Caplacizumab-yhdp and its Use For Acquired Thrombotic Thrombocytopenic Purpura

Overview

Caplacizumab-yhdp is a von Willebrand factor-directed antibody fragment used to treat acquired thrombotic thrombocytic purpura in adult patients. It is used in combination with plasma exchange and immunosuppressive therapies. It was considered an orphan medicine, as it was used for rare diseases. It was approved on February 6th, 2019 by the United States Food and Drug Administration and was also authorized for use in the European Union due to its greater benefits.

How Does Caplacizumab Work?

The von Willebrand factor is a glycoprotein responsible for the clotting of blood; however, in patients with acquired thrombotic thrombocytic purpura, the levels of the von Willebrand factor are increased. Caplacizumab is the active substance in Caplacizumab-yhdp, which gets attached to the von Willebrand factor and stops its action on the platelets, thus preventing clot formation.

What Are the Indications for Caplacizumab?

Caplacizumab-yhdp is indicated for treating adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppression therapy.

What Are the Contraindications of Caplacizumab?

Caplacizumab-yhdp is contraindicated in patients with a history of severe hypersensitivity reactions.

What Is the Dosage of Caplacizumab?

Caplacizumab-yhdp is available as 11 mg (milligram) lyophilized powder in a single dose vial; it must be administered after plasma exchange therapy and is recommended in the following doses;

• 11 mg bolus intravenous (IV) injection is given 15 minutes before plasma exchange therapy followed by 11 mg through subcutaneous injection after the completion of plasma therapy on the first day of treatment. The first dose is administered by the healthcare provider, and the subsequent doses can be injected by the patients or the caregivers subcutaneously after receiving proper training.

• On subsequent days, 11 mg of Caplacizumab-yhdp is administered subcutaneously once daily after plasma exchange therapy.

• Subcutaneous injection of 11 mg Caplacizumab-yhdp once daily is continued for 30 days following the last dose of plasma exchange treatment. If the symptoms persist even after the treatment, it can be extended for a maximum of 28 days.

What Are the Drug Warnings and Precautions?

• The risk of bleeding is increased in patients under the treatment of Caplacizumab-yhdp. The treatment is interrupted if clinically significant bleeding occurs, and von Willebrand factor concentrate is rapidly administered to correct hemostasis. On restarting the therapy with Caplacizumab-yhdp, the patient must be monitored for any signs of bleeding or other adverse reactions.

• Caplacizumab-yhdp must be stopped seven days before elective surgery, invasive interventions, or dental procedures. In case of emergency surgeries, von Willebrand factor concentrate is administered to achieve hemostasis. The treatment is resumed after the risk of surgical bleeding is resolved, along with frequent monitoring of the patient.

What Are the Adverse Effects of Caplacizumab?

Serious adverse effects of Caplacizumab-yhdp include;

• Heavy bleeding may occur from the nose, gums, injection site, rectum, and vagina.

• Vomiting blood.

• Blood in the urine.

• Red or black tarry stools.

• Sudden and severe headache.

• Frequent and painful urination.

• Severe and sharp abdominal pain.

Some of the common side effects include:

• Itching at the site of injection.

• Tingling or numbness on the skin.

• Shortness of breath.

• Back pain and muscle pain.

• Fever and fatigue.

For Patients

What Is Acquired Thrombotic Thrombocytopenic Purpura?

A rare disorder in which blood clots are formed in the small blood vessels throughout the body is termed acquired thrombotic thrombocytopenic purpura (aTTP). It occurs when the body produces antibodies against an enzyme called ADAMTS13 (von Willebrand factor cleaving protease). The blood clots block the blood flow and oxygen supply to the organs, leading to a reduction in the platelet count. Signs and symptoms include; tiny red or purple spots on the skin, anemia, bleeding problems, chest pain, fever, kidney problems, and nervous system problems.

What Is Caplacizumab?

Caplacizumab-yhdp belongs to the class of medications called antithrombotic agents and is used in patients with aTTP. It blocks the action of the von Willebrand factor (which helps the platelets stick to the walls of the blood vessels at the site of injury), thus preventing the formation of blood clots. It is used along with plasma exchange therapy and immunosuppressive medications.

What Should Patients Inform the Doctor Before Taking Caplacizumab?

• Patients must inform the doctor in case of allergy to Caplacizumab-yhdp , or any other medications before the initiation of the treatment.

• Immunizations or vaccinations must not be taken during the treatment with Caplacizumab-yhdp.

