Artículo destacado

Drug News & Perspectives
Vol. 20, No. 1, 2007, pp. 17-44
ISSN 0214-0934
Copyright 2007 Prous Science, S.A.
CCC: 0214-0934/2007
http://www.prous.com

DRUGLINE

This year, 41 new products, including new chemical entities and biologics for therapeutic use as well as new diagnostic agents, reached their first markets in 2006.

The Year's New Drugs and Biologics-2006

by A.I. Graul, L.A. Sorbera, J. Bozzo, N. Serradell, L. Revel and J.R. Prous

Summary

This annual series presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2006, 41 new medicines—this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents and, for the first time this year, an important new herbal medicine—reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for more than 20 of the new medicines launched in 2006. This year’s edition of the article also includes several new features: a deeper insight into the five first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an analysis of the discovery and development periods for the year’s new products; a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines; and an analysis of the market for these new medicines. New generic drug approvals are also reviewed, as well as a brief glimpse at selected drugs and biologics which could reach their first markets in the foreseeable future. © 2007 Prous Science. All rights reserved.

Inaugurated 19 years ago, this annual series provides the opportunity to present from both a historical and a research perspective those molecular entities and biological drugs that were launched or approved in various countries for the first time during the past year.

Information on these drugs is provided to serve as a guide to the most recent developments in drug therapy, highlighting new-generation compounds with therapeutic gains over existing drugs and new therapeutic entities arising from innovative approaches to drug research.

According to our records, 41 new products-this figure includes new chemical entities and biologics for therapeutic use as well as new diagnostic agents-reached their first markets in 2006. Another nine new products were approved for the first time in 2006 but were not launched before year-end. Following a growing tendency in recent years, drug repositioning had a significant impact, with line extensions (new formulations, new indications and/or new combinations of previously marketed products) accounting for 33% of the products considered in this review.

Also discussed in this year’s review, but not considered for purposes of statistical calculation, are two products that were reintroduced in 2006 after having been withdrawn from the market. Mention is also made of a product that was launched in 2005, after last year’s edition of this article had already gone to press.

During the past year “Immunomodulators and Agents for Immunization” was the most active therapeutic group in terms of new chemical entities launched for the first time (Table I), with nine market introductions. The United States was again the most active single market for new products, with a total of 22 new launches in 2006, constituting 54% of the total of new introductions for the year (Fig. 1).

Fig. 1. Geographic distribution of new products first launched in 2006.

The information in this review was compiled from company communications and the Prous Science databases. Products are grouped by therapeutic category and mechanism of action according to the classification scheme followed in Prous Science publications, DailyDrugNews.com and the Integrity^® portal.

New drugs and biologics by therapeutic group

The complete list of new products mentioned herein can be found at the end of this section in Table II.

ANALGESIC & ANESTHETIC DRUGS

ZARS’ Synera^TM, a topical local anesthetic patch delivering lidocaine and tetracaine, was launched for the first time in the U.S. in June 2006. The patch, which is indicated for use in both adults and children (aged 3 years and older), is used to numb the skin before various medical procedures such as superficial venous access as well as certain dermatological procedures. Synera has a thin layer of a local anesthetic formulation integrated with an oxygen-activated heating element which enhances the delivery of the local anesthetics into the skin. When removed from its storage pouch, the patch begins to heat, warming the skin after application.

Last year in Germany, Mundipharma received marketing approval for and launched Targin^®, a novel pain product incorporating the opioid analgesic oxycodone hydrochloride and naloxone hydrochloride, the latter being an opioid receptor antagonist. The new combination product was developed in order to treat patients with severe pain while simultaneously addressing one of the major side effects of opioids: their propensity to cause bowel dysfunction.

PSYCHOPHARMACOLOGIC DRUGS

The γ-aminobutyric acid (GABA) analogue pregabalin (Lyrica^®; Pfizer) was approved last year in the European Union and launched for the first time in the United Kingdom for a new indication: treatment of generalized anxiety disorder (GAD). The approval was based on five randomized, double-blind, placebo-controlled trials involving over 2,000 patients. Data from a combination of the five studies demonstrate that pregabalin provides rapid and sustained efficacy for the treatment of GAD. As early as the first week of treatment, the drug provided relief of both emotional symptoms, such as depressive symptoms and panic, and physical symptoms, including headaches and muscle aches. Pregabalin, an α₂δ ligand that is believed to work by calming hyperexcited neurons, had previously been approved for the treatment of epilepsy and neuropathic pain.

In February 2006 the FDA ap-proved Emsam^® (selegiline transdermal system), the first transdermal patch for the treatment of major depressive disorder (MDD) in adults. Emsam, a transdermal delivery system manufactured by Mylan Technologies for Somerset, incorporates a monoamine oxidase inhibitor (MAOI) that has been shown to relieve depressive symptoms in patients with MDD. The efficacy of the treatment was established in two double-blind, placebo-controlled studies of 6- and 8-week durations that included adult outpatients ages 18-70 years old with single and recurrent episodes of MDD. The 6-week trial showed that a 6-mg/24-hour dose of Emsam was significantly more effective than placebo in improving depressive symptoms as determined using the 17-item Hamilton Rating Scale for Depression (HAM-D). In the 8-week dose titration trial, patients with major depressive disorder who received Emsam or placebo at a starting dose of 6 mg/24 hour, with possible increases to 9 mg/24 hour or 12 mg/24 hour based on clinical response, showed significant improvement compared with placebo on the primary outcome measure, the 28-item HAM-D total score. The benefit of maintaining patients with MDD on therapy with Emsam after achieving a responder status for an average of 25 days was demonstrated in a controlled clinical trial. A total of 322 patients with major depressive disorder who had responded to Emsam 6 mg/24 hour during an initial 10-week open-label treatment phase were randomized either to continuation of Emsam at the same dose or to placebo under double-blind conditions for observation of relapse. Approximately 52% of the Emsam-treated patients as well as about 52% of the placebo-treated patients had discontinued treatment by week 12 of the double-blind phase. Patients continually receiving Emsam experienced a significantly longer time to relapse. Bristol-Myers Squibb has exclusive distribution rights to commercialize the product in the U.S., where it was launched in early April, and in Canada.

The year 2006 also saw the reintroduction of Lundbeck’s antipsychotic agent sertindole (Serdolect^®) in Estonia. Sertindole was first launched in 1996, but marketing was suspended in 1998 due to safety concerns. Sertindole is an effective antipsychotic drug for the treatment of schizophrenia without sedative effect and with placebo-level extrapyramidal symptoms. It has an inhibitory effect on central dopamine D₂ and 5-HT₂ receptors as well as on α-adrenergic receptors. Through testing in more than 17,000 patients, the clinical and pharmacological profile of the drug indicates that it may increase the likelihood of patients remaining in therapy, improve daily functioning and thereby increase quality of life and reduce remission rates. Since the temporary suspension by the European Committee for Medicinal Products for Human Use (CHMP) of the marketing authorization for sertindole in 1998, Lundbeck has included an additional 5,000 patients in a study confirming that the drug can be prescribed safely. Lundbeck holds global rights to the product.

