New Drug and Drug Formulation Approvals for Children
On February 14, 2014, the FDA approved elosulfase alfa (Vimizim™) for the treatment of mucopolysaccharidosis type IVA. This rare genetic lysosome storage disease, also referred to as Morquio A syndrome, is caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Elosulfase alfa was studied in a 24-week randomized, double-blind, placebo controlled trial prior to approval. A total of 176 patients, 5–57 years of age were randomized to receive a 2 mg/kg infusion of elosulfase alfa weekly, every other week, or placebo. Weekly treatment resulted in significant improvements in mobility compared to placebo. The mean effect on 6 minute walk test at 24 weeks was 22.5 meters (95% CI 4.0, 40.5, p = 0.017). Of the original 176 patients, 173 chose to continue treatment in an open-label extension study. Results of this study have shown no evidence of a reduction in efficacy over time.
The most common adverse effects reported during the original trial included fever, headache, chills, fatigue, nausea, vomiting, and abdominal pain. There have also been reports of anaphylactic reactions during infusions. Prescribing information for the drug contains a black box warning regarding this risk. Elosulfase alfa was the first drug to be given a Rare Pediatric Disease Priority Review Voucher, a new FDA designation designed to stimulate the development of new treatments for rare diseases. Healthcare providers and families can obtain more information about elosulfase alfa from BioMarin Pharmaceuticals by calling 1-855-MORQUIO (1-855-667-7846) or sending an email to bpps@bmrn.com.
Metreleptin (MyaleptTM), a recombinant analogue of leptin, was approved on February 24, 2014, with an orphan product designation to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystropy. This condition may lead to severe insulin resistance and the development of treatment-resistant diabetes mellitus and hypertriglyceridemia. Metreleptin was studied in an open-label study of 55 patients prior to approval. The median patient age was 25 years (range 7–68 years). Median duration of treatment was 2.5 years. The mean reduction in HgbA1c was 2.1 ± 0.5%, with a reduction in fasting triglycerides of 35.4 ± 13.7%.
In patients weighing 40 kg or less, metreleptin should be initiated at a dose of 0.06 mg/kg given once daily by subcutaneous injection. In males over 40 kg, treatment should be initiated with a daily dose of 2.5 mg and in females over 40 kg, a dose of 5 mg should be used. The dose may be titrated up to a maximum of 0.13 mg/kg/day in patients weighing 40 kg or less and 10 mg/day in those over 40 kg. The most common adverse effects in clinical trials were headache, hypoglycemia, and abdominal pain. Prescribers treating infants with metreleptin should be aware that the injection contains benzyl alcohol.
Because of the risk for development of anti-metreleptin antibodies with neutralizing activity to leptin/metreleptin and the risk for serious infection or T-cell lymphoma, metreleptin is only available through the Myaleptâ„¢ Risk Evaluation and Mitigation Strategy (REMS) Program. The REMS program, in addition to other post-marketing studies, has been required by the FDA to provide a mechanism for assessing immunogenicity and capturing information on potentially rare, but serious adverse effects.
On March 19, 2014, the FDA approved miltefosine (Impavido®) for the treatment of leishmaniasis in children 12 years of age and older and adults. Miltefosine was approved to treat visceral, cutaneous, and mucosal leishmaniasis. It is the first drug to be approved by the FDA for cutaneous or mucosal leishmaniasis. Because of the rarity of the infection and the limited number of treatment options available, miltefosine was given a fast track designation and a Tropical Disease Priority Review Voucher. It has also been granted orphan product designation. Miltefosine is available as a 50 mg capsule. The recommended dose for patients weighing 30–44 kg is 50 mg twice daily, and for patients 45 kg or greater, 50 mg three times daily, for 28 days. It is contraindicated in pregnant women due to evidence of teratogenicity and fetal death in animal models. The most common adverse effects reported during four clinical trials included nausea, vomiting, abdominal pain, decreased appetite, diarrhea, headache, dizziness, and elevated serum transaminases and creatinine.
