FDA BRIEF: Week of August 28, 2017

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KYMRIAH (tisagenlecleucel) suspension for intravenous infusion

Novartis

REGULATORY PATHWAY

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

ADDRESSING UNMET NEED:

• 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

REG PATHWAY: BLA

• 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.

EFFICACY:

• 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)

SAFETY:

• 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

PACKAGE INSERT

REIMBURSEMENT PATHWAY:

• 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

CMS ANNOUNCEMENT

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MYLOTARG (gemtuzumab ozogamicin) injection

Pfizer

INDICATION:

• 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

ADDRESSING UNMET NEED:

• 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

EFFICACY:

• 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

SAFETY:

• 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

LABEL

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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

ADDRESSING UNMET NEED:

• 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

EFFICACY:

• 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%

SAFETY:

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

LABEL

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• 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

EFFICACY:

• 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%

SAFETY:

• 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

LABEL

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Image credits: FDA, CDC, Pfizer, Medicines Company