Paliperidone (Invega™), a dual inhibitor of 5-HT₂ and dopamine D₂ receptors, was approved by the FDA in the final days of December 2006 for the treatment of schizophrenia. Discovered and developed by Johnson & Johnson, paliperidone is the active metabolite of the company’s marketed antipsychotic agent risperidone and is formulated as a once-daily oral tablet incorporating OROS^® extended-release technology. Janssen launched paliperidone in January 2007.

Following its approval in April 2006, Daytrana™ (methylphenidate transdermal system), the first and only transdermal medication approved to treat the symptoms of attention deficit-hyperactivity disorder (ADHD), was launched by Shire in June. Daytrana was developed by Noven and combines methylphenidate with Noven’s patented DOT Matrix™ transdermal technology to provide continuous release of medication throughout the day. Daytrana is available in four dosage strengths, all designed for 9-hour wear times with 12-hour efficacy.

In October 2006 the FDA approved Janssen’s Risperdal^® (risperidone) for a new indication: the treatment of irritability associated with autistic disorder, including symptoms of aggression, deliberate self-injury, temper tantrums and quickly changing moods, in children and adolescents aged 5-16 years. This is the first time the FDA has approved any medication for use in children and adolescents with autism: the company began marketing it for the new indication immediately. While risperidone does not treat the core symptoms of autism, it has been shown to be beneficial in treating the associated behavioral disturbances that can interfere with school and learning and family life. Two 8-week, placebo-controlled trials in 156 children between the ages of 5 and 16 years who met the DSM-IV criteria for autistic disorder studied the efficacy of risperidone according to two assessment scales, the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Change (CGI-C) scale. The studies found that patients with irritability associated with autistic disorder who received the drug experienced significant behavioral symptom improvement versus those who were given placebo. Risperidone was previously approved in the U.S. to treat acute manic or mixed episodes of bipolar I disorder and for the treatment of schizophrenia in adults.

NEUROLOGIC DRUGS

Much ado was made in July about the re-launch of natalizumab (Tysabri^®; Biogen Idec/Elan), a humanized monoclonal antibody against α4 integrin, in the U.S. Natalizumab was first approved and launched in the U.S. in 2004 for the treatment of relapsing forms of multiple sclerosis (MS). However, just months after the product was launched, the companies voluntarily suspended marketing of natalizumab as well as dosing in all clinical trials based on reports of progres- sive multifocal leukoencephalopathy (PML), a rare and frequently fatal, demyelinating disease of the central nervous system. Following an extensive safety evaluation of the product, in September 2005, Elan and Biogen Idec submitted a supplemental BLA for the product to the FDA. The filing included final 2-year data from the phase III AFFIRM monotherapy trial and SENTINEL add-on trial with Avonex^® (interferon beta-1a) in MS, integrated safety assessment of patients treated with natalizumab in clinical trials, and revised label and risk management plan. In March 2006, after an extensive review of the data submitted, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously to recommend reintroduction of natalizumab as a treatment for relapsing forms of multiple sclerosis. The new data revealed that only those patients taking natalizumab in combination with Avonex developed PML, for which reason the advisory committee also recommended that the drug should not be used in combination with other available MS therapeutics. In June 2006, the FDA approved the reintroduction of natalizumab, with revised labeling and a specially designed risk management plan, known as the TOUCH Prescribing Program.

In February the European Medicines Agency (EMEA) granted marketing authorization for Schwarz Pharma’s Neupro^® (rotigotine ) for the treatment of Parkinson’s disease as monotherapy. The first launches, in Germany and the U.K., took place in March 2006. Neupro is a nonergolinic dopamine D₂/D₃ receptor agonist that is formulated as a transdermal patch for once-daily application. Multinational clinical studies in patients with early-stage Parkinson’s disease were completed at the end of 2003. In 15 clinical trials, more than 1,500 patients with Parkinson’s disease have been treated with rotigotine transdermal patch. Rotigotine exhibits rapid metabolism and low potential for pharmacokinetic drug-drug interactions. In November, the CHMP voted in favor of extending the approved indication to include combination therapy of Parkinson’s disease. In the U.S., an approvable letter has been received for the product.

In April the European Commission approved Boehringer Ingelheim’s Mirapexin^® (pramipexole dihydrochloride) for the treatment of moderate to severe restless legs syndrome (RLS) in the E.U. It is the first medication to be approved throughout the E.U. for this new indication. The first launches took place in Germany and the U.K. immediately upon approval. Study results confirmed that pramipexole provides rapid relief from symptoms after just 1 week of starting treatment. The efficacy and tolerability of pramipexole in RLS continues to be investigated in a comprehensive clinical trials program with more than 1,000 patients, to further assess the therapeutic potential in this condition. Boehringer Ingelheim also filed a supplementary NDA in the U.S. for the RLS indication; it was approved in November. A dopamine D₃ agonist, pramipexole was first licensed in 1997 as a treatment for Parkinson’s disease.

Neurologic Drugs

RESPIRATORY DRUGS

Ranbaxy’s Avessa, a combination asthma therapy incorporating the β₂-adrenoceptor agonist formoterol fumarate and fluticasone propionate, an inhaled corticosteroid, was launched last year for the first time in India. The drugs are formulated using the novel Rheocaps inhalation capsule formulation for use with Rheodose, the world’s first capsule-based multidose dry powder inhaler system. Chiesi introduced Foster™ (formoterol fumarate/beclometasone dipropionate), a similar product incorporating the same β₂ agonist but a different corticosteroid, in Germany last October. Foster was developed using Chiesi’s proprietary Modulite^® technology, which utilizes the ozone-friendly propellant HFA.

Sepracor’s Brovana™ (arformoterol tartrate), a nebulized long-acting bronchodilator for chronic obstructive pulmonary disease (COPD), received FDA approval on October 6, 2006. The product is indicated for the twice-daily, long-term maintenance treatment of bronchoconstriction in patients with COPD, which includes chronic bronchitis and emphysema. It is the first long-acting nebulized bronchodilator to be approved by the FDA for this indication. Until now, patients requiring nebulized bronchodilator treatment only had short-acting bronchodilators to choose from as a nebulized treatment option. Other long- acting β₂-agonist bronchodilators currently available in the U.S. are formulated in dry powder inhalers only. Sepracor is targeting completion of launch preparations and introduction of Brovana during the second quarter of 2007.

