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OXBRYTA (voxelotor) tablets

Global Blood Therapeutics

INDICATION FOR USE: Treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older.

ADDRESSING UNMET NEED: Treatment option for 100,000 people in the U.S., and the more than 20 million globally, who live with this debilitating blood disorder

MECHANISM OF ACTION: Hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs) – increasing the affinity of Hb for oxygen

EFFICACY:

  • Randomized, double-blind, placebo-controlled, multicenter trial, n=274 patients with sickle cell disease, OXBRYTA vs. placebo
  • Endpoint: Hb response rate defined as a Hb increase of >1 g/dL from baseline to Week 24
  • 51.1% (OXBRYTA) vs. 6.5% (placebo),  (p < 0.001); no outlier subgroups observed

SAFETY:

  • Common side effects: Headache, diarrhea, abdominal pain, nausea, fatigue, rash and pyrexia

REGULATORY PATHWAY: NDA

  •  Accelerated Approval, Fast Track designation. Orphan Drug designation
  • Accelerated approval requirements: Phase 3, randomized, doubleblind, placebo-controlled trial in pediatric patients (age 2 years to < 15 years) with Sickle Cell Disease , long-term (5 years) followup

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ADAKVEO (crizanlizumab-tmca) injection

Novartis

INDICATION FOR USE: Reduce the frequency of vasoocclusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease.

ADDRESSING UNMET NEED: First targeted therapy approved for sickle cell disease, specifically inhibiting selectin, a substance that contributes to cells sticking together and leads to vaso-occlusive crisis- a painful condition

MECHANISM OF ACTION: Humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.

EFFICACY:

  • 52-week, randomized, multicenter, placebo-controlled, double-blind study, n=198 patients with sickle cell disease, any genotype, ADAKVEO vs placebo
  • Endpoint: Annual rate of vaso-occlusive crisis (VOC) to a healthcare visit
  • Median annual rate of 1.63 visits (ADAKVEO) vs. 2.98 visits (placebo)
  • 36%  on Adakveo did not experience VOC during the study, delayed the time of first VOC experience

SAFETY:

  • Common side effects: Back pain, nausea, pyrexia, arthralgia
  • Need to monitor patients for infusion-related reactions,  interference with automated platelet counts or platelet clumping

REGULATORY PATHWAY: BLA

  •  Priority Review and Breakthrough Therapy designation, Orphan Drug designation
  • Postapproval requirements: Further evaluation of immune mediated safety

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XCOPRI® (cenobamate tablets)

SK Lifesciences

INDICATION FOR USE: Treatment of partial-onset seizures in adult patients

ADDRESSING UNMET NEED: New option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life

MECHANISM OF ACTION: Precise mechanism unknown; demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents

EFFICACY:

  • Two multicenter, randomized, double-blind, placebo-controlled studies, N=655 adult patients
  • Endpoint: % change from baseline in seizure frequency per 28 days in the treatment period
  • 55.6%  reduction (XCOPRI 200 mg) vs 21.5% reduction (placebo), p< 0.0001

SAFETY:

  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),  shortening of the QT interval and ventricular fibrillation – dose needs to be titrated
  • Increased risk of suicidal thoughts or behavior and other neurological adverse reactions
  • Most common side effects: Somnolence (sleepiness), dizziness, fatigue, diplopia (double vision), headaches

REGULATORY PATHWAY: NDA

  • Contains cenobamate – (Controlled substance schedule to be determined after review by the Drug Enforcement Administration
  • Required pediatric assessments

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CaptureCapture.JPGCALQUENCE® (acalabrutinib) capsules

AstraZeneca

INDICATION FOR USE: treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

EFFICACY & SAFETY:

  • Two randomized, actively controlled trials in patients with CLL
  • Endpoint:  Progression-free survival (PFS) as assessed by independent review; significantly improved in both acalabrutinib arms, p<0.0001
  • Most common adverse reactions: Anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, diarrhea

REGULATORY PATHWAY: Supplemental NDA

  • First approved in 2017 
  • This review conducted under Project Orbis, framework for concurrent submission and review by FDA, the Australian Therapeutic Goods Administration, and Health Canada
  • FDA review used the Real-Time Oncology Review (RTOR) and Assessment Aid pilot programs, to sreamline data submission, Priority Review and Breakthrough Therapy designation

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CaptureGIVLAARI (givosiran) injection

Alnylam Pharmaceuticals

INDICATION FOR USE: Treatment of adults with acute hepatic porphyria (AHP)

MECHANISM OF ACTION: Double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes;  leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid
(ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP

EFFICACY: 

  • Randomized, double‑blind, placebo‑controlled, multinational trial, n=94 patients with AHP, GIVLAARI vs placebo
  • Endpoint: Rate of porphyria attacks requiring hospitalizations, urgent healthcare visit, or intravenous hemin administration at home
  • 1.9 (95% CI:1.3,2.8) with GIVLAARI vs, 6.5 (95% CI:4.5, 9.3) with placebo
  • 70% (95% CI: 60%, 80%) fewer porphyria attacks with GIVLAARI

SAFETY:

  • Most common adverse reactions: Nausea and injection site reactions
  • Warnings for anaphylactic reactions, hepatic and renal toxicities, and injection site reactions

REGULATORY PATHWAY: NDA

  • Priority Review, Orphan product, Breakthrough Therapy designations
  • Postmarketing commitments: Trial in pediatric patients age greater than or equal to 12 years to less than 17 years with AHP

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Image credit: Global Blood Therapeutics, Novartis, SK Lifesciences, AstraZeneca, Alnylam