug.

Prior to Erwinaze’s approval, there were two asparagine-specific enzyme products for ALL (asparaginase injection and pegaspargase), both of which are E coli derived. Erwinaze has been designated as an orphan drug.

The approval of Erwinaze was based on one clinical trial that enrolled 58 subjects with ALL who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The subjects received 25,000 IU/m² of Erwinaze intramuscularly (IM) for 2 weeks as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. The main endpoint was determination of the proportion of patients who achieved a serum trough asparaginase level ≥0.1 IU/mL. More than 50% of the subjects reached this endpoint at 48 or 72 hours following the third dose. In another study, 42 E coli asparaginase–allergic children with ALL were switched to twice-weekly Erwinaze 25,000 IU/m² to complete 30 weeks of asparaginase treatment. At a median follow-up of 5.4 years, event-free survival in those children was similar to that of children without E coli–asparaginase allergy (86% vs. 81%).

Pharmacology and Pharmacokinetics^3,4: Erwinaze contains an asparaginase-specific enzyme derived from E chrysanthemi. This enzyme catalyzes the hydrolysis of asparagine to aspartic acid and ammonia, resulting in lower circulating levels of asparagine and selective killing of leukemic cells that depend on an exogenous source of asparagine for their survival. Normal human cells are able to make asparagine through biosynthesis and are not affected by treatment with Erwinaze.

The pharmacokinetics of Erwinaze have not been fully determined. Serum asparaginase activity levels were >0.4 IU/mL for 80% of trial patients evaluated at 48 hours and 38% at 72 hours.

Adverse Reactions and Drug Interactions^3,4: Adverse effects associated with Erwinaze treatment include serious allergic reactions (anaphylaxis), pancreatitis, abnormal transaminases and bilirubin, blood clotting, hemorrhage, nausea, vomiting, and hyperglycemia. Allergy to the drug was reported in 33% of trial patients. Erwinaze is contraindicated in patients who have a history of serious pancreatitis, thrombosis, or serious hemorrhagic events with prior L-asparaginase therapy. Erwinaze is classified as a Pregnancy Category C drug. No formal drug interaction studies have been performed.

Dosage and Administration^3,4: Erwinaze is supplied as a solution for IM administration. To substitute for a dose of pegaspargase, the recommended dosage of Erwinaze is 25,000 IU/m² IM three times a week for 6 doses for each planned dose of pegaspargase. To substitute for a dose of native E coli asparaginase, the recommended dosage is 25,000 IU/m² IM for each scheduled dose of native E coli asparaginase within a treatment. The volume of Erwinaze administered at a single injection site should be limited to 2 mL; if the administered dose is >2 mL, use multiple injection sites.

Brentuximab vedotin (Adcetris, Seattle Genetics, Inc.)

Indication and Clinical Profile^5,6: Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin’s lymphoma (FIGURE 2) and non-Hodgkin’s lymphoma. Hodgkin’s lymphoma is distinguished from other lymphomas by the presence of one characteristic type of cell, known as the Reed-Sternberg cell, which generally expresses CD30.

Brentuximab vedotin is specifically approved for two indications: 1) Hodgkin’s lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and 2) systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

The brentuximab approvals were based on data from two pivotal trials in Hodgkin’s lymphoma patients who relapsed after ASCT (n = 102) and in relapsed sALCL patients (n = 58). The primary endpoint of both trials was overall response rate as assessed by an independent review facility. In this study, 73% of patients achieved an objective response following treatment with brentuximab, including 32% with complete remissions and 40% with partial remissions. The median duration of objective response was 6.7 months. There are no data available demonstrating improvement in patient-reported outcomes or survival with brentuximab.

Pharmacology and Pharmacokinetics^5,6: Brentuximab vedotin is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. sALCL is an aggressive type of T-cell
non-Hodgkin’s lymphoma that also expresses CD30.

Maximum concentrations of brentuximab are typically observed immediately postinfusion, and serum concentrations decline in a multiexponential manner with a terminal half-life of about 4 to 6 days. Only a small fraction of MMAE released from brentuximab is metabolized, primarily by oxidation of CYP3A4/5. The majority of the drug is excreted in the feces as unchanged MMAE.

