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                Resources for Information | Approved Drugs

Resources for Information | Approved Drugs

                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
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          FDA D.I.S.C.O.: FDA approval of Cablivi for acquired thrombotic thrombocytopenic purpuraResources for Information | Approved Drugs FDA D.I.S.C.O.: FDA approval of Cablivi for acquired thrombotic thrombocytopenic purpura
  
  	
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*FDA medical oncologists discuss the February 6, 2019, approval of caplacizumab-yhdp for acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.*

Dr. Abhi Nair: Welcome back to the DISCO, FDA’s Drug Information Soundcast in Clinical Oncology from the Oncology Center of Excellence. We are based in Silver Spring, MD and during our soundcasts, we discuss recent FDA approvals of cancer drugs and therapies. We hope this information will help you in better understanding these approvals and how new drugs and therapies are benefitting patients. Today, we’ll be discussing the recent approval of caplacizumab-yhdp, marketed as Cablivi, indicated for adult patients with acquired thrombotic thrombocytopenic purpura, or aTTP, in combination with plasma exchange and immunosuppressive therapy.

I’m Dr. Abhi Nair, a medical oncologist at FDA, and I am joined by my colleague Dr. Sanjeeve Bala, also a medical oncologist and clinical team leader at the Oncology Center of Excellence here at the FDA.

Dr. Sanjeeve Bala: Hi everyone. Thanks for joining us. We’ve gotten some emails and tweets, so thanks your interest in the DISCO. Please keep them coming and let us know what else you’d like to hear about from the OCE.

SB: Acquired thrombotic thrombocytopenic purpura or aTTP is a rare disease with an incidence of about three cases per million adults per year. aTTP is a thrombotic microangiopathy, a disease of excessive clotting in small vessels. It’s caused by inhibitory autoantibodies against ADAMTS13, a protease that cleaves von Willebrand factor. When von Willebrand factor isn’t cleaved, aberrant coagulation produces small-vessel platelet-rich thrombi that cause consumptive thrombocytopenia, microangiopathic hemolytic anemia, bleeding, and end organ damage.

AN: Sanjeeve, what has been the standard of care for patients with aTTP?

SB: Abhi, until now there were no FDA approved drugs for the treatment of aTTP. In clinical practice, the treatment for aTTP includes daily plasma exchange therapy until the patient’s platelet counts have returned to baseline and there is no further evidence of microangiopathic hemolytic anemia and end organ damage. For patients who don’t respond to daily plasma exchange, or for those whose initial disease presentation is considered severe, that is, when ADAMTS13 activity levels remain below 10%, corticosteroids are generally added to the daily plasma exchange.

AN: Other treatments have included off-label use of rituximab, and sometimes, additional immunosuppressive agents such as cyclophosphamide, vincristine, or cyclosporine. A high proportion of patients, anywhere from15‐20%, have a recurrence of the disease when plasma exchange is stopped.

SB: Caplacizumab is an injectable humanized bivalent anti‐von Willebrand Factor (vWF) antibody fragment that consists of two identical building blocks, linked by three alanine residues. Caplacizumab is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy.

AN: It’s administered as an 11 mg intravenous infusion prior to the first plasma exchange, and then an 11 mg subcutaneous dose after each daily plasma exchange and for 30 days after the plasma exchange period has been completed.

SB: If after the initial treatment course, signs of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 additional days. Caplacizumab received regular approval for this indication. The drug also received orphan drug designation and fast track designation from FDA. Abhi, tell us about the trial design.

AN: Sure, Sanjeeve. Caplacizumab was evaluated in the HERCULES trial, a double-blind trial in 145 patients with aTTP who were treated with a single caplacizumab 11 mg bolus intravenous injection or placebo prior to the first plasma exchange. This was followed by caplacizumab 11mg administered daily subcutaneously or placebo after completion of plasma exchange, for the duration of the plasma exchange period and for 30 days thereafter. 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.

SB: So, Abhi, patients in both groups received plasma exchange and immunosuppressive therapy.

AN: That’s right Sanjeeve. Patients were stratified according to the severity of neurological involvement (Glasgow Coma Scale score ≤12 or 13 to 15). Patients with sepsis, infection with E. coli 0157, atypical hemolytic uremic syndrome, disseminated intravascular coagulation, or congenital thrombotic thrombocytopenic purpura were not eligible for enrollment.

