Velmanase-alfa-tycv - Pharmacological Aspect

Overview:

Velmanase alfa-tycv is a form of the enzyme lysosomal alpha-mannosidase, made using recombinant DNA (deoxyribonucleic acid) technology in Chinese Hamster ovary (CHO) cells. The structure is identical to the naturally occurring human enzyme, and the molecular weight is approximately 130 kDa (kilodalton). Velmanase alfa-tycv is provided as a sterile, preservative-free white to off-white powder for IV (intravenous) infusion after reconstitution with a solution. Each vial contains 10 mg (milligrams) of Velmanase alfa-tycv with other inactive ingredients consisting of sodium phosphate, glycine, and mannitol. The concentration of the solution is two mg per mL, and it has a pH of 7.5 after mixing with five mL of sterile water. Velmanase alfa-tycv was approved by the Food and Drug Administration on July 17, 2023.

Available Doses and Dosage Forms:

Velmanase-alfa-tycv is given as 10 mg per vial in the form of white to off-white powder that resembles a cake. It needs to be dissolved in liquid before application.

For Patients:

How Does Velmanase-alfa-tycv Work in Alpha Mannosidosis?

Alpha-mannosidosis is a rare lysosomal storage disorder. Complex sugars in the body cannot be broken down, and thus accumulate within cells. This can disrupt a range of organ and system unit functions in an individual, including disruptions to the function units of the brain. Symptoms range from mild to severe. Velmanase alfa-tycv is an injection that may help to reduce some of the symptoms of alpha-mannosidosis without impacting the brain. Alpha-mannosidosis is a rare genetic disorder caused by a lack of the enzyme alpha-mannosidase. This medication must be given by a doctor or under their close supervision.

What Is the Dosage of Velmanase-alfa-tycv?

• Before starting Velmanase alfa-tycv, the doctor may recommend taking medications like antihistamines, fever reducers, or corticosteroids to reduce potential side effects.

• The usual dosage of Velmanase alfa-tycv is one mg per kg of body weight, given once a week through an intravenous (IV) infusion.

• For patients weighing less than 108 pounds, the infusion should last at least 60 minutes.

• For those weighing 110 pounds or more, the infusion rate should not exceed 25 mL per hour to control the amount of protein being introduced.

How Effective Is Velmanase-alfa-tycv?

Studies so far have not shown any specific issues in children that would prevent the use of Velmanase alfa-tycv injection. It has been proven safe and effective for use in kids.

What Are the Things to Inform the Doctor Before Taking the Velmanase-alfa-tycv?

• Before using Velmanase alfa-tycv, it is important to weigh the risks and benefits with the doctor.

• Inform the doctor if the person has any allergic reactions to this or other medicines. Also, mention any allergies to foods, dyes, preservatives, or animals.

• If the person is breastfeeding, consider the potential benefits and risks with the doctor.

• Some medicines may interact with Velmanase alfa-tycv, requiring a dose adjustment or extra precautions. Tell the healthcare provider about all other medicines the person is taking.

• Interactions may occur with certain foods, alcohol, or tobacco. Discuss their use with the healthcare provider when taking this medicine.

How Is Velmanase-alfa-tycv Administered?

• To give Velmanase-alfa-tycv, use an infusion set with a pump and a 0.2-micron filter that prevents the protein from binding.

• Do not shake the syringe.

• The total amount of the infusion depends on the patient's weight.

• For patients weighing 49 kg (108 lbs (pound by weight)) or less, the infusion should last at least 60 minutes.

• For patients weighing 50 kg (110 lbs) or more, the infusion should be given at a rate no faster than 25 mL per hour to manage the protein intake.

• After the final syringe is empty, switch to a 20 mL syringe filled with 0.9 percent sodium chloride (saltwater solution) and infuse an extra 10 mL of it to make sure all the Velmanase-alfa-tycv left in the line is delivered to the patient.

What Are the Side Effects of Velmanase-alfa-tycv?

While a medicine is meant to help, it can sometimes cause unwanted side effects. Not everyone experiences them, but if they do occur, seek medical help. Common side effects to watch for includes:

• Back pain, chest tightness, fever, headache, muscle aches, nausea, vomiting, trouble breathing, and unusual tiredness.

• Urinary problems, skin reactions like rashes or hives, and flu-like symptoms such as cough, sore throat, and runny nose.

Less common but serious side effects:

• Dizziness, confusion, seizures, swelling, rapid weight gain, or fainting.

• Heart-related symptoms like irregular heartbeat or chest pain.

Side effects may be temporary and disappear as the body adjusts to this particular type of medication. If they continue or worsen, discuss them with the physician. If anything unusual is noted, it is always best to inform the healthcare professional.