Adverse Reactions and Drug Interactions^5,6: Adverse events most commonly reported with brentuximab therapy (incidence ≥20%) included neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough, and vomiting. Infusion-related reactions, including anaphylaxis, were also reported. If this occurs, interrupt the infusion and institute appropriate medical management. Due to the risk of tumor lysis syndrome, patients with rapidly proliferating tumor and high tumor burden should be monitored closely. Concomitant use of brentuximab with bleomycin is contraindicated due to risk of pulmonary toxicity. Brentuximab is classified as a Pregnancy Category D drug.

MMAE, the active component of brentuximab, is primarily metabolized by CYP3A. Therefore, coadministration of brentuximab with a potent CYP3A4 inhibitor or inducer may significantly increase or decrease MMAE exposure, respectively. Patients who are receiving strong CYP3A4 inhibitors or inducers concomitantly with brentuximab should be closely monitored for adverse reactions or treatment failure. Brentuximab does not inhibit CYP enzymes at relevant clinical concentrations and thus is not expected to alter the exposure to drugs that are metabolized by CYP isozymes.

Dosage and Administration^5,6: Brentuximab vedotin is supplied as a solution for IV infusion. The recommended dosage is 1.8 mg/kg administered IV over 30 minutes every 3 weeks. Treatment should be continued until a maximum of 16 cycles are completed or disease progression or unacceptable toxicity occurs. The company has established a patient assistance program (SeaGen Secure) that offers patients and providers access to drug reimbursement support, benefit investigations, and patient assistance programs.

Glucarpidase (Voraxaze, BTG International Inc.)

Indication and Clinical Profile^7,8: Glucarpidase is approved for the treatment of toxic plasma methotrexate (MTX) concentrations (>1 µmol/L) in patients with delayed MTX clearance due to impaired renal function. High-dose methotrexate (HD-MTX) is frequently used in the treatment of various malignancies. However, around 2% to 10% of patients experience grade ≥2 HD-MTX–related nephrotoxicity and renal failure, which results in disruption of therapy and may be life threatening. Precipitation of MTX in renal tubules is thought to be the main mechanism of HD-MTX–induced renal failure and, consequently, of prolonged exposure to toxic MTX levels. Prolonged exposure can cause bone marrow suppression, oral and gastrointestinal ulceration, and hepatic toxicity. Administration of leucovorin (folinic acid) with aggressive IV hydration and alkalinization of urine can reduce these toxicities.

The efficacy of glucarpidase was established in a single-arm, open-label study in 22 patients with delayed MTX clearance secondary to renal dysfunction. The main outcome of the study was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in MTX plasma concentration. Forty-five percent of patients receiving glucarpidase achieved an RSCIR in MTX concentrations (95% CI, 27%-65%). In the 9 patients with preglucarpidase MTX concentrations >50 µmol/L, all achieved a >95% reduction in MTX concentrations for up to 8 days following the initial injection. None, however, achieved an RSCIR. Since glucarpidase does not reduce intracellular concentrations of MTX, continuation of leucovorin is still required during MTX therapy.

Pharmacology and Pharmacokinetics^7,8: Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as MTX. This enzyme converts MTX to its inactive metabolites 4-deoxy-4-amino-N¹⁰-methylpteroic acid (DAMPA) and glutamate. DAMPA and glutamate are further metabolized by the liver, providing an alternative route of MTX elimination to renal clearance during high-dose MTX treatment. Thus, glucarpidase lowers plasma levels of MTX, reducing its concentration to below the threshold for serious toxicity, without altering intracellular MTX levels.

In a pharmacokinetic study, IV administration of glucarpidase-produced mean concentration (C_max) was 3.3 µg/mL and the mean AUC_0-inf was 23.3 µg·h/mL. Serum glucarpidase activity levels declined with a mean elimination half-life of 5.6 hours. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (Vd) was 3.6 L, which suggests that glucarpidase distribution is restricted to plasma volume.

Adverse Reactions and Drug Interactions^7,8: The most common adverse reactions (occurring in >1% of patients) in glucarpidase clinical trials included paresthesia, flushing, nausea and/or vomiting, hypotension, and headache. Serious allergic reactions, including anaphylactic reactions, occurred in <1% of patients. Glucarpidase is classified as Category C for use during pregnancy.

Leucovorin is a substrate for glucarpidase and should not be administered within 2 hours before or after a dose of glucarpidase. No dose adjustment is recommended for the continuing leucovorin regimen because the dose is based on the patient’s preglucarpidase MTX concentration. Other folates and folate antimetabolite drugs are also potential substrates for glucarpidase and therefore may interact.