A new nasal spray formulation of the corticosteroid ciclesonide (Omnaris™; Altana) was approved last year by the FDA for the treatment of nasal symptoms associated with seasonal and perennial forms of allergic rhinitis. The drug is initially indicated for use in patients aged 12 years and older, although the FDA deemed it approvable for use in children as young as 2 years of age. Pending negotiations with potential partners, Altana plans to launch Omnaris during the year 2007. Ciclesonide has been marketed since 2005 for the treatment of asthma.

CARDIOVASCULAR DRUGS

The late-stage sodium channel blocker ranolazine (Ranexa™; CV Therapeutics) was launched in the U.S. in March 2006. Ranolazine is approved as second-line treatment for chronic angina. It has antianginal and antiischemic effects that do not depend upon reductions in heart rate or blood pressure. Because the drug prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs. It is to be used in combination with amlodipine, β-blockers or nitrates.

Recordati’s Zanipress^®, a combination product incorporating the cal-cium channel blocker lercanidipine and enalapril, an ACE inhibitor, was approved last year for the first time in Germany for the treatment of hypertension. Germany will now act as reference member state for the mutual recognition approval process, which is expected to be completed throughout the rest of the E.U. during 2007.

In late December the FDA also approved a new combination product for the treatment of hypertension: Novartis’ Exforge^®. This product incorporates the angiotensin II receptor blocker valsartan and amlodipine besylate, a dihydropyridine calcium channel blocker, in a single tablet. The FDA issued tentative approval of the product on December 22 because Exforge had met all safety, efficacy and manufacturing quality requirements. However, Exforge cannot be launched until late September 2007, pending expiration of market exclusivity and patent protection for amlodipine. In a clinical program involving more than 5,000 patients, Exforge helped 9 out of 10 patients to reach their treatment goal (diastolic BP <90 mmHg or more than a 10 mmHg reduction in DBP from baseline). The European Commission approved the product in January 2007. Exforge will be launched shortly in Germany followed by launches in most other E.U. countries throughout the year, pending expiration of the patent protection for amlodipine. Valsartan (Diovan^®) is the leading angiotensin receptor blocker by sales worldwide (USD 4.2 billion net sales in 2006, according to Novartis 2006 annual report), while amlodipine (marketed by Pfizer as Norvasc^®) is the most widely prescribed antihypertensive medication worldwide (sales of USD 4.8 billion in 2006, according to Pfizer’s fourth-quarter report).

In July 2006 Ovation Pharmaceuticals announced the launch of NeoProfen^® (ibuprofen lysine), the first new treatment option in 20 years for patent ductus arteriosus (PDA) in premature infants. PDA is a potentially life-threatening condition in which the ductus arteriosus, a part of the fetal pathway that helps distribute oxygen from the mother to the baby’s organs in utero, fails to close after birth. Premature infants, particularly those with low birth weight, are particularly susceptible to PDA.

In November Encysive launched Thelin^® (sitaxsentan sodium) in the U.K. for the treatment of pulmonary arterial hypertension (PAH), following European Commission approval in August 2006. Sitaxsentan is the first selective endothelin A (ETA) receptor antagonist, and the first once-daily oral treatment available for patients with PAH. It is 6,500-fold selective in the targeting of ETA versus ETB receptors. Sitaxsentan is indicated for improving exercise capacity in PAH patients classified as World Health Organization (WHO) functional class III. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. In the U.S., Encysive has submitted a complete response to an approvable letter received from the FDA in July.

Cardiovascular Drugs

RENAL-UROLOGIC DRUGS

Within the diuretic drug class, one of the newer mechanisms of action to emerge in recent years is that of vasopressin antagonists. The peptide hormone vasopressin is synthesized in the hypothalamus and released from the posterior pituitary. There are two forms, which differ only in the amino acid at position 8: arginine vasopressin (AVP), which is widespread, and lysine vasopressin, which is found only in pigs. Circulating AVP is a potent vasoconstrictor, and high levels of AVP may contribute to systemic vasoconstriction and hyponatremia. AVP activity is mediated via V₁ and V₂ receptors; the latter mediate the effects of AVP on water retention. Late last year, a new vasopressin (V_1A/V₂) antagonist was granted marketing approval by the FDA: Astellas Pharma’s Vaprisol^® (conivaptan hydrochloride). Conivaptan is the first drug specifically indicated for the treatment of euvolemic hyponatremia, a condition that occurs when the body’s blood sodium level falls significantly below normal. The drug blocks the activity of AVP, resulting in increased urine output without loss of valuable electrolytes such as sodium and potassium. This aquaresis helps to correct serum sodium levels in patients with hyponatremia due to increased body water. The drug was launched in April 2006. The FDA also issued an approvable letter for conivaptan as a treatment for hyper-volemic hyponatremia.

In October 2006 another vasopressin V₂ antagonist-Otsuka’s mo-zavaptan hydrochloride (Physuline)- was launched in Japan, where it is indicated for the treatment of hyponatremia in subjects with inappropriate antidiuretic hormone (ADH) secretion syndrome due to tumors with ectopic ADH production.

Kissei Pharmaceutical and Daiichi Pharmaceutical last year announced the Japanese launch of Urief (silodosin), indicated for urinary disturbances associated with an enlarged prostate. The product was developed primarily by Kissei and will be jointly marketed by Kissei and Daiichi. The two companies also collaborated on a domestic, double-blind phase III trial that used the International Prostate Symptom Score (I-PSS) and showed a significant improvement in urinary disturbance for silodosin compared with placebo. Silodosin improves urethral resistance and eliminates prostate tension and urinary disturbances associated with an enlarged prostate by selectively blocking the α_1A receptor subtype, which exists mainly in the prostate. Overseas, silodosin is in development by Watson Pharmaceutical in the U.S., Canada and Mexico, by Recordati in Europe and the Middle East, by Daiichi in China, and by Choongwae Pharma in Korea.

Fresenius Medical Care received German regulatory approval for OsVaren (calcium acetate and magnesium carbonate), a new phosphate binding agent, in July 2006 and said it planned to introduce the product to the German market in the first quarter of 2007. Fresenius will use the mutual recognition procedure to gain accelerated approval for the new phosphate binding agent in other countries within the E.U., and a launch across Europe is anticipated for 2007. The combination of calcium acetate and magnesium carbonate is expected to support bone health while optimizing the levels of calcium.