A recombinant form of Factor IX, Alprolixâ„¢, was approved on March 28, 2014 for the treatment of children and adults with hemophilia B. This formulation offers the advantage of a longer duration of effect, resulting from the linking of the Factor IX molecule to the Fc protein fragment of human IgG. Binding of the Fc portion to neonatal Fc receptors delays lysosomal degradation of immunoglobulins by directing it back into the circulation, and gives recombinant Factor IX a prolonged half-life.
A total of 123 patients, ages 12–71 years, with severe hemophilia B were studied for over a year as part of a multicenter open-label clinical trial to establish the safety and efficacy of this new formulation. Patients were treated on one of three regimens: a fixed-week interval, an individualized interval, or on an as needed basis. In all groups, recombinant Factor IX was effective in reducing bleeding episodes. There were no significant adverse effects associated with the Factor. Pharmacokinetic studies in children under 12 years of age have shown a higher bodyweight-adjusted clearance than that seen in older children and adults. In a study of 29 children, mean elimination half-life was 66.40 hrs in patients 2–5 years, 72.23 hrs in those 6–11 years, and 83.59 hrs in those 12–17 years. For comparison, the mean half-life in a study of adults was 86.52 hrs. This shorter half-life may result in the need to adjust recombinant Factor IX dosing intervals in younger patients.
The first sublingual allergen extract tablet, Oralair®, was approved by the FDA on April 2, 2014, for the treatment of grass pollen allergies in patients between 10 and 65 years of age. Oralair® contains a mixture of freeze-dried extracts from five common grasses: Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass. The tablets are available in 100 and 300 IR (index of reactivity). Patients 17 years of age and older should receive one 300 IR tablet. Younger patients should undergo a dose titration with a 100 IR tablet the first day, two 100 IR tablets the second day, and a 300 IR tablet the third day and thereafter.
The first dose for all patients should be administered in the healthcare provider's office or clinic to allow a minimum of 30 minutes of observation and potential treatment of a severe hypersensitivity reaction, including anaphylaxis. If tolerated, further doses may be taken by the patient at home, providing a more convenient alternative to allergy shots. The recommended regimen is one tablet daily, beginning 4 months before the start of grass pollen season and continuing until the end of the season. The manufacturer recommends that patients be trained in the use of an epinephrine auto-injector and the need to seek medical attention if symptoms of hypersensitivity develop. Patients with severe or uncontrolled asthma, cardiac disease, or who require medications known to reduce the efficacy of epinephrine should not be treated with sublingual allergen extracts.
Oralair® was studied in six clinical trials in over 1,000 adults throughout the United States and Europe. In addition, 278 children (ages 5–17 years) were enrolled in a placebo-controlled study. The mean daily total symptom score was significantly lower in the treatment group than in the controls (2.52 versus 3.13) with a relative difference of -30.6% (95% CI -47.0%, -14.1%), as was the mean daily rescue medication score (0.46 versus 0.65) with a relative difference of -29.5% (95% CI -50.9%, -8.0%). A subset of 154 children was included in a safety analysis. The most commonly reported adverse effects in children were similar to those in adults: upper respiratory infections, tonsillitis, worsening asthma, dysphonia, pruritus, and atopic dermatitis. Approximately 1% of patients experienced a severe adverse effect, including hypersensitivity reactions and laryngeal edema.
On April 14, 2014 Merck announced the FDA approval of their sublingual Timothy grass pollen allergen extract tablet, Grastek®. This product is approved for a wider patient population, from 5 to 65 years of age. Grastek® should be started 12 weeks prior to the onset of grass pollen season and continue to the end of the season. A second sublingual allergen extract tablet from Merck was recently approved adults 18 years of age and older with ragweed allergy. Short ragweed allergen pollen extract (Ragwitek™) was approved by the FDA on April 17, 2014. As with Grastek®, treatment should begin 12 weeks before the onset of ragweed pollen season and continue throughout the season. Like Oralair®, the first dose of either Grastek® or Ragwitek™ should be given in the office or clinic to allow observation for a minimum of 30 minutes. Both products carry the same black box warning and precautions as Oralair®.