Dosage and Administration^7,8: Glucarpidase is supplied in single-use vials containing 1,000 U of the drug for reconstitution and IV administration. It is administered as a bolus injection over 5 minutes, at a dose of 50 U/kg. Monitoring levels of MTX concentration during the initial 48 hours of treatment with glucarpidase should be performed using chromatography, since immunoassay will result in overestimations due to products formed from metabolized MTX. Additional monitoring can resume using immunoassays following the initial 48 hours of treatment. Therapy with leucovorin should be continued until the MTX concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. However, leucovorin should not be administered within 2 hours of a dose of glucarpidase because it is a substrate for glucarpidase. For 48 hours after glucarpidase administration, the leucovorin dose should be based on the patient’s preglucarpidase MTX concentration. Even with glucarpidase use, hydration and alkalinization of the urine should be continued as indicated.

Ipilimumab (Yervoy, Bristol-Myers Squibb)

Indication and Clinical Profile^9,10: Ipilimumab is approved to treat patients with unresectable or metastatic melanoma. Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the U.S. during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute. Current treatment options for metastatic melanoma include dacarbazine (DTIC), high-dose interleukin-2, and gp100 peptide vaccine with high-dose interleukin-2. However, none of these therapies have been found to significantly delay disease progression or increase overall survival in a significant number of patients.

Ipilimumab’s efficacy and safety were established in a single international study involving 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. Participants had disease that had spread or that could not be surgically removed. The study was designed to measure overall survival, the length of time from when this treatment started until a patient’s death. The randomly assigned patients received ipilimumab plus an experimental tumor vaccine called gp100, ipilimumab alone, or the gp100 vaccine alone. Survival rate at 1 year was 46% in the ipilimumab arm versus 25% in the gp100 arm. The estimated survival rate at 2 years was 24% in the ipilimumab arm versus 14% in the gp100 arm. Subjects treated with ipilimumab had a 34% reduction in the risk of death over the gp100 control arm, and those treated with ipilimumab plus gp100 had a 32% reduction in the risk of death over the gp100 control arm. Those who received the combination of ipilimumab plus the vaccine or ipilimumab alone lived an average of about 10 months, while those who received only the experimental vaccine lived an average of 6.5 months.

Another trial in 502 patients with previously untreated metastatic melanoma compared ipilimumab 10 mg/kg plus dacarbazine with dacarbazine alone. Overall survival, which was the primary endpoint, was significantly longer with ipilimumab plus dacarbazine (11.2 vs. 9.1 months).

Pharmacology and Pharmacokinetics^9,10: Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a molecule on T cells that suppresses the immune response. Ipilimumab binding blocks the interaction of CTLA-4 with its ligands, enhancing 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.

Peak concentration (C_max), trough concentration (C_min), and AUC of ipilimumab appear to be dose proportional. The drug has a terminal half-life of 14.7 days, systemic clearance (CL) of 15.3 mL/h, and volume of distribution at steady state (Vss) of 7.21 L. The pharmacokinetics of ipilimumab do not appear to be significantly altered by renal or hepatic impairment.

Adverse Reactions and Drug Interactions^9,10: In clinical trials, the most common adverse effects of ipilimumab included diarrhea, nausea, fatigue, pruritus, rash, and colitis. In the controlled trial with gp100, severe or fatal (grade 3 or 4) immune-related adverse reactions, mostly diarrhea, occurred in 10% to 15% of ipilimumab-treated patients, compared to 3% of patients receiving gp100 alone. In the controlled trial with dacarbazine, grade 3 or 4 adverse effects occurred in 56.3% of patients treated with both drugs and in 27.5% of those treated with dacarbazine alone. Immune-related adverse effects of ipilimumab have included colitis, hepatitis, toxic epidermal necrolysis, neuropathy, and endocrinopathy.

Due to the unusual and severe side effects associated with this drug, it was approved with a black box warning concerning severe immune-related adverse effects and a Risk Evaluation and Mitigation Strategy (REMS) to inform health care professionals about these serious risks. No formal drug-drug interaction studies have been conducted with ipilimumab. It is classified as Category C for use during pregnancy.

Dosage and Administration^9,10: Ipilimumab is supplied as 5 mg/mL solutions (10 and 40 mL) for IV administration. The recommended dosage is 3 mg/kg IV over 90 minutes every 3 weeks for a total of four doses. The ipilimumab dose should be withheld for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy, and permanently discontinued if patients experience serious immune-related reactions (skin or other organs), colitis, neuropathies, or significantly elevated liver function enzymes (>5 times the upper limit of normal [ULN]).