• The doctor must be informed if the patient is suffering from bleeding disorders or liver diseases.

• Female patients must inform the doctor if they are pregnant or breastfeeding or if they become pregnant during the treatment with Caplacizumab-yhdp.

• If the patients have surgical appointments or dental procedures planned, the doctor must be informed, and Caplacizumab-yhdp doses must be discontinued seven days prior to the surgery.

• The doctor must be informed if the patient is taking any over-the-counter (OTC) medicines or herbal or vitamin supplements before starting the treatment with Caplacizumab-yhdp .

• Caplacizumab-yhdp must not be taken by others or used for conditions other than prescribed, as it may cause harm.

How Should Caplacizumab Be Stored?

• Caplacizumab-yhdp must be stored in the refrigerator between 2 to 8 degrees Celsius.

• The mixed Caplacizumab-yhdp solution must be used immediately, or if needed, it can be stored for upto four hours in the refrigerator at 2 to 8 degrees. It must not be kept in a freezer.

• Unopened Caplacizumab-yhdp vials can be stored at room temperature upto 30 degrees Celsius In the original carton for upto two months.

• Once stored at room temperature, Caplacizumab-yhdp must not be kept in a refrigerator; the drug must be kept away from light and out of reach of children.

• Medication that is not needed must be safely disposed of, ensuring that it is not consumed by children or pets.

What Are the Important Instructions Regarding Caplacizumab Therapy?

• Caplacizumab-yhdp is a prescription medicine, and the treatment is started and supervised by specialist doctors who manage patients with clotting disorders. Caplacizumab-yhdp is started with a dose of 11 mg and injected into a vein before the plasma exchange therapy. The treatment is continued daily along with plasma exchange therapy, by an injection administered under the skin in the belly (subcutaneous) and upto 30 days after the plasma exchange therapy is stopped. The treatment may be extended if necessary. Patients or their caretakers may also inject Caplacizumab-yhdp, but only after receiving appropriate training from the healthcare provider.

• Bruising and bleeding may occur more easily in patients under the treatment of Caplacizumab-yhdp; bleeding from the nose and gums may occur and may take longer than usual to clot; however, if excessive bleeding occurs, a healthcare provider must be contacted immediately.

What Are the Precautions To Be Taken During the Administration of Caplacizumab-yhdp?

• The first dose is administered by the healthcare provider, and the following subsequent doses can be injected by the patients or the caregivers under aseptic precautions after receiving proper training on the preparation and administration from the healthcare providers.

• The name Caplacizumab-yhdp appears on the carton and the vial label, and one carton of Caplacizumab-yhdp is needed for each injection for single use. Expiry date must be checked before using the drug. The instructions provided must be read before administering the drug.

• The supplies provided in the carton must only be used to prepare the dose, and after the injection, the used vial and other supplies must be disposed of along with the adapter attached; it must not be reused for the following doses.

What Are the Side Effects of Caplacizumab?

Common side effects include;

• Bleeding or itching at the site of injection.

• Headache.

• Back pain, joint pain, muscle cramps.

• Tingling or numbness.

• Bleeding from nose and gums.

• Difficulty in breathing.

• Chest tightness.

• Difficulty and painful urination.

• Fever and severe fatigue.

Less common side effects include;

• Stomach pain.

• Nausea and vomiting.

• Heavy and longer menstrual bleeding.

• Bleeding from the anus.

• Vaginal bleeding.

For Doctors

Description

Caplacizumab-yhdp is a drug produced by recombinant DNA technology. It is a bivalent nanobody produced by Escherichia coli, consisting of two identical, genetically linked building blocks joined by a tri-alanine linker. It targets the von Willebrand factor and prevents platelet adhesion. Transient reductions of von Willebrand factor and factor VIII C levels may be observed during the treatment.

Caplacizumab-yhdp for injection is available as a sterile, preservative-free lyophilized powder in a vial containing 11 mg of Caplacizumab-yhdp, along with the following ingredients:

• Polysorbate-80.

• Sucrose.

• Anhydrous citric acid.

• Trisodium citrate dihydrate.

The final concentration after reconstitution with one ml of sterile water is 11 mg/ml at a pH of approximately 6.5.

Mechanism of Action:

Caplacizumab yhdp acts by binding to the A1 domain of vWF, a key protein in hemostasis. It inhibits the interaction between the von Willebrand factor and platelets and reduces the vWF-mediated adhesion and consumption of platelets. The drug can interact in both its active and inactive forms, and the biological activity is assessed using a Biacore potency assay.