Missed Dose:

Velmanase-alfa-tycv should be resumed as soon as possible if a person misses their dose three days or more before the next scheduled dose. If it is within three days of the next dose, skip the missed dose and resume the regular schedule.

Storage:

Velmanase-alfa-tycv should be kept refrigerated between two to eight degrees Celsius (36°F (Fahrenheit) to 46°F) in its original packaging to protect it from light. Do not freeze.

For Doctors:

Indication: Velmanase-alfa-tycv is used to treat symptoms of alpha mannosidosis that affect the body, but not the brain, in both adults and children.

Dose: Velmanase-alfa-tyc is a powder that is mixed with liquid for injection. Each vial contains 10 mg for a single use.

Dosing Considerations:

For Mild to Moderate Reactions:

• Stop the infusion for 15 to 30 minutes and then decrease the rate to 25 to 50 percent of the normal rate.

• If symptoms do not improve then stop the infusion and monitor the patient.

• If the symptoms continue, stop the infusion completely. Consider restarting the infusion after seven to 14 days at 25 to 50 percent of the normal rate with pre-treatment.

• The person should be monitored closely if symptoms resolve while resuming the infusion slowly and gradually increasing the rate.

For Severe Reactions:

• Stop the infusion at once and start appropriate treatment.

What Are the Pharmacological Aspects of Velmanase-alfa-tycv?

• Pharmacodynamics: In patients with alpha-mannosidosis, oligosaccharides in the blood are higher than usual. A clinical assessment of these sugar levels was performed in patients with alpha-mannosidosis and reports the quantity of 2-mannose oligosaccharides. The concentration of these sugars in the blood was decreased with Velmanase-alfa-tycv treatment in patients with alpha-mannosidosis.

• Mechanism of Action: Alpha-mannosidosis results from the insufficient activity of alpha-mannosidase, an enzyme, caused by genetic alterations in the Mannosidase alpha class 2B member one gene. This enzyme typically breaks down sugar molecules called mannose-containing oligosaccharides. The accumulation of these matters in cells, especially in lysosomes, causes assorted problems in different parts of the body because of the anomalous functioning of the enzymes. Velmanase alfa-tycv, on the other hand, works by providing an exogenous source of the deficient enzyme. It gets into the cells by binding to a specific receptor, mannose-6-phosphate receptor, and works in the lysosomes to facilitate the breaking down of the accumulated sugars.

• Pharmacokinetics: The way Velmanase alfa-tycv moves through the body was studied in adults with alpha-mannosidosis. On average, at the recommended dose of one mg per kg, the highest level of the drug in the blood was 7.9 μg (microgram) per mL, and the overall exposure (AUC) was 159.8 μg∙h per mL.

  • Distribution: The drug diffuses all over the body at a rate of 276 mL per kilogram of body weight.

  • Elimination: The body eliminated the drug with an elimination rate of 5.7 mL per hour per kilogram, and it was about 33.6 hours before the drug concentration in the body would be reduced by half.

  • Metabolism: The drug will be metabolized into small proteins due to normal processes of metabolism.

Toxicity:

• Carcinogenesis (Cancer Risk): None has been done in animals to know if Velmanase alfa-tycv would induce tumors. In a rat carcinogenicity study, one female rat had ovarian histiocytic sarcoma at a high dose of the drug. It is not clear if the drug caused the tumor, but it is not impossible. The dose that led to the development of the tumor was 10 times more than what a patient is usually prescribed.

• Fertility: When Velmanase alfa-tycv was given to rats twice a week for two weeks before mating, and then until day six of pregnancy, it did not affect their ability to reproduce. The doses used in the study were about ten times higher than the amount given to human patients.

Clinical Studies: The side effects of Velmanase-alfa-tycv in clinical trials were variable, so comparing the rate of adverse reactions in one trial to another or real-world experiences cannot be done directly.

• Trial 1: It comprised 15 patients, including eight adults and seven children, treated weekly with Velmanase-alfa-tycv for 52 weeks.

One serious case of acute kidney failure was reported in seven percent of patients. Common side effects in at least 2 patients included:

• Nasopharyngitis.

• Fever.

• Headache.

• Joint pain, tonsillitis, eye itch, stomach issues, hypersensitivity, flu-like symptoms, fainting, and toothache.

• Trial 2: Involved 5 children aged three to five, treated weekly for an average of 121 weeks. One serious reaction included chills and high fever. Common side effects (in at least 2 patients) included cough, ear infections, runny nose, conjunctivitis, falls, sprains, throat pain, and facial swelling.

• Trial 3: Combined data from earlier phases with 33 patients (20 males, 13 females), treated weekly for an average of 89 weeks for adults and 155 weeks for children. One patient withdrew due to repeated infusion reactions but later resumed treatment after a long break. Additional side effects seen in 10 percent of patients included abdominal pain, bruising, skin issues, post-lumbar puncture symptoms, weight gain, rashes, and tooth extractions.

