Cablivi (Caplacizumab-yhdp): First Targeted, Nanobody-Based Therapy Approved for Adults with Acquired Thrombotic Thrombocytopenic Purpura

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening autoimmune blood disorder that causes the formation of blood clots in small blood vessels throughout the body.¹ Acquired or immune-mediated TTP is characterized by thrombocytopenia and anemia and involves the inhibition of the von Willebrand factor–cleaving protease ADAMTS13 through autoantibodies. This inhibition leads to platelet destruction and microvascular thrombosis, resulting in tissue ischemia and multiorgan failure, and potentially in death.² Conditions that can trigger acquired TTP include cancer, lupus, pregnancy, and certain infections that affect the immune system, including HIV, hepatitis, and Helicobacter pylori.¹

In most cases, acquired TTP occurs suddenly and lasts for days or weeks, but the condition can also last for months. Acquired TTP can cause bleeding disorders, hemolytic anemia, and other serious health conditions if the blood clots block the flow of oxygen-rich blood to the brain, heart, and kidneys.^1,2 Refractory disease, which affects approximately 1 in 6 patients, is associated with poor outcomes.² As many as 60% of patients with this condition will have a recurrence. Immediate treatment is crucial to prevent long-term consequences, including stroke or brain damage.¹

Treatments for acquired TTP include plasma exchange (plasmapheresis), which replaces the ADAMTS13 enzyme and removes antibodies; and immunosuppressive therapy, including corticosteroids and rituximab (Rituxan), which can slow or suppress antibodies to the ADAMTS13 enzyme.^1,2 Recently, the first targeted, ­nanobody-based therapy indicated specifically for the treatment of acquired TTP became available.

Caplacizumab Approved for Acquired TTP

On February 6, 2019, the US Food and Drug Administration (FDA) approved caplacizumab-yhdp injection (Cablivi; Sanofi/Genzyme), in combination with plasma exchange and immunosuppressive therapy, for the treatment of adults with acquired TTP. Caplacizumab, a von Willebrand factor–directed antibody fragment, is the first targeted, nanobody-based therapy that inhibits blood clots formation to receive approval for adults with acquired TTP. The FDA granted caplacizumab an orphan drug designation.³

“Patients with acquired TTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence. “Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of acquired TTP. Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences,” he added.³

Mechanism of Action

Caplacizumab is a von Willebrand factor–directed antibody fragment that targets the A1 domain of von Willebrand factor, thereby inhibiting the interaction between von Willebrand factor and platelets. This activity reduces von Willebrand factor–mediated platelet adhesion and platelet consumption and blocks the formation of blood clots.^3,4

Dosing and Administration

Caplacizumab is available for injection as a lyoph­ilized powder in a single-dose vial at a dose of 11 mg. Caplacizumab should be administered at the initiation of plasma exchange therapy. The recommended dosing schedule is⁴:

• Day 1: 11-mg bolus intravenous (IV) injection at least 15 minutes before plasma exchange, followed by an 11-mg subcutaneous injection after plasma exchange is completed
• Subsequent daily treatment during plasma exchange: 11 mg via subcutaneous injection, once daily, after plasma exchange
• Treatment after the plasma exchange period: 11-mg subcutaneous injection, once daily, for 30 days beyond the last plasma exchange

After the initial course of therapy, if any sign of ­underlying disease (ie, suppressed ADAMTS13 activity levels) persists, treatment with caplacizumab may be extended for a maximum of 28 days. The first dose of caplacizumab should be administered by a healthcare provider as a bolus IV injection. Subsequent doses should be administered subcutaneously in the abdomen. Caplacizu­mab should be discontinued if the patient has more than 2 TPP recurrences while receiving caplacizumab.⁴

Pivotal Clinical Trial: HERCULES

The randomized, double-blind, placebo-controlled phase 3 HERCULES clinical trial evaluated the efficacy of caplacizumab in combination with plasma exchange and immunosuppressive therapy.^2,4 A total of 145 adults with acquired TTP (median age, 45 years) were randomized to caplacizumab or to placebo. The median capla­cizumab treatment duration was 35 days, and the mean dose used in the study was 11 mg.⁴

The primary efficacy outcome was the time to a platelet count response (ie, platelet count ≥150,000/μL, followed by cessation of daily plasma exchange within 5 days). Patients who received treatment with caplacizu­mab achieved a significantly faster platelet count response compared with placebo.^2,4 In fact, at any given interval during the study, patients in the caplacizumab group were 1.55 times more likely to achieve a normalized platelet count than patients in the placebo group.²