Lucinactant (Surfaxin, Discovery Laboratories, Inc.)

Indication and Clinical Profile^11,12: The FDA has approved lucinactant for the prevention of respiratory distress syndrome (RDS) in high-risk premature infants (FIGURE 3). RDS is a condition in which premature infants are born with an insufficient amount of pulmonary surfactant, a substance produced naturally in the lungs and essential for breathing. Infants with RDS often require animal-derived surfactant replacement therapy along with mechanical ventilation to survive.

Approximately 90,000 premature infants in the U.S. are treated annually with currently available animal-derived surfactants. Lucinactant is the fifth surfactant approved in the U.S. to treat RDS in premature infants; the others are Survanta (beractant), Curosurf (poractant alfa), Infasurf (calfactant), and Exosurf (colfosceril palmitate), which is no longer marketed.

The safety and efficacy of lucinactant were determined on the basis of a large, multinational trial involving 1,294 premature infants in Europe and Latin America. Within the first 30 minutes after birth, infants were randomized to receive one of three surfactants, lucinactant (5.8 mL/kg), colfosceril palmitate (5.0 mL/kg), or beractant (4.0 mL/kg). Infants in the lucinactant and beractant groups could be given up to three additional doses between 6 and 24 hours of birth, as often as every 6 hours, if they subsequently developed RDS and required mechanical ventilation. Infants in the colfosceril palmitate group could receive up to two additional doses at least 12 hours apart if they met the retreatment criteria. Some infants received placebo air to maintain blinding of the study.

All dosages were calculated based on birth weight, and the trial infants were followed through 12 months’ corrected age. Coprimary endpoints were the incidence of RDS at 24 hours and RDS-related mortality at 14 days, with the intent of demonstrating superiority over colfosceril palmitate. Beractant served as an additional active comparator. Compared to colfosceril palmitate, lucinactant demonstrated a statistically significant improvement in both RDS at 24 hours (39% vs. 47%) and RDS-related mortality through day 14 (5% vs. 9%).

Pharmacology and Pharmacokinetics^11,12: Lucinactant is a synthetic formulation consisting of phospholipids, a fatty acid, and sinapultide (KL4 peptide), a 21–amino acid hydrophobic synthetic peptide. It functions as a nonpyrogenic pulmonary surfactant, thereby lowering surface tension at the air-liquid interface of the alveolar surfaces during respiration and stabilizing the alveoli against collapse at resting transpulmonary pressures. Thus, lucinactant compensates for the deficiency of surfactant and restores surface activity to the lungs of these infants. Based on its route of administration and presumed lack of absorption, no human pharmacokinetic studies have been performed to characterize the absorption, distribution, metabolism, or elimination of lucinactant.

Adverse Reactions and Drug Interactions^11,12: The most common side effects of lucinactant are related to its administration via an endotracheal tube and include endotracheal tube reflux, skin paleness, endotracheal tube obstruction, and need for dose interruption. If bradycardia, oxygen desaturation, endotracheal tube reflux, or airway obstruction occurs during administration, therapy should be interrupted and the infant’s clinical condition assessed and stabilized. No significant drug interactions are expected with this drug due to the anticipated lack of absorption from its site of administration.

Dosage and Administration^11,12: Lucinactant is supplied as a solution for intratracheal administration only. The recommended dosage is 5.8 mL per kg of birth weight. Up to four doses can be administered in the first 48 hours of life, but doses should be given no more frequently than every 6 hours. Lucinactant should be administered only by clinicians trained and experienced with intubation, ventilator management, and general care of premature infants in a highly supervised clinical setting. Infants receiving the drug should undergo frequent clinical assessments so that oxygen and ventilatory support can be modified to respond to changes in respiratory status.

REFERENCES

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7. Voraxaze (glucarpidase) package insert. Brentwood, TN: BTG International Inc; January 2012.
8. BC Widemann, Balis FM, Kim A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. 2010;28:3979-3986.
9. Yervoy (ipilimumab) package insert. Princeton, NJ: Bristol-Myers Squibb; March 2011.
10. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med. 2010;363:711-723.
11. Surfaxin (lucinactant) package insert. Warrington, PA: Discovery Laboratories, Inc; 2012.
12. Moya FR, Gadzinowski J, Bancalari E, et al; International Surfaxin Collaborative Study Group. A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants. Pediatrics. 2005;115:1018-1029.

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