Renal-Urologic Drugs

HEMATOLOGIC AGENTS

The European Commission granted market authorization in August for ATryn^®, GTC Biotherapeutics’ recombinant form of human antithrombin, for the prophylaxis of venous thromboembolism in surgery of patients with congenital antithrombin deficiency. GTC produces ATryn in the milk of goats that have a transgene for human antithrombin. ATryn is the first transgenically produced protein to be approved for human therapeutic use anywhere in the world. It is also the first recombinant antithrombin product approved anywhere in the world and the first antithrombin product, whether recombinant or derived from the human blood supply, that has been approved through the centralized procedure for use in all 25 countries of the E.U. Negotiation of the reimbursement rates with each country’s health system and establishment of sales and marketing efforts in Europe will be performed by GTC’s partner LEO Pharma. GTC will continue to produce the product. Market launch is targeted for the second quarter of 2007 as reimbursement rates are finalized.

GASTROINTESTINAL DRUGS

Chronic idiopathic constipation is a form of constipation that is characterized by the infrequent or difficult passage of stools for a period of at least 3 months. It is caused by abnormal colonic motility, which can delay the movement of intestinal contents and impede evacuation. Previous treatment options were limited to lifestyle and dietary changes, laxatives and stool softeners. Sucampo’s lubiprostone (Amitiza™), the first selective chloride (ClC-2) channel activator approved for therapeutic use, was introduced in the U.S. in April 2006, representing a new pharmacotherapy for patients with chronic idiopathic constipation. The FDA approval of lubiprostone was primarily based on data from two pivotal, double-blind, placebo-controlled studies that showed that approximately 60% of patients who used the drug experienced a spontaneous bowel movement within the first 24 hours. Additionally, lubiprostone was shown to decrease abdominal bloating, abdominal discomfort and constipation severity when administered over 6-12 months of treatment. It works by increasing fluid secretion and motility in the intestine, and thereby increases the passage of the stool and alleviates symptoms associated with chronic idiopathic constipation. Amitiza is jointly marketed by Sucampo and Takeda.

In March the FDA granted marketing approval for OsmoPrep™ Tablets (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP). OsmoPrep Tablets, developed and marketed by Salix, are indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older. This new agent represents a significant advance over existing purgative products, such as 4-liter PEG and sodium phosphate, which are difficult to tolerate for many patients. The tablets are virtually tasteless and have been shown in clinical studies to improve patient compliance and satisfaction.

The DNA polymerase inhibitor telbivudine (Sebivo^®) was approved and launched in Switzerland in September for the treatment of chronic hepatitis B, with U.S. approval following in October. Swiss regulatory approval was based on the GLOBE study, the largest worldwide registration trial ever conducted in patients with chronic hepatitis B. The 2-year, multicenter, international phase III trial compared telbivudine with lamivudine in the treatment of 1,367 adults with chronic hepatitis B. In this study, telbivudine was shown to produce significantly greater viral suppression on a number of virologic markers as compared with lamivudine after 1 year of treatment. Therapeutic response among HBeAg-positive patients was significantly higher with the study drug than with the standard therapy, while among HBeAg-negative subjects, response to the two treatments was similar. Furthermore, patients on telbivudine showed significantly less viral resistance and less treatment failure at 1 year as compared with those on lamivudine. Telbivudine was discovered by Idenix and was codeveloped with Novartis. Norvartis holds exclusive commercialization rights to the product in most of the world, including Switzerland.

Gastrointestinal drugs

ENDOCRINE DRUGS

Since its discovery 20 years ago, insulin has been the gold standard of treatment for patients with type 1 diabetes and is ultimately required by nearly half of all patients with type 2 diabetes as well. Last year the first noninjectable, inhalable form of insulin became commercially available, representing a major advance in improving the treatment regimen and quality of life of insulin-requiring diabetic patients. The product, Exubera^® (inhaled human insulin), originated at Nektar Therapeutics and was codeveloped and marketed by Pfizer. Exubera is a fast-acting, dry powder formulation of human insulin that is inhaled into the lungs via the mouth before meals using a simple-to-use, handheld device that does not require batteries or electricity. The device is designed to deliver an accurate and precise dose of insulin each time it is used. It was approved in both the E.U. and U.S. in January, and was launched for the first time in Germany and Ireland in May. The U.S. launch took place later in the year.

Another landmark was achieved in 2006 with the August launch of sitagliptin phosphate (Januvia™; Merck & Co.), the first dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Mexican authorities were the first to approve the product, and the first launch took place in that country as well. DPP IV inhibitors act by enhancing the body’s incretin system, which helps to regulate glucose by affecting β cells and α cells in the pancreas. Through DPP IV inhibition, sitagliptin works only when blood sugar is elevated to address diminished insulin due to α-cell dysfunction and uncontrolled production of glucose by the liver due to α-cell and β-cell dysfunction. In controlled international clinical studies, sitagliptin demonstrated substantial reduction in glucose levels and was not associated with weight gain from baseline. The incidence of hypoglycemia in these studies was similar to placebo. Sitagliptin was approved in the U.S. in October; in Japan, Banyu has initiated phase III testing.

GlaxoSmithKline’s Avandaryl™, a new combination product incorporating the thiazolidinedione-class insulin sensitizer rosiglitazone maleate and glimepiride, a sulfonylurea, in a single tablet formulation, was launched early in 2006 in the U.S. Avandaryl is the first fixed-dose combination tablet containing a TZD and a sulfonylurea, and was designed with the intention of simplifying the management of type 2 diabetes.

Takeda’s Duetact™, a similar combination product incorporating the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone hydrochloride and glimepiride was approved last July for the first time in the U.S., where it is indicated for the treatment of type 2 diabetes. Duetact is designed to simplify the treatment regimen of diabetic patients, who are often prescribed the two drugs in combination due to their complementary mechanisms of action. The product was introduced in November.

In January 2006 Tercica launched Increlex^TM (mecasermin [rDNA origin]) for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency (primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone. The FDA has designated Increlex as an orphan drug for severe Primary IGFD. The active ingredient of Increlex is identical to the natural hormone IGF-1, which the body produces in response to stimulation by growth hormone. Approval, which came within the 6-month priority review time line, was based on clinical trial data from 71 patients. Data reported in 2004 demonstrated a statistically significant increase in growth rate over an 8-year period in response to therapy. Compared to pretreatment growth patterns, on average, children gained an additional inch per year for each year of therapy over the course of 8 years. In addition, an analysis of safety concluded that long-term treatment with Increlex appears to be well tolerated and has an acceptable safety profile.

A related product, Insmed’s mecasermin rinfabate [rDNA origin] (iPlex^TM), was also launched last year for the treatment of growth failure in children with severe primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. Mecasermin rinfabate is a complex of recombinant human insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3). As an orphan drug, the product is entitled to 7 years of marketing exclusivity for the treatment of primary IGFD. Orphan drugs are described in greater detail in the article “Promoting, Improving and Accelerating the Drug Development and Approval Processes,” pp. 48-49 in this issue.

