FDA Supplemental Indication Approvals: KALYDECO, KEYTRUDA – Drug and Device Digest

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FDA News: Week of May 15, 2017

FDA approved

KALYDECO (ivacaftor) tablets, oral granules

Vertex Pharmaceuticals

SUPPLEMENTAL INDICATION: Treatment of cystic fibrosis (CF) in patients age 2 years and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

ADDRESSING UNMET NEED:

  • CF affects cells that produce mucus, sweat and digestive juices; rare disease that affects about 30,000 people in US
  • Expanded indication triples the number of rare gene mutations that the drug can now treat
  • Many rare mutations have small patient populations precluding clinical trials
  • Alternative approach, based on precision medicine, to identify certain gene mutations that are likely to respond to Kalydeco

REG PATHWAY: sNDA

  • Approval based, in part, on the results of laboratory testing, used in conjunction with evidence from earlier human clinical trials
  • Pathway for adding additional rare mutations of the disease based on laboratory data
  • Serves as an example of how successful patient-focused drug development can provide greater understanding about disease
  • Cystic Fibrosis Foundation maintains 28,000-patient registry, including genetic data, for research

EFFICACY:

  • Evidence from laboratory-based in vitro assay data
  • Previous approval covered 10 different mutations; efficacy against 23 additional mutations based on stringent criteria
  • Good understanding of the disease, thorough knowledge of clinical aspects of disease, data on thousands of CF patients and their mutations
  • Existing large efficacy and safety database, well-established risk/benefit profile
  • Solid understanding of the drug’s mechanism of action
  • In vitro data also able to identify types of CFTR mutations  NOT responsive to drug

SAFETY:

  • Common side effects: Headache; upper respiratory tract infection,  abdominal pain; diarrhea; rash; nausea; and dizziness.
  • Risks: Elevated transaminases, pediatric cataracts

LABEL

Image result for keytruda IMAGE

KEYTRUDA (pembrolizumab) injection

Merck

SUPPLEMENTAL INDICATIONS:

  • Treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy
  • Treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

REG PATHWAY: sNDA, Priority Review, Breakthrough Designation

  • Regular approval for locally advanced or metastatic urothelial carcinoma with progression during or following platinum-containing chemotherapy
  • Accelerated approval for locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy
  • Accelerated approval based on tumor response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials

EFFICACY:

Previously Treated Urothelial Carcinoma: Multicenter, randomized, active-controlled trial, n=270, patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy; KEYTRUDA vs. investigator’s chemotherapy choice

  • Major efficacy outcomes: Overall survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) assessed by BICR per RECIST 1.1
  • Median OS: 10.3 vs. 7.4 months (p=0.004)
  •  ORR:  21% vs. 11%, (p=0.002)
  • No statistically significant difference in PFF

Cisplatin Ineligible Patients with Urothelial Carcinoma: Multicenter, open-label, single-arm trial, n=370, patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy

  • Major efficacy outcome measures: ORR according to RECIST 1.1, Duration of Response (DOR)
  • ORR: 28.6% (95% CI 24, 34), median DOR not reached (range 1.4+, 17.8+ months)

SAFETY:

  • Most common adverse reactions: Fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash
  • Serious adverse reactions: Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, and endocrinopathies

LABEL

Image credits: Vertex, Google

Published by Drug & Device Advisory Group

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