FDA Approvals: KYMRIAH, MYLOTARG, VABOMERE, Benznidazole – Drug and Device Digest

FDA BRIEF: Week of August 28, 2017

FDA approved

CAR T Cell


KYMRIAH (tisagenlecleucel) suspension for intravenous infusion



INDICATION:  CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse


  • First gene therapy available in the US
  • New approach to treatment of cancer and other serious and life-threatening diseases
  • New treatment option where very limited options existed,  with promising remission and survival rates in clinical trials


  • Priority Review and Breakthrough Therapy designations
  • Coordinated, cross-agency approach
  • Clinical review : Oncology Center of Excellence
  • All other review aspects and final product approval determination: CBER

MECHANISM OF ACTION:  CD19-directed genetically modified autologous T cell immunotherapy which involves reprogramming patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. Upon binding to CD19-expressing cells, CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the KYMRIAH cells.


  • Open-label, multicenter single-arm trial, n=107, pediatric and young adults with R/R B-cell precursor ALL, lymphodepleting chemotherapy  followed by a single dose of KYMRIAH
  • Endpoints: Complete Remission (CR) within 3 mo., CR duration, proportion of patients with CR and minimal residual disease (MRD) <0.01% by flow cytometry (MRD-negative)


  • Boxed Warning: Cytokine release syndrome (CRS)  causing high fever and flu-like symptoms, and for neurological events
  • Severe side effects: Serious infections, hypotension, acute kidney injury, fever, hypoxia
  • Destruction of normal B cells that produce antibodies – increased risk of infections for a prolonged period of time



  • Modernization of current healthcare payment systems need to ensure access to new high-cost therapies
  • Innovative payment arrangements including outcome-based pricing in relation to clinical outcomes
  • Center for Medicare and Medicaid Innovation (CMMI)  to test payment and service delivery models on value-based payment arrangements
  • Issue guidance on sponsor engagement in innovative payment arrangements


Capture.JPGMYLOTARG (gemtuzumab ozogamicin) injection



  • Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML): Treatment of newly-diagnosed CD33-positive acute myeloid leukemia in adults
  • Relapsed or Refractory CD33-positive AML: Treatment of relapsed or refractory CD33-positive acute myeloid leukemia in adults and in pediatric patients 2 years and older


  • AML is rapidly progressing cancer, forms in bone marrow, results in increased white blood cell
  • ~21,380 diagnosed this year in US,  10,590 will die of disease
  • Importance of examining alternative dosing, scheduling, and administration of therapies

REG PATHWAY: BLA, Orphan Drug Designation

  • Accelerated Approval  in 2000 at higher dose for stand-alone treatment for older patients with CD33-positive AML who had experienced a relapse
  • Voluntary withdrawal in 2010 after confirmatory trial failed to show clinical benefit and higher rate of fatal toxicity
  • This approval includes a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population

MECHANISM OF ACTION: CD33-directed antibody-drug conjugate (ADC), small molecule  N-acetyl gamma calicheamicin, is a cytotoxic agent covalently attached to antibody. Activity due to binding of ADC to CD33-expressing tumor cells, internalization of ADC-CD33 complex, intracellular release of small molecule


  • Two, separate trials
  • First trial:  newly diagnosed AML, n=237,  MYLOTARG vs. best supportive care
  • Median Overall Survival: 4.9 months vs. 3.6 months
  • Second trial: Single-arm study,  CD33-positive AML, n=57,  single course of MYLOTARG
  • Complete Remission.  26% that lasted a median 11.6 months


  • Boxed Warning: Hepatotoxicity, veno-occlusive disease or sinusoidal obstruction syndrome
  • Severe side effects: Low blood counts, infections, liver damage, hepatic veno-occlusive disease, infusion-related reactions, hemorrhage
  • Common side effects: Pyrexia, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, neutropenia


Image result for vabomere logo

VABOMERE™ (meropenem and vaborbactam) for injection

Rempex Pharmaceuticals (The Medicines Company)

INDICATION: Treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex


  • Antibacterial product to treat serious or life-threatening infections
  • Additional treatment option for patients with cUTI

REG PATHWAY: NDA, Priority Review

  • Designated as a qualified infectious disease product (QIDP) under Generating Antibiotic Incentives Now (GAIN)
  • Postmarketing Requirements/Commitments:   Surveillance study for drug resistance, extractable/leachable studies

MECHANISM OF ACTION: Penem antibacterial drug that inhibits cell wall synthesis in most gram-positive and gram-negative bacteria


  • Double-blind, double dummy, multi-center trial,  N=545 adults with cUTI, including pyelonephritis, VABOMERE vs.  piperacillin/tazobactam
  • Clinical and microbiological response at the end of IV treatment (EOIVT): Clinical outcome of cure or improvement + microbiologic outcome of eradication
  • Clinical and microbiological response at Test of Cure (TOC) visit at 7 d
  • Cure/improvement in symptoms + negative urine culture test: 98% vs 94%
  • TOC with resolved symptoms + negative urine culture: 77% vs 73%


  • Most common adverse reactions: Headache, infusion site reactions and diarrhea
  • Serious risks : Allergic reactions,  seizures


Image result for chagas disease

BENZNIDAZOLE tablets, for oral use

Exeltis USA

INDICATION:   Indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi


  • First approved treatment approved in US
  • There may be ~  300,000 US patients
  • Granted tropical disease priority review voucher under section 524 of FDCA
  • Voucher entitles designation of a human drug/biologic application as qualifying for a priority review
  • Accelerated Approval: Based on negative Immunoglobulin G (IgG) antibody  test
  • Accelerated Approval Requirement:  Prospective, single-arm, multicenter trial, with historical controls, to evaluate safety, efficacy and pharmacokinetics in children
  • Postmarketing Requirements: ADME study, Fertility toxicity study

MECHANISM OF ACTION: Inhibits synthesis of DNA, RNA, and proteins within parasite


  • Two adequate and well-controlled trials
  • Trial 1 (Argentina): Randomized, double-blind, placebo-controlled trial, children 6-12 yr with chronic indeterminate Chagas disease, n=106, benznidazole vs placebo, followed for 4 years
  • Trial 2 (Brazil): Randomized, double-blind, placebo-controlled trial, children 7 -12 yr with chronic indeterminate Chagas disease, n=129, benznidazole vs placebo
  • Endpoint: Antibodies measured by conventional and nonconventional assays
  • Benznidazole treatment resulted in significantly higher percentage of seronegative patients: 55-60% vs  5-14%


  • Most common adverse reactions: Stomach pain, rash, decreased weight, headache, nausea, vomiting, abnormal white blood cell count, urticaria, pruritus, decreased appetite
  • Serious risks: Serious skin reactions, nervous system effects and bone marrow depression
  • Based on animal findings: Could cause fetal harm when administered to pregnant woman


Image credits: FDA, CDC, Pfizer, Medicines Company

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