SB: What were the endpoints used for this approval?

AN: The primary endpoint of the study was time to platelet response, defined by platelet count ≥150,000/μL and cessation of daily plasma exchange within 5 days of satisfying the platelet threshold. A key secondary endpoint was a composite of the proportion of patients with aTTP‐related death, recurrence of aTTP, or at least one‐treatment-emergent major thromboembolic event. The median time to platelet count response was 2.7 days in the caplacizumab treatment group compared to 2.9 days in the placebo treatment group.

SB: But, Abhi, I’m sure our listeners are thinking to themselves that the platelet response numbers really don’t seem like much of a difference.

AN: Possibly, but the important thing to note here is that a response in platelet count is only one characteristic of a response of aTTP to treatment. More importantly, if you look at the composite endpoint of patients with aTTP‐related death, recurrence of aTTP or at least one treatment-emergent major thromboembolic event, this endpoint was significantly lower in the caplacizumab treatment arm compared to the placebo arm: 13% in the caplacizumab group compared to 49% in the placebo group, and this difference was statistically significant. Also, the proportion of patients with a recurrence of aTTP in the overall study period was significantly lower in the caplacizumab group—13%—compared to the placebo group at 38%, again a statistically significant and clinically meaningful difference.

SB: Those are significant efficacy findings. Let’s look at the safety of this new drug. What were the main safety signals observed?

AN: The safety of caplacizumab was evaluated among 106 patients with aTTP who received at least one dose of caplacizumab in the HERCULES trial or in the supportive phase 2 TITAN trial. The most frequently reported adverse events (>15% incidence) were epistaxis, headache, and gingival bleeding. Seven patients (7%) who received caplacizumab had an adverse reaction leading to study drug discontinuation. None of the adverse reactions leading to discontinuation were reported in more than 1% of patients. Overall, bleeding adverse events were reported in 59% patients in the caplacizumab treatment arm and 43% patients in the placebo arm. Serious bleeding adverse reactions included epistaxis in 4% of patients and subarachnoid hemorrhage in 2% of patients. Sanjeeve, the prescribing information for caplacizumab includes a warning to advise health care providers and patients about the risk of severe bleeding.

SB: Abhi, it’s interesting that although caplacizumab acts in aTTP by improving platelet counts, it also increases the risk of bleeding, likely due to its mechanism of action of interfering with von Willebrand Factor and platelet adhesion. For our listeners, detailed safety information is available in the product label.

SB: Abhi, please give us the three take-aways for this D.I.S.C.O.

AN: All right. 1) Caplacizumab is the first FDA approval for a drug specifically indicated for the treatment of adult patients with aTTP, in combination with plasma exchange and immunosuppressive therapy. 2) The dosing of caplacizumab follows a complex schedule and prescribers should refer to the prescribing information for details. 3) Serious adverse reactions reported with its use include epistaxis and subarachnoid hemorrhage.

You can find more detailed prescribing and safety information in the approved prescribing information, also available on the web at drugs@fda.

For a transcript of this Soundcast, visit the FDA Oncology Center of Excellence D.I.S.C.O. website at www.fda.gov/DISCO. The FDA analysis and review were conducted by a multidisciplinary team of FDA experts. More information can be found on the FDA website.

SB: Thank you Abhi. Are there other FDA oncology drug approvals that you would like to hear about? Leave us your questions and comments on Twitter @FDAOncology and as always, we welcome your feedback at our email address, FDAOncology@fda.hhs.gov. I’m Sanjeeve Bala. Thanks for tuning in to D.I.S.C.O. today.

AN: And until next time at the D.I.S.C.O., I’m Abhi Nair.

Acknowledgements
This Drug Information Soundcast in Clinical Oncology was developed by Sanjeeve Bala, Abhilasha Nair, Andrew Dmytrijuk, Kathy Robie Suh, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.

                                                                                  Content current as of:
      04/12/2019Resources for Information | Approved Drugs

          
                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
          Ongoing | Cancer Accelerated Approvals
          Verified Clinical Benefit | Cancer Accelerated Approvals
          Withdrawn | Cancer Accelerated Approvals
          Other | Cancer Accelerated Approvals


                        Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description
 
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