Endocrine drugs

DERMATOLOGIC DRUGS

Last year CollaGenex introduced Oracea™, a new formulation of doxycycline for the treatment of rosacea. The product is the flagship member of CollaGenex’s IMPACS class, which stands for “inhibitors of multiple proteases and cytokines.” These molecules are chemically modified tetracyclines that inhibit matrix metalloproteinases (MMPs) and cytokines involved in rosacea. In May 2006, CollaGenex received FDA approval of Oracea for the treatment of inflammatory lesions (papules and pustules) of rosacea in adult patients. Oracea is the first FDA-approved, orally administered, systemically delivered drug to treat this dermatologic disorder. The NDA included highly significant results from two double-blind, placebo-controlled pivotal phase III trials that enrolled 537 patients in 28 U.S. centers. In the two studies, patients receiving Oracea experienced a 61% and 46% mean reduction in inflammatory lesions compared to 29% and 20% mean reduction, respectively, in patients receiving placebo. Oracea was launched in July 2006.

Veregen™, a botanical drug from the German company MediGene, was approved by the FDA in October for the treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent adults (aged 18 and older). Kunecatechins, the active substance in Veregen, is an extract from green tea leaves with a defined catechin composition. The substance shows antioxidant activity in vitro, although its mechanism of action in this indication is not yet clear. Bradley Pharmaceuticals, MediGene’s U.S. marketing partner, plans to launch Veregen in the second half of 2007.

ANTIINFECTIVE THERAPY

Fungi and humans are both eukaryotes, therefore new antifungal compounds must focus on fungus-specific targets in order to minimize potential toxicity to the human host. Biosynthesis of the fungal cell wall offers many potential pathogen-specific therapeutic targets. Foremost among compounds acting on these cell wall targets in Candida sp., Aspergillus sp. and Pneumocystis carinii are the 1,3-β-D-glucan synthesis inhibitors. A newer class of antifungal compounds called the echinocandins inhibits this key enzyme system. The echinocandins are synthetically modified lipopeptides that were originally derived from the fermentation broths of various fungi. They have several advantageous properties including low toxicity, few drug interactions, rapid fungicidal activity against most strains of Candida and predictable pharmacokinetics with a once-daily dosing schedule. Their chief drawback is that they are available only as intravenous formulations, as their large molecular weight results in poor oral absorption. The first member of the echinocandin class, caspofungin acetate (Cancidas^®; Merck & Co.), was launched in 2001 and the second, micafungin sodium (Funguard; Astellas), arrived one year later. In 2006, the new echinocandin antifungal agent anidulafungin (Eraxis™) was launched by Pfizer in the U.S., its first market. It is indicated for the treatment of candidemia and other forms of Candida infections (intra-abdominal abscess and peritonitis).

In June following receipt of accelerated approval from the FDA, Tibotec Therapeutics launched the HIV protease inhibitor darunavir (Prezista™) in the U.S. The drug is indicated for co-administration with ritonavir and with other antiretroviral agents, for the treatment of HIV infection in antiretroviral treatment-experienced patients, such as those with HIV-1 strains resistant to more than one protease inhibitor. In December the European Committee for Human Medicinal Products recommended approval of the drug in the E.U.; a decision from the European Commission is anticipated in early 2007.

The use of combination products has greatly simplified and improved the treatment of patients with HIV. Last year the FDA approved Atripla™ (tenofovir disoproxil fumarate/em-tricitabine/efavirenz) for the treatment of HIV-1 infection in adults. Atripla is the first-ever once-daily single tablet regimen for HIV intended as a stand-alone therapy or in combination with other antiretrovirals. The product combines the nonnucleoside reverse transcriptase inhibitor efavirenz, manufactured by Bristol-Myers Squibb and Truvada^® (emtricitabine/ tenofovir disoproxil fumarate), manufactured by Gilead Sciences. Atripla was made available in the U.S. on July 17, just days after approval. Bristol-Myers Squibb and Gilead established a U.S. joint venture in December 2004 to develop and commercialize the single-tablet regimen. Total global sales for the individual components of Atripla™ (Truvada and efavirenz) during the first three quarters of 2006 are reported to be in excess of USD 1.4 billion.

Antiinfective therapy

THERAPY OF MUSCULOSKELETAL AND CONNECTIVE TISSUE DISEASES

Another new biological introduced in 2006 was Bristol-Myers Squibb’s abatacept (Orencia^®), the first selective modulator of a costimulatory signal required for full T-cell activation, indicated for the treatment of rheumatoid arthritis (RA). Abatacept is specifically indicated for reducing the signs and symptoms of RA, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs), such as methotrexate or tumor necrosis factor (TNF) antagonists.

The chimeric anti-CD20 antibody rituximab (Rituxan^®; Biogen Idec/ Genentech) was approved and launched last year in the U.S. for the new indication of rheumatoid arthritis; an application for this new indication was also approved later in the year in the European Union. The novel biologic, the first and only selective B-cell therapy, is indicated for the treatment of active RA in patients who have had an inadequate response to TNFα inhibitors. Rituximab is a therapeutic antibody that selectively targets B cells without affecting stem, pro-B or plasma cells, therefore allowing continuation of normal protective function of the immune system. Rituximab aims to break the inflammatory cascade that inflames the synovia and leads to cartilage loss and bone erosion that is characteristic of RA. Rituximab has been marketed for nearly 10 years for the treatment of non-Hodgkin’s lymphoma.

In July Roche received approval in Malaysia for mycophenolate mofetil (MMF; CellCept^®) for the induction and maintenance treatment of lupus nephritis, when used concomitantly with corticosteroids. Malaysia is the first country to have regulatory approval of MMF in any autoimmune disease. Approval was supported by published clinical papers and an expert clinical report. A trial, conducted at eight centers in Malaysia, compared intravenous cyclophosphamide with MMF in the induction therapy of proliferative lupus nephritis. MMF is an immunosuppressant drug that has been marketed for more than 10 years for use in combination with other immunosuppressive drugs (ciclosporin and corticosteroids) for the prevention of rejection of heart, kidney and liver transplants. Aspreva signed a collaboration agreement with Roche in July 2003 for the exclusive worldwide rights (excluding Japan) to develop and, upon regulatory approval, commercialize MMF for all autoimmune disease applications, including lupus nephritis. Aspreva is also conducting a global phase III study to assess the efficacy and safety of MMF in inducing response and maintaining remission in patients with lupus nephritis.

