FDA Approvals: BRINEURA, ROXYBOND, RYDAPT, STIVARGA, – Drug and Device Digest

FDA BRIEF: week of April 24, 2017

FDA approved

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BRINEURA (cerliponase alfa) injection, for intraventricular use

BioMarin Pharmaceutical Inc., Novato, CA

INDICATION:  To slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency


  • CLN2 disease is rare (2-4/100,000 live births) inherited disorder primarily affecting nervous system affecting essential motor skills
  • Individuals require wheelchair use by late childhood and typically do not survive past teenage
  • First drug for the treatment of this form of Batten disease


  • Priority Review, Breakthrough Therapy designation, Orphan Drug Designation,Rare Pediatric Disease Priority Review Voucher
  • Post-marketing Requirements: Observational post approval safety study to evaluate the long-term safety,  sensitive cellular uptake assay  to evaluate neutralizing capacity of anti-drug antibodies,  immunogenicity study

MECHANISM OF ACTION:  Enzyme replacement therapy. Active ingredient, cerliponase alfa, is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease.


  • Non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with CLN2 disease, confirmed by TPP1 deficiency, 96 weeks, n=24, BRINEURA vs. natural history cohort
  • Primary endpoint: Motor domain of a CLN2 Clinical Rating Scale to assess disease progression; Scores from 3 (grossly normal) to 0 (profoundly impaired)
  • Descriptive Comparison: 21 (95%) did not decline vs 42 (50%) in natural history cohort
  • Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype:  Lesser decrease in motor function in treated patients


  • Most common adverse reactions: Fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure
  • Not to be administered if signs of acute intraventricular access device-related complications
  • Routinely test patient CSF samples to detect device infections


sidebar imageROXYBOND (oxycodone hydrochloride) tablets

Inspirion Delivery Sciences, KS, USA

INDICATION: For the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate

  • Limitations of Use:  Because of the risks of addiction, abuse, and misuse with opioids, reserve for use in patients for whom alternative treatment options have not been tolerated, have not provided adequate analgesia


  • First immediate-release opioid analgesic approved with labeling describing its abuse-deterrent properties consistent with the FDA’s Guidance


  • Schedule II
  • Post-marketing Requirements: Toxicology studies, Abuse and related clinical outcomes,  Formal observational studies to assess whether use result in a meaningful decrease in misuse and abuse, consequences, addiction overdose, death

MECHANISM OF ACTION: Full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses

  • Has physicochemical properties expected to make abuse via injection difficult – forms viscous gel when in contact with liquid
  • Not expected to deter oral abuse


  • Evaluate ability of abuse-deterrent technology to reduce abuse potential
  • In vitro laboratory manipulation, extraction, and syringeability studies; In vivo intranasal clinical abuse potential study
  • Human Abuse Potential Study: Randomized, double-blind, double-dummy, placebo-controlled, single-dose four-way crossover study, n=29, non-dependent recreational opioid users with history of intranasal drug abuse
  • Endpoint: Abuse potential of crushed intranasal ROXYBOND tablets vs. crushed intranasal oxycodone immediate release tablets
  • Drug liking and willing to take drug again measured on visual analog scale (VAS)
  • Statistically significantly lower drug liking and take drug again (Emax) scores with ROXYBOND

SAFETY: Boxed Warning for Addiction, Abuse and misuse, life threatening respiratory depression, accidental ingestion, neonatal opioid withdrawal syndrome, Cytochrome P450 interactions, risks from concomitant use with benzodiazepines or other CNS depressants.


RYDAPT (midostaurin) capsules

Novartis Pharmaceuticals, East Hanover, NJ, USA

LEUKOSTRAT CDx FLT3 Mutation Assay

Invivoscribe Technologies Inc., San Diego, CA, USA


  • Acute Myeloid Leukemia: In combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by FDA approved test (LeukoStrat CDx FLT3 Mutation Assay)
  • Systemic Mastocytosis: Treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL)


  • 19,930 people diagnosed with AML in 2016; 10,430 were projected to die of disease
  • First targeted therapy to treat patients with AML, in combination with chemotherapy
  • Ability to detect gene mutation with diagnostic test helps identification of specific patients who may benefit from treatment


  • Priority Review, Fast Track (for the mastocytosis indication) and Breakthrough Therapy (for the AML indication) designations
  • Post-marketing Requirements: Worldwide Pregnancy Surveillance Program

MECHANISM OF ACTION: Inhibits multiple receptor tyrosine kinases, FLT3 receptor signaling and cell proliferation, induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Can inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.


  • Randomized, double-blind placebo-controlled trial, n=717 patients with newly-diagnosed FLT3-mutated AML; RYDAPT RYDAPT  in combination with daunorubicin /cytarabine
  • Primary Endpoint: Overall Survival (OS), date of randomization until death by any cause;  Hazard Ratio 0.77; 95% CI 0.63, 0.95; 2 sided p=0.016
  • Single-arm, open-label, multicenter trial, n=116 in patients with ASM, SM-AHN, and MCL, RYDAPT as single agent
  • Primary Endpoint: Confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles
  • Confirmed major or partial responses: 46 of 73 patients with KIT D816V mutation, 7 of 16 with wild-type or unknown status, 21 of 32 having prior therapy for SM


  • Common side effects:  Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia and upper respiratory tract infection
  • Patients with pulmonary toxicity should stop treatment
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STIVARGA (regorafinib) tablets 

Bayer, Whippany, NJ, USA

SUPPLEMENTAL INDICATION: Treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

  • HCC originates in the liver and is the most common form of liver cancer
  • 40,710 people will be diagnosed; 28,920 will die
  • First FDA-approved treatment for a liver cancer in almost a decade

REG PATHWAY: Supplemental NDA

  • Priority Review, Orphan Drug Designation

MECHANISM OF ACTION:  Inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity


  • International, multicenter, randomized (2:1), doubleblind, n=760 patients with previously-treated metastatic colorectal cancer, STUVARAG vs placebo
  • Major efficacy outcome: Overall survival (OS); additional efficacy outcome measures included progression-free survival (PFS) and overall tumor response rate
  • Number of Deaths:  275 (55%) vs. 157 (62%), p=0.0102
  • Number of Deaths or Progressions: 417 (83%) vs. 231 (91%), p<0.0001
  • Common side effects: Pain, hand-foot skin reaction, fatigue, diarrhea, decreased appetite, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash and nausea
  • Serious risks: Hepatotoxicity, infections, hemorrhage, gastrointestinal perforation or fistula, dermatologic toxicity, hypertension, cardiac ischemia and infarction, reversible posterior leukoencephalopathy syndrome, wound healing complications


Photo Sources: Google, Novartis, Inspirion, Bayer


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