New Drug Approvals
Elosulfase Alfa
On February 14, 2014, the FDA approved elosulfase alfa (Vimizim™) for the treatment of mucopolysaccharidosis type IVA. This rare genetic lysosome storage disease, also referred to as Morquio A syndrome, is caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Elosulfase alfa was studied in a 24-week randomized, double-blind, placebo controlled trial prior to approval. A total of 176 patients, 5–57 years of age were randomized to receive a 2 mg/kg infusion of elosulfase alfa weekly, every other week, or placebo. Weekly treatment resulted in significant improvements in mobility compared to placebo. The mean effect on 6 minute walk test at 24 weeks was 22.5 meters (95% CI 4.0, 40.5, p = 0.017). Of the original 176 patients, 173 chose to continue treatment in an open-label extension study. Results of this study have shown no evidence of a reduction in efficacy over time.
The most common adverse effects reported during the original trial included fever, headache, chills, fatigue, nausea, vomiting, and abdominal pain. There have also been reports of anaphylactic reactions during infusions. Prescribing information for the drug contains a black box warning regarding this risk. Elosulfase alfa was the first drug to be given a Rare Pediatric Disease Priority Review Voucher, a new FDA designation designed to stimulate the development of new treatments for rare diseases. Healthcare providers and families can obtain more information about elosulfase alfa from BioMarin Pharmaceuticals by calling 1-855-MORQUIO (1-855-667-7846) or sending an email to bpps@bmrn.com.
Metreleptin
Metreleptin (MyaleptTM), a recombinant analogue of leptin, was approved on February 24, 2014, with an orphan product designation to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystropy. This condition may lead to severe insulin resistance and the development of treatment-resistant diabetes mellitus and hypertriglyceridemia. Metreleptin was studied in an open-label study of 55 patients prior to approval. The median patient age was 25 years (range 7–68 years). Median duration of treatment was 2.5 years. The mean reduction in HgbA1c was 2.1 ± 0.5%, with a reduction in fasting triglycerides of 35.4 ± 13.7%.
In patients weighing 40 kg or less, metreleptin should be initiated at a dose of 0.06 mg/kg given once daily by subcutaneous injection. In males over 40 kg, treatment should be initiated with a daily dose of 2.5 mg and in females over 40 kg, a dose of 5 mg should be used. The dose may be titrated up to a maximum of 0.13 mg/kg/day in patients weighing 40 kg or less and 10 mg/day in those over 40 kg. The most common adverse effects in clinical trials were headache, hypoglycemia, and abdominal pain. Prescribers treating infants with metreleptin should be aware that the injection contains benzyl alcohol.
Because of the risk for development of anti-metreleptin antibodies with neutralizing activity to leptin/metreleptin and the risk for serious infection or T-cell lymphoma, metreleptin is only available through the Myaleptâ„¢ Risk Evaluation and Mitigation Strategy (REMS) Program. The REMS program, in addition to other post-marketing studies, has been required by the FDA to provide a mechanism for assessing immunogenicity and capturing information on potentially rare, but serious adverse effects.
Miltefosine
On March 19, 2014, the FDA approved miltefosine (Impavido®) for the treatment of leishmaniasis in children 12 years of age and older and adults. Miltefosine was approved to treat visceral, cutaneous, and mucosal leishmaniasis. It is the first drug to be approved by the FDA for cutaneous or mucosal leishmaniasis. Because of the rarity of the infection and the limited number of treatment options available, miltefosine was given a fast track designation and a Tropical Disease Priority Review Voucher. It has also been granted orphan product designation. Miltefosine is available as a 50 mg capsule. The recommended dose for patients weighing 30–44 kg is 50 mg twice daily, and for patients 45 kg or greater, 50 mg three times daily, for 28 days. It is contraindicated in pregnant women due to evidence of teratogenicity and fetal death in animal models. The most common adverse effects reported during four clinical trials included nausea, vomiting, abdominal pain, decreased appetite, diarrhea, headache, dizziness, and elevated serum transaminases and creatinine.