IMMUNOMODULATORS AND AGENTS FOR IMMUNIZATION

Sinovac Biotech’s seasonal influenza vaccine Anflu™ was launched for the first time last year in China. The product, a split influenza vaccine, was developed specifically to meet the growing need for flu vaccines in China, a country in which significant flu vaccine shortages (as many as 15-20 million doses) are registered each year.

Last year health officials in the U.S., Mexico and the E.U. issued marketing approvals for Merck & Co.’s Gardasil^® (quadrivalent human papillomavirus [types 6, 11, 16, 18] recombinant vaccine), the first and only vaccine to prevent cervical cancer and vulvar and vaginal precancers caused by HPV types 16 and 18 and to prevent low-grade and precancerous lesions and genital warts caused by HPV types 6, 11, 16 and 18. In the U.S., where the first product launch took place in early June, Gardasil was approved for the prevention of cervical cancer; cervical precancers (cervical intraepithelial neoplasia [CIN] 2/3 and adenocarcinoma in situ [AIS]); vulvar precancers (vulvar intraepithelial neoplasia [VIN] 2/3); and vaginal precancers (vaginal intraepithelial neoplasia [VaIN] 2/3) caused by HPV types 16 and 18. Gardasil was also approved for the prevention of genital warts and low-grade cervical lesions (CIN 1) caused by HPV types 6, 11, 16 and 18. The FDA approved Gardasil for use in girls and women aged 9-26 years. The efficacy of the vaccine was demonstrated in four placebo-controlled, double-blind, randomized phase II and phase III studies. Together, the studies evaluated 20,541 women aged 16 to 26 years who were followed for up to 5 years after enrolment. In the combined analyses Gardasil prevented 100% of HPV 16- and 18-related cervical precancers and noninvasive cervical cancers (CIN 2/3, and AIS, or adenocarcinoma in situ). Gardasil prevented 95% of low-grade cervical dysplasia and precancers (CIN 2/3 or AIS) caused by HPV 6, 11, 16 or 18, and 99% of cases of genital warts caused by HPV 6 or 11. Further, Gardasil prevented 100% of HPV 16- and 18-related vulvar and vaginal precancers (VIN 2/3 or VaIN 2/3) in women not previously exposed to the relevant HPV types. These studies also showed that administration of Gardasil to women who are already infected with one or more vaccine-related HPV types prior to vaccination protects them from clinical disease caused by the remaining vaccine types but may not alter the course of an infection that is already present. A secondary analysis was conducted in women regardless of whether they were infected with HPV prior to vaccination, developed an infection after the start of vaccination or may not have completed the three-dose vaccination, and showed that Gardasil reduced the risk for development of cervical precancerous lesions and cervical cancer caused by HPV types 16 and 18 by approximately 40% in just 2-4 years. Genital warts were reduced by almost 70%.

Rotaviruses are among the most common pathogens causing gastrointestinal disease in infants and children. By the age of 3-4 years, nearly all children have been infected by the disease; approximately 2 million hospitalizations result annually. Rotaviruses are furthermore the most common infectious cause of death in infants and young children throughout the world, being responsible for about 440,000 deaths per year, 80% of which occur in developing countries. In spite of its pathogenicity, development of an effective vaccine has presented a significant challenge to scientists throughout the years and the only previously validated vaccine, Wyeth’s RotaShield^®, was withdrawn from the market in 1999 due to serious side effects. In 2005 GlaxoSmithKline launched Rotarix^® rotavirus vaccine for the prevention of gastroenteritis caused by rotavirus infection, and last year Merck & Co. followed suit with a rotavirus vaccine of its own: RotaTeq^® (rotavirus vaccine, live, oral, pentavalent). RotaTeq is a pentavalent vaccine that targets the rotavirus strains responsible for more than 90% of rotavirus disease in the U.S. Launched in the U.S. in February, the vaccine was also approved in June in the E.U., where it will be marketed by Sanofi Pasteur MSD.

In May 2006 both the FDA and the European Commission approved Zostavax^® (zoster vaccine live) for prevention of herpes zoster (shingles) in individuals aged 60 years or older; in the E.U. the approval is also for prevention of herpes zoster-related postherpetic neuralgia (PHN). Zostavax is the first and only vaccine approved for the prevention of shingles. In the SPS (Shingles Prevention Study) phase III study, including 38,546 men and women aged 60 and older who received one dose of vaccine or placebo, Zostavax reduced the incidence of shingles by 51% compared to placebo. Zostavax also reduced by 67% the incidence of PHN and the total burden of pain and discomfort caused by shingles by 61%, when compared with placebo. The results of the study show that vaccination of immunocompetent persons 60 years of age and older with Zostavax markedly decreased the morbidity associated with shingles and the incidence of postherpetic neuralgia. Zostavax was developed by Merck & Co. and Sanofi Pasteur MSD, and was launched in the U.S. by Merck. It will be marketed in Europe by Sanofi Pasteur MSD.

Quinvaxem™, a fully liquid pentavalent vaccine developed by Berna Biotech (a subsidiary of Crucell), was first approved last March in Korea, and was launched for the first time last October in Honduras. Quinvaxem combines antigens for protection against five important childhood diseases: diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B. It is the first internationally available fully liquid vaccine containing all five of these antigens to reach the market. The Quinvaxem product dossier was filed in 2005 with both the Korean FDA and the World Health Organization (WHO). As a next step, the WHO is expected to finalize its own review in order to grant WHO prequalification, a prerequisite for the combination vaccine to be made available to supranational purchasing organizations.

Bharat Biotech’s Rabirix™ (rabies vaccine) was launched last year in India for the prevention and treatment of human rabies infection. The rabies strain was provided by the U.S. Centers for Disease Control and Prevention (CDC). Rabirix is chromatographically purified to reduce cellular DNA content and foreign protein content. Rabies is an acute viral encephalitis that is transmitted from an infected animal to a human by exposure to saliva. Human infection with rabies is nearly always caused by an animal bite, with dogs as the principal reservoir for human disease. Every year 4 million people are exposed to rabies worldwide, and some 60,000 people fall victim to it. As many as 50% of these victims are reported in India.

In January the FDA approved Cangene’s HepaGam B™ (hepatitis B immune globulin [human]) for the treatment of acute exposure to blood containing hepatitis B surface antigen (HBsAg), perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to HBsAg-positive persons and household exposure to persons with acute HBV infection. HepaGam B, which is distributed in the U.S. by Apotex, was launched in April 2006.