Selected Reactions:

• Kidney Failure: Three percent of patients had an episode of acute kidney failure, which resolved within 12 weeks.

• Vasculitis (IgA): Three percent experienced an immune reaction called IgA vasculitis.

• Seizures: Three percent had seizures, though it is unclear if they were related to Velmanase-alfa-tycv.

• Pediatric Reactions: 36 percent of adults and 58 percent of children experienced hypersensitivity.

• Patients with anti-drug antibodies (ADA) had a higher rate of infusion-related reactions (80 percent vs. 20 percent for ADA-negative).

Warnings and Precautions:

• Allergic Reactions and Anaphylaxis: Some patients treated with Velmanase-alfa-tycv have experienced allergic reactions, including anaphylaxis (a severe allergic reaction). In clinical trials, 50 percent of patients (both adults and children) had allergic reactions, with five percent experiencing anaphylaxis. Most of the severe reactions were seen in patients with antibodies to the drug. Symptoms of severe reactions included skin rashes, low blood pressure, vomiting, fever, and swelling. Before starting Velmanase-alfa-tycv, the doctor may recommend pre-treating with medications like antihistamines or steroids to reduce the risk of reactions. Medical support, including resuscitation equipment, should be on hand during the infusion. If a severe reaction occurs, stop the treatment immediately and seek medical attention.

• Infusion-Related Reactions: Another phenomenon that has been noticed is called infusion-related reactions (IARs). IARs have been demonstrated in 50 percent of patients in the clinic, although it has only been necessary to pre-treat in only 13 percent of the cases. One patient stopped treatment because of recurring reactions. Common symptoms included fever, chills, rashes, vomiting, and coughing. The doctor may suggest pre-treating with antihistamines or steroids to reduce the risk of IARs, though these reactions may still happen. If a severe IAR occurs, the infusion should be stopped, and medical treatment should be given. After tolerating slower infusions, patients may return to the recommended rate. For mild or moderate reactions, the infusion may be slowed or paused.

• Risk During Pregnancy: Animal studies suggest that Velmanase-alfa-tycv may harm a developing fetus. In studies with pregnant rats and rabbits, abnormalities were observed. If the patient is pregnant, the physician will balance the potential benefit of continuing Velmanase-alfa-tycv against the potential risk it may pose to the unborn baby. Should the patient be likely to become pregnant, she should inform the physician that she is pregnant before receiving Velmanase-alfa-tycv and confirm her nonpregnancy before initiation, and should utilize a reliable form of birth control during treatment and for 14 days following discontinuation of Velmanase-alfa-tycv.

What Are the Drug Interactions of Velmanase-alfa-tycv?

While certain medicines are never to be taken together, in some cases, two different medicines may be appropriately used together, even though interaction is possible. The clinician may need to reduce a dose or take other precautions if two medicines are used together, which may interact. Be sure to inform the healthcare provider if the person takes prescription or OTC medicines.

Specific Considerations:

• Pregnancy: Animal studies such as tests on pregnant rats and rabbits showed major malformations, like organ deformities, in their offspring when given doses higher than what humans receive. However, so far, there is limited information on its use in human pregnancies that either confirms or rules out the fact that this drug causes birth defects or complications. Pregnant women should, therefore, be informed of possible risks, and a further decision to continue therapy pregnancy weighs the mother's need for Velmanase-alfa-tycv against possible risks to the baby as well as consequences of leaving alpha-mannosidosis un-treated. In the general U.S. population, the chance of a birth defect has been estimated at two to four percent, and the chance of miscarriage is roughly 15 to 20 percent.

• Lactation: It is unknown whether Velmanase-alfa-tycv is excreted in human milk and also the effects on an infant breastfed by a mother treated with Velmanase-alfa-tycv. Nursing mothers should decide if the benefits of breastfeeding outweigh the possible hazards to the breastfed infant from Velmanase-alfa-tycv.

• Reproductive Potential: Velmanase-alfa-tycv can cause embryotoxicity and teratogenicity when administered in the pregnancy state. Therefore, a woman of childbearing potential must be cautioned that she is not pregnant before the first dose of the drug, and the patient should use effective birth control measures during the course of treatment and for 14 days after the last dose if the patient is stopped from the drug.

• Pediatric Use: Velmanase-alfa-tycv is safe and effective in patients with alpha-mannosidosis; however, it is only based on clinical trials. The drug has shown a higher number of hypersensitivity reactions in children as compared to adults when given as treatment.

• Geriatric Use: Alpha-mannosidosis primarily affects children and young adults. No clinical efficacy studies of Velmanase-alfa-tycv enrolled subjects 65 years of age or older; thus, there are no studies to determine its effect on the elderly population.