Recombinant Factor IX
A recombinant form of Factor IX, Alprolixâ„¢, was approved on March 28, 2014 for the treatment of children and adults with hemophilia B. This formulation offers the advantage of a longer duration of effect, resulting from the linking of the Factor IX molecule to the Fc protein fragment of human IgG. Binding of the Fc portion to neonatal Fc receptors delays lysosomal degradation of immunoglobulins by directing it back into the circulation, and gives recombinant Factor IX a prolonged half-life.
A total of 123 patients, ages 12–71 years, with severe hemophilia B were studied for over a year as part of a multicenter open-label clinical trial to establish the safety and efficacy of this new formulation. Patients were treated on one of three regimens: a fixed-week interval, an individualized interval, or on an as needed basis. In all groups, recombinant Factor IX was effective in reducing bleeding episodes. There were no significant adverse effects associated with the Factor. Pharmacokinetic studies in children under 12 years of age have shown a higher bodyweight-adjusted clearance than that seen in older children and adults. In a study of 29 children, mean elimination half-life was 66.40 hrs in patients 2–5 years, 72.23 hrs in those 6–11 years, and 83.59 hrs in those 12–17 years. For comparison, the mean half-life in a study of adults was 86.52 hrs. This shorter half-life may result in the need to adjust recombinant Factor IX dosing intervals in younger patients.
Sublingual Allergen Extracts
The first sublingual allergen extract tablet, Oralair®, was approved by the FDA on April 2, 2014, for the treatment of grass pollen allergies in patients between 10 and 65 years of age. Oralair® contains a mixture of freeze-dried extracts from five common grasses: Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass. The tablets are available in 100 and 300 IR (index of reactivity). Patients 17 years of age and older should receive one 300 IR tablet. Younger patients should undergo a dose titration with a 100 IR tablet the first day, two 100 IR tablets the second day, and a 300 IR tablet the third day and thereafter.
The first dose for all patients should be administered in the healthcare provider's office or clinic to allow a minimum of 30 minutes of observation and potential treatment of a severe hypersensitivity reaction, including anaphylaxis. If tolerated, further doses may be taken by the patient at home, providing a more convenient alternative to allergy shots. The recommended regimen is one tablet daily, beginning 4 months before the start of grass pollen season and continuing until the end of the season. The manufacturer recommends that patients be trained in the use of an epinephrine auto-injector and the need to seek medical attention if symptoms of hypersensitivity develop. Patients with severe or uncontrolled asthma, cardiac disease, or who require medications known to reduce the efficacy of epinephrine should not be treated with sublingual allergen extracts.
Oralair® was studied in six clinical trials in over 1,000 adults throughout the United States and Europe. In addition, 278 children (ages 5–17 years) were enrolled in a placebo-controlled study. The mean daily total symptom score was significantly lower in the treatment group than in the controls (2.52 versus 3.13) with a relative difference of -30.6% (95% CI -47.0%, -14.1%), as was the mean daily rescue medication score (0.46 versus 0.65) with a relative difference of -29.5% (95% CI -50.9%, -8.0%). A subset of 154 children was included in a safety analysis. The most commonly reported adverse effects in children were similar to those in adults: upper respiratory infections, tonsillitis, worsening asthma, dysphonia, pruritus, and atopic dermatitis. Approximately 1% of patients experienced a severe adverse effect, including hypersensitivity reactions and laryngeal edema.
On April 14, 2014 Merck announced the FDA approval of their sublingual Timothy grass pollen allergen extract tablet, Grastek®. This product is approved for a wider patient population, from 5 to 65 years of age. Grastek® should be started 12 weeks prior to the onset of grass pollen season and continue to the end of the season. A second sublingual allergen extract tablet from Merck was recently approved adults 18 years of age and older with ragweed allergy. Short ragweed allergen pollen extract (Ragwitek™) was approved by the FDA on April 17, 2014. As with Grastek®, treatment should begin 12 weeks before the onset of ragweed pollen season and continue throughout the season. Like Oralair®, the first dose of either Grastek® or Ragwitek™ should be given in the office or clinic to allow observation for a minimum of 30 minutes. Both products carry the same black box warning and precautions as Oralair®.