The two-dose recombinant hepatitis B vaccine Supervax, developed by Rhein Biotech and approved in 2003, was finally launched for the first time in Argentina in December 2006. Dynavax acquired Rhein Biotech in April 2006 and subsequently launched the vaccine. Supervax is a recombinant DNA hepatitis B vaccine produced using the Hansenula polymorpha technology and is combined with the fully synthetic adjuvant RC-529, developed by Corixa.

Grazax^®, a novel grass pollen allergy oral immunotherapy, was approved for the first time in Sweden last March. Manufacturer ALK-Abelló subsequently filed applications for approval in other E.U. countries through the Mutual Recognition Procedure, and received marketing authorization in all 27 countries of the E.U. in September. Grazax was launched for the first time in Germany in November. The product, a fast-dissolving, once-daily oral tablet formulation, induces a protective immune response that reduces and potentially halts the allergic reaction to grass pollen. The company expects that it will primarily be used by patients with moderate to severe allergic rhinitis who are not satisfied with their current treatment.

ONCOLYTIC DRUGS

In January 2006 the FDA approved the multiple tyrosine kinase inhibitor sunitinib malate (Sutent^®; Pfizer) for the treatment of gastrointestinal stromal tumors (GIST) in patients whose disease has progressed or who are unable to tolerate treatment with Gleevec^® (imatinib mesylate). The agency also granted accelerated approval to sunitinib for the treatment of patients with advanced renal cell carcinoma (RCC). This was the first time that the FDA had approved a new oncology product for two indications simultaneously. The GIST indication was approved based on the drug’s ability to slow the growth of the tumors, whereas the RCC indication was approved based on sunitinib’s ability to induce tumor regression. Sunitinib inhibits multiple receptor tyrosine kinases, including those involved in tumor growth, pathogenic angiogenesis and metastatic progression of cancer. The drug was launched in the U.S. in February; in August, the European Commission approved it for the GIST indication.

Late in June the FDA granted accelerated approval of a second multiple tyrosine kinase inhibitor, dasatinib (Sprycel™; Bristol-Myers Squibb), for two leukemia indications: the treatment of chronic myeloid leukemia (CML; chronic, accelerated or myeloid or lymphoid blast phase) in patients with resistance or intolerance to prior therapy including imatinib; and the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Dasatinib is the first approved oral tyrosine kinase inhibitor which binds to multiple conformations of the ABL kinase. At nanomolar concentrations, dasatinib inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2 and PDGFR-B. By targeting these kinases, dasatinib inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ ALL and allows normal red cell, white cell and blood platelet production to resume. The drug, which has orphan drug status in both the U.S. and Europe, was launched in the U.S. just one week after receipt of the accelerated FDA approval. European approval for dasatinib was received in late November.

Another first-in-class approval this year was granted to Merck & Co.’s vorinostat (Zolinza™), a histone deacetylase inhibitor. The drug, which has orphan drug status, was approved by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma that affects some 20,000 patients in the U.S. Vorinostat was shown in in vitro studies to inhibit the enzymatic activity of HDAC1, HDAC2, HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations. In some cancer cells, excess amounts of HDAC prevent the activation of genes that control normal cell activity. HDAC inhibition may enable this normal gene activation to take place, thereby slowing or stopping the growth of cancer cells.

In early May the FDA approved SuperGen’s Dacogen™ (decitabine) for the treatment of patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation and chronic myelomonocytic leukemia), and Intermediate-1, Intermediate-2 and High-Risk International Prognostic Scoring System (IPSS) groups. Decitabine, which has orphan drug status in the U.S., is a hypomethylating agent that is believed to exert its antineoplastic effects by incorporation into DNA and inhibition of DNA methyltransferase. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and drug incorporated into DNA. Nonproliferating cells, in contrast, are relatively insensitive to the agent. Codevelopment and marketing partner MGI Pharma launched decitabine in late May.

Another antimetabolite, the purine biosynthesis inhibitor nelarabine (Arranon^®; GlaxoSmithKline), was launched in the U.S. in October. It is indicated for the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in pa-tients who have not responded to or have relapsed on at least two chemotherapy regimens. Nelarabine has orphan drug status in the U.S. and was approved under the accelerated approval program.

Lenalidomide (Revlimid^®), the lead clinical compound in Celgene’s IMiDs^® (immunomodulatory drugs) family, was launched in the U.S. in the last days of December 2005, too late to be included in last year’s edition of this annual article. The product is indicated for the treatment of patients with transfusion-dependent anemia due to myelodysplastic syndromes (MDS) associated with a 5q deletion chromosomal abnormality with or without additional cytogenetic abnormalities. An orally available small molecule, lenalidomide affects multiple intracellular biological pathways, including TNFα production inhibition and angiogenesis inhibition and has demonstrated antiinflammatory properties. Lenalidomide was assigned orphan drug designation in the U.S. and Europe for this indication as well as fast track designation in the U.S. Due to the potential for birth defects and other serious side effects, it is available through an education and prescribing safety program called RevAssist(SM) only via contracted pharmacies.

Last September Amgen received FDA approval for Vectibix™ (panitumumab) following priority review. Panitumumab is the first entirely human monoclonal antibody for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after disease progression on, or following, fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. It is the first anti-EGFR antibody shown to significantly improve progression-free survival in patients with metastatic colorectal cancer, and approval was based on this progression-free survival endpoint. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with panitumumab. The product was launched in October. Prescribing information includes warning language as part of evolving FDA labeling for the anti-EGFR class, including warnings over dermatological toxicities and severe infusion reactions. Marketing applications were

submitted to the European Medicines Agency in April 2006 and to regulatory authorities in Canada, Australia and Switzerland in May 2006. Clinical trials continue to evaluate the antibody as both a monotherapy and in combination with other agents for the treatment of various types of cancer.

In July 2006 India’s Drug Controller General granted marketing approval to nimotuzumab, an anti-EGFR (epidermal growth factor receptor) monoclonal antibody, for the treatment of head and neck cancer. Originally discovered by the Center for Molecular Immunology, nimotuzumab was licensed to YM BioSciences for major markets including Europe, North America and the Pacific Rim countries but excluding China, where Biotech Pharmaceuticals holds rights. Biocon Biopharmaceuticals was granted rights to the product in India, where it was launched for the first time in September 2006 (as BIOMAb EFGR) for the treatment of head and neck cancer overexpressing EGFR.

Oncolytic Drugs

OPHTHALMIC DRUGS

Allergan’s combination product Ganfort^® (bimatoprost/timolol maleate) was approved and launched for the first time last year in the U.K. for the treatment of open-angle glaucoma and ocular hypertension. The product, which combines the prostaglandin analogue bimatoprost and the β₂-adrenoceptor antagonist timolol in a single eyedrop formulation, is indicated for the treatment of patients who are insufficiently responsive to topical monotherapy (β blocker or prostaglandin analogue).

