News from the FDA Approvals through June 2003 Pharmacophilic minutes News from the FDA Approvals through June 2003

Emend (aprepitant) March 26, 2003 Approved for use in combination with other anti-nausea and anti-vomiting drugs for delayed N&V associated with initial and repeat courses of chemotherapy. Novel site of action: NK1 receptor PK: Expected interactions with warfarin (CYP2C9) and OC. Metabolized by CYP3A4 (main) and CYP1A2 (minor) Studies: 2 trials with > 1000 patients Manufactured by Merck Website: http://www.emend.com . MECHANISM OF ACTION 1. Aprepitant is a neurokinin-1 (NK-1)-receptor antagonist (substance P antagonist) under investigation primarily for use in chemotherapy-induced nausea and vomiting (Sorbera et al, 2002; Bleiberg, 2000; Campos et al, 2001). Substance P is a tachykinin (neurokinin) located in neurons of the central and peripheral nervous system; it is associated with a variety of functions, including emesis, depression, pain after inflammation, and inflammatory/immune responses in asthma and other diseases (Bleiberg, 2000; Diemunsch & Grelot, 2000; Lieb et al, 2002; De Vane, 2001). Effects of substance P are mediated via the NK-1 receptor, a G-protein receptor coupled to the inositol phosphate signal pathway (antagonism of this receptor has thus been investigated as mechanism to treat conditions considered to be mediated at least in part by substance P. 2. Aprepitant exhibits high selectivity and affinity for the human NK-1 receptor. Clinically, it has been given orally (tablet) or intravenously in the form of a water-soluble N-phosphorylated prodrug 3. Aprepitant has controlled both acute and delayed emesis induced by cisplatin in ferrets B. REVIEW ARTICLES 1. Therapy of nausea and vomiting, including NK-1 antagonists (Ladabaum & Hasler, 1999). 2. Reviews of NK-1-receptor antagonists, including aprepitant (Bleiberg, 2000; Rittenberg, 2002). 3. Synthesis, pharmacology, and clinical use of aprepitant (Sorbera et al, 2002). 4. Use of NK-1 antagonists in depression (Krishnan, 2002). 5. Mechanisms of emesis and antiemetic agents (Hornby, 2001).

West Nile ELISA test July 9, 2003 Test approved as aid in diagnosis of WNV in patients with clinical symptoms consistent with viral encephalitis/meningitis. Sensitivity 90 - 99% Specific testing needed for confirmation.

Cypher (sirolimus-eluting coronary stent) April 24, 2003 Approved for angioplasty procedures to open clogged coronary arteries. Review based on laboratory and animal tests and 2 clinical trials. SIRIUS Study (US Study) N = 1058, Cypher vs uncoated stent At 9-months treated group with less repeat procedures: 4.2 vs 16.8% Lower restenosis 8.9 vs 36.3% Combined endpoints 8.8 vs 21% RAVEL Study (outside US) Cordis (J&J) Website: http://www.cypherusa.com

Prilosec OTC June 20, 2003 Approved for “frequent heartburn”. Formulation: 20 mg delayed release Taken before meals once daily for 14 days Labeled for a single 2-week course not more often than every 4 months. Drug interactions to discuss with patients: Based on interaction with CYP2C19 and CYP3A4 Warfarin, chlorazepate, quinolone antibiotics, ketoconazole, propranolol, quinidine, ticlopidine, phenytoin, methotrexate. Consumer website: http://www.priloseconline.com/

Fabrazyme (agalsidase beta) April 24, 2003 Approved for treatment of Fabry Disease Orphan drug Deficiency in alpha-galactosidase A Agalsidase is human form of enzyme produced by recombinant DNA technology Approval under accelerated mechanism based on blood vessel biopsies of treated patients Genzyme Co. www.genzyme.com Administered IV 1mg/kg every 2 weeks Infusion reactions are frequent and can be severe. Replagal is alpha-galactosidase A by Transkaryotic Therapies Inc

Agalsidase alpha Compare: use Micromedex Micromedex on THR or Caregate

Iressa (genfitinib) May 5, 2003 Approved as single agent treatment for advanced NSCLC Accelerated approval Mechanism of action not known Developed to block stimulatory signals in cancer cells mediated by tyrosine kinase including EGFR Large studies showed no benefit Subset analysis suggested selected benefit. “Third-line” drug for patients with no other options Studies are on-going. AstraZeneca Website: http://www.iressa-us.com/

Velcade (bortezomib) May 13, 2003 Approved for treatment of multiple myeloma under accelerated approval protocol. Approved for patients who relapse after 2 prior treatments or are resistant to last treatment. Study: 202 patients (188 evaluated). 28% response rate. Smaller study with similar results (54) ADE: Nausea, fatigue, diarrhea, headache, neutropenia, anemia, fever, peripheral neuropathy.

Boronic acid dipeptide Velcade, cont. Marketed by Millennium Pharmaceuticals Millineum pharmaceuticals website Boronic acid dipeptide

Specific/selective inhibitor of 26S proteasome Bortezomib, cont’d. Specific/selective inhibitor of 26S proteasome Multicatalytic protease in all eukaryotic cells Degrades proteins that have been conjugated to ubiquitin Major mechanism for orderly intracellular protein degradation (80%) regulatory proteins: cellular integrity, cell-cycle control, cellular apoptosis, transcription factor activation, and tumor growth Exerts a dysregulating effect on these regulatory proteins, resulting in disruption of cell proliferation and apoptosis.

FluMist (influenza virus vaccine, live) June 17, 2003 First nasally administered vaccine in US First live influenza virus vaccine approved in US Study: 20,228 patients including 10,000 children. Efficacy of 87% (pediatric) For patients > 50 yo the “safety and efficacy has not been established”. Not for use in people with chronic underlying conditions that may predispose them to severe flu. Use injected vaccine. Made by Medimmune Website http://www.medimmune.com/