Pharmacodynamics:

Ristocetin cofactor (RICO) activity was incorporated to assess the activity of the von Willebrand factor. Subcutaneous administration of Caplacizumab-yhdp at doses greater than or equal to the recommended dose to patients with aTTP showed a decrease in the RICO activity levels below 20 percent approximately four hours post-administration. The RICO activity values returned to baseline within seven days of discontinuation of the drug.

Pharmacokinetics:

The pharmacokinetics of Caplacizumab-yhdp depend on the expression of the von Willebrand factor and are not proportional to the dose administered. A steady state concentration was achieved following the administration of Caplacizumab-yhdp in healthy patients, with minimal accumulation. After a single subcutaneous dose of 10 mg Caplacizumab-yhdp to healthy subjects, the mean peak concentration was 528 ng/ml (nanograms per milliliter), and the area under the curve (AUC) was 7951 (16 percent). After administration of Caplacizumab-yhdp daily for 14 days to healthy subjects, the maximum concentration was 348 ng/ml, and the AUC was 6808 ng/ml.

• Absorption: The bioavailability of Caplacizumab-yhdp was approximately 90 percent on subcutaneous administration, and the maximum concentration was noted six to seven hours following the subcutaneous injection of 10 mg once daily.

• Distribution: The central volume of distribution of Caplacizumab-yhdp in patients with aTTP is 6.33 L.

• Metabolism: The available data suggests that Caplacizumab-yhdp is metabolized in the liver, as Caplacizumab-yhdp is catabolized by various proteolytic enzymes.

• Excretion: The half-life of Caplacizumab-yhdp is dependent on the concentration and target level of the drug; according to data from non-clinical studies, the unbound Caplacizumab-yhdp is excreted by the kidneys.

• Drug interaction studies have not been conducted with Caplacizumab-yhdp, and no significant differences were observed in the pharmacokinetics of the drug based on age, sex, race, blood group, and in patients with mild, moderate, or severe renal impairment.

Drug Interactions-

• Using anticoagulant drugs or other medications that affect hemostasis and coagulation along with Caplacizumab-yhdp may increase the risk of bleeding; hence the patient must be closely monitored in such cases.

• Increased risk of bleeding may be seen in patients with hemophilia and other coagulation factor deficiencies; in such cases, von Willebrand factor concentrate may be administered to achieve hemostasis.

Clinical Studies-

The efficacy of treatment with Caplacizumab-yhdp in adult patients with aTTP in combination with plasma exchange and immunosuppressive therapies was determined by a pivotal, randomized, multicenter, double-blind, placebo-controlled trial called the HERCULES study.

• A total of 145 patients with a median age of 45 years were enrolled and randomized either to Caplacizumab-yhdp or a placebo and both groups received the plasma exchange and immunosuppressive therapies.

• Patients are administered an 11 mg single dose of Caplacizumab-yhdp injection or placebo before the first plasma exchange therapy, followed by a subcutaneous injection of 11 mg Caplacizumab-yhdp daily after the plasma exchange till the duration of plasma exchange therapy, and 30 days thereafter. The treatment with Caplacizumab-yhdp showed less number of patients with TTP-related death or major thromboembolic event. The recurrence rate of TTP was also known to be reduced compared to the placebo group.

Non-clinical Toxicology-

No studies have been conducted to determine the carcinogenicity, genotoxicity, and animal fertility effects of Caplacizumab yhdp.

Use of Caplacizumab in Specific Populations-

• Pregnancy: No substantial data is available regarding the drug-associated risk of using Caplacizumab-yhdp in pregnant women; however, there may be potential risks of hemorrhage in the mother and fetus; hence, pregnant women receiving the therapy must be carefully monitored for excessive bleeding.

• Nursing Mothers: No information is available regarding the presence of Caplacizumab-yhdp in the milk of nursing mothers or the effects of the drug on the breastfed child or milk production; therefore, the benefits of breastfeeding must be considered along with the need for the drug to the mother, and any potential side effects that may be caused to the infant from the drug.

• Pediatric Use: The safety and effectiveness of Caplacizumab-yhdp in pediatric patients is not established as no relevant data is available.

• Geriatric Use: Sufficient number of subjects above 65 years of age were not included in the clinical studies of Caplacizumab-yhdp; therefore, the response compared to younger subjects is not determined.

• Hepatic Impairment: No data is available regarding the use of Caplacizumab-yhdp in patients with severe acute or chronic liver impairment, as no clinical studies have been conducted.