Section Vii Trends And Perspectives

Editor : Annette M. Doherty Pfizer Global Research & Development

Chapter 33 . To Market, To Market - 2002

Cécile Boyer-Joubert, Edwige Lorthiois and François Moreau Pfizer Global Research & Development Fresnes, France

A significant increase in the number of new therapeutic chemical and biological entities was observed in 2002 compared to 2001 (33 vs 25) (1-6). From the 31 NCEs and 2 NBEs launched on the market last year, the US market saw 17 new entities introduced, the Japanese market 8 and the European only 6. These drugs originated for the most part from Europe (13) mostly from UK (8), followed by the US (11) and Japan (9). Astra Zeneca discovered the highest number of products in 2002 with a total of 4 new entities, followed by Pharmacia and Glaxo-Smithkline with 3 compounds discovered, and Merck & Co and Ono Pharmaceuticals (2 compounds). Finally, Novartis and Pfizer were at the origin of 1 new molecular entity and marketed or co-marketed 2 substances.

With 8 new launches, antiinfectives were the most active therapeutic area. Three quinolones, Q-Roxln® (balofloxacin), Pasil® (pazufloxacin) and Sword® (prulifloxacin) were launched for the treatment of urinary tract or bacterial infections.Two new 1-p-methyl carbapenems with broad spectrum antimicrobial activity reached the market, Omegacin® (biapenem) and Invanz® (ertapenem sodium). Funguard® (micafungin), the second member of the echinocandin class, and Vfend® (voriconazole) are two new agents introduced for the treatment of fungal infections caused by Aspergillus and Candida spp. Hepsera® (adefovir dipivoxil) is the first nucleotide analog to be launched against hepatitis B virus infections.

The anticancer field was also well represented with 5 new drugs launched. Calsed® (amrubicin hydrochloride) is a completely synthetic anthracycline derivative launched for the treatment of small-cell and non-small-cell lung cancer (NSCLC). Iressa® (gefitinib) was introduced for the treatment of NSCLC. The first "pure" steroidal estrogen antagonist, Faslodex® (fulvestrant), was marketed for the treatment of breast cancer in postmenopausal women with disease progression following estrogen therapy. Foscan® (temoporphin), a second generation photosensitizer, was launched for the photodynamic therapy of advanced head and neck cancers. Finally, Zevalin™, the first radiolabeled antibody, was launched for the treatment of non-Hodgin lymphomas.

In the cardiovascular area, 4 drugs were introduced: Arixtra® (fondaparinux sodium), a synthetic copy of the heparin pentasaccharide sequence, for the prophylaxis of deep vein thrombosis following major orthopaedic surgery, Onoact® (landiolol), an ultra-short acting |31-adrenergic blocker, for the treatment of tachyarrhythmia during surgery, Benicar® (olmesartan medoxomil), for the treatment of hypertension and Remodulin® (treprostinil sodium), a prostacyclin mimetic for the treatment of pulmonary hypertension.

In the field of allergic and respiratory diseases, 3 NCEs were marketed. Elidel® (pimecrolimus) was introduced for the treatment of atopic dermatis in patients for whom conventionals therapies are inadvisable. Elaspol® (sivelestat), a neutrophil elastase inhibitor was launched for the treatment of acute lung injury associated with systemic


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inflammatory response syndrome. Finally, Spiriva® (tiotropium bromide), an antimuscarinic agent was developed for the treatment of chronic obstructive pulmonary disorder.

In the CNS area, Ability® (aripiprazole), a partial dopamine D2 agonist which has a new mechanism of action compared to typical and atypical antipsychotic, was launched for the treatment of psychoses including schizophrenia. Focalin® (dexmethylphenidate hydrochloride), the eutomer of Ritalin® was marketed for the treatment of attention deficit hyperactivity disorder in children. Cipralex® (escitalopram oxalate), the S-enantiomer of citalopram, was introduced for the treatment of depression and panic disorders.