Outcomes for the key secondary end points showed that fewer patients who received caplacizumab had a TTP-related death or TTP recurrence during the treatment period compared with patients who received placebo (Table). The incidence of patients with at least 1 treatment-emergent major thromboembolic event was similar in both arms (Table).⁴

In addition, during the overall study period (ie, drug treatment period plus the 28-day follow-up time after treatment discontinuation), fewer patients in the cap­lacizumab group had a TTP recurrence than patients in the placebo group (13% vs 38%, respectively; P <.001).⁴

Adverse Reactions

The most common adverse reactions (incidence >15%) associated with caplacizumab were epistaxis (29%), headache (21%), and gingival bleeding (16%). In clinical trials, 7 (7%) of patients discontinued caplacizumab because of adverse reactions. Serious bleeding reactions, including epistaxis (4%) and subarachnoid hemorrhage (2%), occurred in ≥2% of 106 patients who received caplacizumab treatment.⁴

Contraindications

Caplacizumab is contraindicated in patients with a history of severe hypersensitivity reaction (ie, urticaria) to caplacizumab or to any of its excipients.⁴

Drug Interactions

The concomitant use of caplacizumab with any anticoagulant is associated with an increased risk for bleeding. Patients should be assessed and monitored closely for bleeding if caplacizumab and an anticoagulant are used concomitantly.⁴

Use in Specific Populations

Data are not available regarding the use of caplaciz­umab in pregnant women; however, caplacizumab is associated with an increased risk for hemorrhage in the mother and fetus. Pregnant women receiving caplaciz­umab should be monitored for excessive bleeding.⁴

Data are not available on the presence of caplacizu­mab in human milk, or its effects on the breastfed child or on milk production. The developmental benefits of breastfeeding and the mother’s need for caplacizumab should be weighed against the potential adverse effects of caplacizumab on the breastfed child or from the mother’s underlying condition.⁴

Data about the use of caplacizumab in patients aged ≥65 years are not sufficient to establish whether older people respond differently than younger patients.⁴

The use of caplacizumab in patients with severe acute or chronic hepatic impairment has not been formally studied. Such patients should be closely monitored for the potential increased risk for bleeding caused by caplacizumab.⁴

Warnings and Precautions

Patients receiving caplacizumab have an increased risk for bleeding. This risk is increased in patients with underlying coagulopathies. Bleeding events occurred in approximately 58% of patients who received caplaciz­umab versus 43% of patients receiving placebo. If clinically significant bleeding occurs, caplacizumab should be interrupted.⁴

Caplacizumab should be withheld 7 days before elective surgery, dental procedures, or other invasive intervention. If the patient requires emergency surgery, the use of von Willebrand factor concentrate may be considered to correct hemostasis. Once the risk for bleeding has resolved and caplacizumab treatment is reintroduced, the patient should be monitored closely for signs of bleeding.⁴

Conclusion

Caplacizumab—a targeted therapy that blocks the formation of blood clots—became the first targeted medicine to receive FDA approval for the treatment, in combination with plasma exchange and immunosuppressive therapy, of adults with acquired TTP. In the HERCULES study that led to the FDA approval, patients who received caplacizumab treatment achieved a significantly faster improvement in platelet counts compared with patients receiving placebo. Moreover, fewer patients in the caplacizumab group had a TTP-related death or recurrence during the treatment period. The number of patients with at least 1 treatment-emergent major thrombotic event was similar between the 2 groups. ­Caplacizumab represents a new treatment option for patients with acquired TTP that may reduce mortality or disease recurrence.

References

1. National Institutes of Health. Thrombotic thrombocytopenic purpura. www.nhlbi.nih.gov/health-topics/thrombotic-thrombocytopenic-purpura. Accessed May 14, 2019.
2. Scully M, Cataland SR, Peyvandi F, et al; for the HERCULES investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380:335-346.
3. US Food and Drug Administration. FDA approves first therapy for the treatment of adult patients with a rare blood clotting disorder. February 6, 2019. www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-treatment-adult-patients-rare-blood-clotting-disorder. Accessed May 10, 2019.
4. Cablivi (caplacizumab-yhdp) for injection, for intravenous or subcutaneous use [prescribing information]. Cambridge, MA: Ablynx N.V.; February 2019.