General Information

Lamzede (velmanase alfa-tycv) is recombinant human lysosomal alpha-mannosidase.

Lamzede is specifically indicated for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients.

Lamzede is supplied as an injection for intravenous administration. Prior to administration, consider pre-treating with antihistamines, antipyretics, and/or corticosteroids as Lamzede carries a risk for severe hypersensitivity reactions.

The recommended dosage of Lamzede is 1 mg/kg (actual body weight) administered once every week as an intravenous infusion. The total volume of infusion is determined by the patient’s actual body weight and should be administered over a minimum of 60 minutes for patients weighing up to 49 kg. Patients weighing 50 kg and greater should be infused at a maximum infusion rate of 25 mL/hour to control the protein load.

 If one or more doses are missed, restart the treatment as soon as possible, as long as it is at least 3 days from the next scheduled dose. If it is within 3 days from the next scheduled dose, give only the next dose per schedule.

Severe Reactions:

• In the event of a severe hypersensitivity reaction (including anaphylaxis) or severe infusion associated reaction (IAR), immediately discontinue Lamzede administration and initiate appropriate medical treatment.
• In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 15 to 30 minutes, slowing the infusion rate to 25% to 50% of the recommended rate, and initiating appropriate medical treatment.

 If symptoms:

• Persist despite temporarily holding or slowing the infusion, stop the infusion and monitor the patient. If symptoms continue to persist, discontinue the infusion, and consider re-initiating the infusion within 7 to 14 days at 25% to 50% of the recommended rate with appropriate pretreatment. 
• Subside following holding or slowing the infusion, resume infusion at 25% to 50% the recommended rate. If tolerated, increase the infusion rate by increments of 25% of the recommended rate until the recommended infusion rate is reached. Closely monitor the patient.

Mechanism of Action

Alpha-mannosidosis is a lysosomal storage disease that results from reduced activity of the enzyme alpha-mannosidase, caused by gene variants in Mannosidase Alpha Class 2B Member 1. Alpha-mannosidase catalyzes the degradation of accumulated mannose-containing oligosaccharides. The deficiency of alpha-mannosidase causes an intra-lysosomal accumulation of mannose-rich oligosaccharides in various tissues. Velmanase alfa-tycv provides an exogenous source of alphamannosidase. Velmanase alfa-tycv is internalized via binding to the mannose-6-phosphate receptor on the cell surface and transported into lysosomes where it is thought to exert enzyme activity.

Side Effects

Adverse effects associated with the use of Lamzede may include, but are not limited to, the following:

• hypersensitivity reactions including anaphylaxis
• nasopharyngitis
•  pyrexia
• headache
• arthralgia

The Lamzede drug label comes with a Black Box Warning for Hypersensitivity Reactions Including Anaphylaxis. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available. If a severe hypersensitivity reaction occurs, discontinue Lamzede immediately and initiate appropriate medical treatment.

Clinical Trial Results

The FDA approval of Lamzede was based on two clinical trials.

A multicenter, randomized, double-blinded, placebo-controlled, parallel group trial in adult and pediatric patients evaluated the efficacy of Lamzede over 52 weeks at a dose of 1 mg/kg given weekly as an intravenous infusion. A total of 25 patients were enrolled (14 males, 11 females), including 13 adult patients (age range: ≥18 to 35 years; mean: 25 years) and 12 pediatric patients (age range: ≥6 to <18 years; mean: 11 years); all patients were White. Ethnicity data were not collected. All patients had alphamannosidase activity below 11% of normal and in the range of 8 to 29 µmol/h/mg at baseline. All patients but one were naïve to Lamzede. Fifteen patients (8 adult and 7 pediatric) received Lamzede and 10 patients (5 adult and 5 pediatric) received placebo. All patients completed the trial. The efficacy results for the clinical endpoints assessed at 12 months, 3-minute stair climbing test (3MSCT), 6-minute walking test (6MWT) and forced vital capacity (FVC) (% predicted), favored the Lamzede group and were supported by a reduction in serum oligosaccharide concentration. 

A single arm trial assessed pediatric alpha-mannosidosis patients less than 6 years of age. All patients had alpha-mannosidase activity below 10% of normal at baseline. The trial enrolled five patients ranging from 3.7 to 5.9 years of age, with a mean age of 4.5 years. Four patients were White, race was not recorded for 1 patient; and 3 were male and 2 were female. Patients received Lamzede 1 mg/kg as intravenous infusion once weekly (4 patients for 24 months, 1 patient for 40 months). The mean (SD) absolute and percentage changes from Baseline for serum oligosaccharides at 24 months were -7.7 (4.27) μmol/L and -65.8% (23.1%) respectively.