The antiinflammatory field was represented by 3 COX-2 inhibitors: Arcoxia® (etoricoxib), launched for the treatment of osteoarthritis, rheumatoid arthritis, dysmenorrhoea, gout, ankylosing spondylitis and pain; Bextra® (valdecoxib) for the treatment of osteoarthritis, rheumatoid arthritis and menstrual pain and Dynastat® (parecoxib), an amide prodrug of valdecoxib, marketed as an antiinflammatory agent for the management of acute pain.

In the area of metabolism regulators, 2 NCEs appeared on the market. Ezetrol® (ezetimibe), a new lipid-altering drug with a novel mechanism of action, was launched as a hypolipaemic agent. Nerixia® (neridronic acid), a second generation bisphosphonate, was introduced for the treatment of the "orphan disease"; osteogenesis imperfecta.

Frova® (frovatriptan), a long-acting antimigraine drug, is the eighth member of the triptan class. Ortho Evra® (norelgestromin) is the first transdermal patch to be launched as a female contraceptive. Orfadin® (nitisinone), an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, was marketed for the treatment of hereditary tyrosinaemia type I. Avodart® (dutasteride), a dual type 1 and type 2 5a-reductase inhibitor, was introduced for the symptomatic treatment of benign prostatic hyperalgesia.

Finally, 3 additional biological entities were launched in 2002 but they are not considered as NBEs:

  • new formulation of already existing products such as pegfilgrastim from Amgen (Neulasta™, a pegylated form of recombinant human GCSF with prolonged half-life for the treatment of chemotherapy-induced neutropenia in patients with thoracic tumors and breast cancers);
  • existing products launched for new indications such as teriparatide from Eli Lilly (Forsteo®, a synthetic peptide of parathyroid hormone launched for the treatment of postmenopausal osteoporosis) and porcine secretin from Repligen (SecreFlo™, a synthetic peptide of porcine secretin hormone launched as diagnostic agent for the prevention of ERCP-induced pancreatitis).

Adefovir dipivoxil (Antiviral) (7-10)

Country of Origin : Originator :

Czech Republic, Belgium Institute of Organic Chemistry and Biochemistry of the Academy of Sciences in the Czech Republic and the REGA Stichting Research Institute

First Introduction : US Introduced by: Gilead Trade Name: Hepsera CAS Registry No.: 142340-99-6 Molecular Weight: 501.48

Adefovir dipivoxil is the first nucleotide analog to be launched in the US as an oral treatment for hepatitis B virus (HBV) infections. It can be easily prepared in 4 steps from adenine. Adefovir dipivoxil acts as a bioavailable ester prodrug which is rapidly hydrolyzed to free adefovir and further anabolized to its active form, adefovir diphosphate, by two intracellular phosphorylation steps. The diphosphate competitively inhibits reverse transcriptase and/or causes chain termination when incorporated into growing DNA. Adefovir dipivoxil has a broad antiviral spectrum against retro-, herpes- and hepadnaviruses. The drug inhibits HBV replication, decreases HBV DNA levels and improves liver histology of patients infected with HBV wild type and resistant to other antivirals such as lamivudine. It also demonstrated activity in hepatitis B"e" antigen-negative, or precore mutant, patients and in patients co-infected with HIV. To date, no adefovir dipivoxil-associated resistance mutations have been identified in patients up to 136 weeks with the drug. The oral bioavailability of adefovir after oral administration of its dipivoxil prodrug is approximately 30%. It is mainly excreted unchanged in the urine and its plasma elimination half-life is 4.2 h. However, a long intracellular half-life (17 h) of the active bisphosphorylated metabolite enables once-daily dosing. The most prominent adverse effect of adefovir dipivoxil is nephrotoxicity (which has prevented the drug from being marketed for HIV infections where the drug required administration at higher doses).

Amrubicin hydrochloride (antineoplastic) (11-14)

Country of Origin : Japan

Originator: Sumitomo

First Introduction : Japan

Introduced by: Sumitomo

Trade Name: Calsed

CAS Registry No. : 92395-36-5

Molecular Weight: 519.13

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