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February 6, 2019, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761112s000lbl.pdf

On February 6, 2019, the Food and Drug Administration approved caplacizumab-yhdp (CABLIVI, Ablynx NV) for adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.

Approval was based on a multicenter, randomized, double-blind, placebo-controlled trial (HERCULES) (NCT02553317) that enrolled 145 patients randomized to caplacizumab-yhdp (n=72) or placebo (n=73). Patients in both groups received plasma exchange and immunosuppressive therapy. Patients received a single 11 mg caplacizumab-yhdp bolus intravenous injection or placebo prior to the first plasma exchange on trial, followed by a daily subcutaneous injection of caplacizumab-yhdp (11 mg) or placebo after completion of plasma exchange, for the duration of the daily plasma exchange period and for subsequent 30 days. If after the initial treatment course, signs of persistent underlying disease such as suppressed ADAMTS13 activity levels remained present, treatment was extended for 7-day intervals for a maximum of 28 days.

The efficacy of caplacizumab-yhdp was established based upon time-to-platelet count response (platelet count ≥150,000/µL followed by cessation of daily plasma exchange within 5 days). Time-to-platelet count response was faster among patients treated with caplacizumab-yhdp, compared to placebo. Treatment with caplacizumab-yhdp resulted in a lower number of patients with TTP-related deaths (0 vs. 3) and TTP recurrence (3 vs. 28) during the treatment period. The proportion of patients with a recurrence of TTP in the overall study period (the drug treatment period plus the 28-day follow-up period after drug treatment discontinuation) was lower in the caplacizumab-yhdp group (9/72 patients [13%]) compared to those receiving placebo (28/73 patients [38%]; p<0.001).

The most common adverse reactions in at least 15% of patients receiving caplacizumab-yhdp were epistaxis, headache, and gingival bleeding.

The recommended first dose of caplacizumab-yhdp is 11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by a 11 mg subcutaneous injection after completion of plasma exchange continuing daily for 30 days following the last plasma exchange. For additional dosing information, view the full prescribing information for CABLIVI.

FDA granted this application priority review and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Caplacizumab-yhdp for the Treatment of Acquired Thrombotic Thrombocytopenic Purpura

Author: Heather Morris, PharmD BCPS
PGY2 Oncology Pharmacy Resident
Duke University Hospital
Durham, NC

What is the potential role for caplacizumab-yhdp in the treatment of acquired thrombotic thrombocytopenic purpura?

  • Caplacizumab-yhdp is a first-in-class anti-von Willebrand factor (vWF) monoclonal antibody approved on February 6, 2019, for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and corticosteroids.1,2 Caplacizumab-yhdp inhibits the interaction between vWF and platelets to prevent thrombus formation.
  • In the randomized placebo-controlled phase 2 TITAN trial, caplacizumab-yhdp induced a faster resolution of acute TTP compared to placebo.3
  • Caplacizumab-yhdp was evaluated in the double-blind placebo-controlled randomized phase 3 HERCULES trial.4
    • This study enrolled 145 patients to receive either caplacizumab-yhdp (n = 72) or placebo (n = 73). Patients were given a 10-mg intravenous loading dose of caplacizumab-yhdp followed by 10 mg subcutaneously daily until 30 days after the last daily plasma exchange. In addition to caplacizumab-yhdp or placebo, patients received the standard-of-care treatment, defined as daily plasma exchange and glucocorticoids.
    • The primary outcome was time to platelet count normalization; secondary outcomes included TTP recurrence at any time during the trial or follow-up period, refractory TTP, normalization of organ-damage markers, and a composite endpoint of TTP-related death, recurrence of TTP, and major thromboembolic event occurrence during the trial treatment period.
    • The median time to normalization of platelet count was 2.69 days with caplacizumab-yhdp versus 2.88 days with placebo and was statistically significant (p = .01).
    • The composite of TTP-related death, recurrence of TTP, or a major thromboembolic event during the trial treatment period was lower with caplacizumab-yhdp compared to placebo (12% vs. 49%; p < .001). Recurrence of TTP in the combined drug treatment and follow-up period was lower with caplacizumab-yhdp compared to placebo (12% vs. 38%; < .001). There was no significant difference in the number of refractory TTP cases (0% vs. 4%; p = .06). The median time to normalization of organ-damage markers was 2.86 days with caplacizumab-yhdp and 3.36 days with placebo. The number of days of plasma exchange, volume of plasma exchanged, days of hospitalization, and days in the ICU were all lower with caplacizumab-yhdp compared to placebo.
    • The most common adverse event was mucocutaneous bleeding, which occurred in 65% of patients in the caplacizumab-yhdp group and in 48% in the placebo group. Serious bleeding occurred in 11% of patients in the caplacizumab-yhdp group and in 1% of patients in the placebo group. During the overall trial period, 96% of patients in the caplacizumab-yhdp group and 90% of patients in the placebo group had at least one adverse event. Serious adverse events (excluding those related to TTP) occurred in 32% of patients in the caplacizumab-yhdp group and in 16% in the placebo group. Adverse reactions occurring in more than 10% of patients in the caplacizumab-yhdp group included headache, fatigue, paresthesia, urticaria, gingival hemorrhage, bleeding complications, epistaxis, and fever.
    • A total of 4 patients died: 1 patient in the caplacizumab-yhdp group and 3 in the placebo group. All deaths were determined to be TTP-related.
    • Thirty-six patients who received at least one dose of caplacizumab-yhdp or placebo discontinued the trial regimen (13 in the caplacizumab-yhdp group and 23 in the placebo group). The most common reasons for discontinuation were adverse events, withdrawal of consent, and the physician’s decision. Five patients in the caplacizumab-yhdp group and 9 patients in the placebo group discontinued therapy because of an adverse event.
  • Expert reviews reference caplacizumab-yhdp as a new or alternative agent at this time.5

What role can the pharmacist play in the management of patients on caplacizumab-yhdp?2

  • On the first day of treatment, ensure that the first dose is given intravenously at least 15 minutes prior to plasma exchange and that the second dose is given subcutaneously after plasma exchange. Subsequent subcutaneous daily doses are given following plasma exchange and continue daily for 30 days beyond the last plasma exchange.
  • If treatment extension is required, the maximum extension is 28 days.
  • If clinically significant bleeding occurs, interrupt treatment. If rapid correction of hemostasis is required, vWF concentrate may be administered.
  • Withhold caplacizumab-yhdp for 7 days prior to elective surgery, dental procedures, or other invasive interventions.

Clinical Pearls2

  • The initial dose is administered by connecting the glass syringe to a standard luer lock; it can be flushed with either normal saline or 5% dextrose in water.
  • Administer subcutaneous doses into the abdomen. Avoid injections around the navel and rotate abdominal quadrants.
  • Contains polysorbate-80; monitor for hypersensitivity reactions.
  • Caplacizumab-yhdp will be provided at no cost to eligible underinsured or uninsured patients. In addition, support is available to cover the cost of caplacizumab-yhdp co-pay or co-insurance for qualified commercially insured patients.

References

  1. U.S. Food and Drug Administration: FDA approved caplacizumab-yhdp. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approved-caplacizumab-yhdp. Accessed May 4, 2019.
  2. Cablivi (caplacizumab-yhdp) [prescribing information]. Cambridge, MA: Genzyme Corp.; February 2019.
  3. Peyvandi F, Scully M, Kremer Hovinga JA, et al; TITAN Investigators. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016;374(6):511-522.
  4. Scully M, Cataland SR, Peyvandi F, et al; HERCULES Investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346.
  5. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846.
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