A similar product, Alcon’s DuoTrav™ (travoprost/timolol maleate), was approved last year in Australia and the E.U. and was launched in the U.K., Germany and Canada for the same indication. About half of all glaucoma patients use more than one glaucoma medication, so that the development of combination products facilitates their treatment regimen significantly.

Age-related macular degeneration (AMD) is the leading cause of untreatable blindness among people aged 65-74 years in the U.S. and other technologically advanced countries. According to the Eye Diseases Prevalence Research Group, in the year 2004, AMD affected more than 1.75 million people in the U.S. alone. Worldwide, approximately 20-25 million people suffer from AMD, a disorder that until recently was untreatable. Last year two new products for the treatment of AMD reached their first markets, thereby doubling the therapeutic number of available therapeutic options for this disorder. Angiogenesis inhibitors target the aberrant neovascularization characteristic of the “wet” or exudative form of AMD. In this form of the disease, abnormal blood vessels grow under the retina and macula. These new blood vessels may bleed and leak fluid, thereby causing the macula to bulge or lift up, thus distorting or destroying central vision. Genentech’s ranibizumab (Lucentis™), a monoclonal antibody fragment targeted to the angiogenic protein VEGF-A, was approved and launched in the U.S. for this indication in June 2006. Another angiogenesis inhibitor, Alcon’s anecortave acetate (Retaane^®), was launched in Australia. The drug, an angiostatic cortisene derived from the steroid class, appears to exert its antiangiogenic effects by downregulating the expression MMP-2 and -9.

Last May Otsuka Pharmaceutical launched a new formulation of the quinolone antibacterial agent tosufloxacin tosilate: Ozex Ophthalmic solution 0.3%. Ozex Ophthalmic solution 0.3% has potent and broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria and anaerobes, and is indicated for various external bacterial eye infections including Chlamydial conjunctivitis. The agent demonstrated its efficacy and safety in a clinical trial for children, including infants and newborns. It is the first antibacterial ophthalmic solution for children in Japan. Ozex ophthalmic solution 0.3% is manufactured by Toyama Chemical and marketed by Otsuka. Ozex tablet formulation has been available since 1990.

Ophthalmic drugs

METABOLIC DRUGS

The European Commission granted marketing authorization in April for Preotact^® (parathyroid hormone [rDNA origin]; Nycomed) for the treatment of postmenopausal women with osteoporosis at high risk for fractures. Preotact is a full-length parathyroid hormone (PTH 1-84) that stimulates the growth of structurally normal bone lost due to osteoporosis. The European marketing application was based on results from the pivotal phase III TOP (Treatment of Osteoporosis with PTH) study. The multicenter, randomized, double-blind, placebo-controlled trial demonstrated a statistically significant reduction in the risk of new vertebral fractures in women with and without preexisting osteoporosis-related fractures. In the U.S., the drug (which will be known as Preos^® in that country) received an approvable letter in March 2006.

According to the Centers for Disease Control and Prevention, based on NHANES data for the period 2003-2004, more than 66% of the adult population of the U.S., the country with the highest prevalence of obesity worldwide, is overweight and half of these are frankly obese. Other developed countries report similar prevalence figures. Thus the launch last year of rimonabant (Acomplia^®; sanofi-aventis), the first antiobesity drug with a new mechanism of action, was received with enthusiasm and significant expectation. Rimonabant, a cannabinoid CB1 receptor antagonist, is targeted at improving multiple cardiometabolic risk factors in obese and overweight patients. It works by selectively blocking CB1 receptors found in the brain and in peripheral organs important in glucose and lipid metabolism, including adipose tissue, the liver, gastrointestinal tract and muscle. CB1 receptor blockade with rimonabant acts to decrease the overactivity of the endocannabinoid system. In June 2006, the European Commission granted marketing authorization for rimonabant as an adjunct to diet and exercise for the treatment of obese patients (BMI = 30 kg/m²), or overweight patients (BMI > 27 kg/m²) with associated risk factors, such as type 2 diabetes or dyslipidemia. The first launch of rimonabant took place in the U.K. later that same month. The marketing authorization was based on the review of efficacy and safety data, including data from the RIO clinical trial program. The label granted by the European Commission states that an estimated 50% of the observed improvements in HbA1c, HDL-cholesterol and triglycerides were beyond what would be expected as a result of weight loss alone.

In March 2002 the European Commission granted marketing authorization of Dynepo™ (epoetin delta, gene-activated erythropoietin) for the then 15 countries of the E.U. Dynepo is a human erythropoietin for the treatment of anemia in patients with chronic renal failure. Dynepo was developed using Transkaryotic Therapies’ patented gene activation technology. Shortly after E.U. approval was granted, however, Amgen filed patent infringement suits attempting to block marketing of the product, claiming that Dynepo and the process for producing it infringe several U.S. and European patents held by Amgen. Although noninfringement decisions were handed down by courts in the U.K. and the U.S., product launch was delayed for several years. Finally in the first half of 2006, Shire (which had previously acquired Transkaryotic Therapies) began rolling out Dynepo. The product may be used in patients on dialysis as well as those who are not receiving dialysis.

Biopure launched its room-temperature-stable oxygen therapeutic Hemopure^® (hemoglobin glutamer-250 [bovine]) in South Africa in January 2006. The product is approved for the treatment of adult surgical patients who are acutely anemic and for the purpose of eliminating, delaying or reducing the need for allogenic red blood cell transfusions in these patients. In April 2001, South Africa’s Medicines Control Council granted marketing clearance for the product; however, issues between Biopure and the original product registration holder and distributor delayed marketing and sales activities. In 2005, Biopure acquired control of the product registration, selected a warehousing and shipping agent and appointed a sales agent. In early January 2006, Biopure announced that it had complied with new import regulations and shipped the product to South Africa to support the initiation of sales and marketing activities. The company has also filed for marketing approval of Hemopure in the U.K.

NIX-0699 (Nicosan™) is an extract from several indigenous plants which demonstrates potent antisickling effects in sickle cells. The phytopharmaceutical product was approved and launched last year in Nigeria, a country with an inordinately high population of patients with sickle cell disease. Nicosan was developed by Nigerian scientists at the National Institute for Pharmaceutical Research and Development, and was licensed to Xechem worldwide. In clinical studies conducted by NIPRD, the drug substantially reduced the degree of sickling of the red blood cells of those afflicted with the disease. While not a cure, the clinical trials confirmed that the large majority of patients taking Nicosan no longer experienced sickle cell crises while on the medication, and even among those whose crises were not eliminated, the number and severity of the crises were substantially reduced.

Pompe’s disease is a rare (approximately 1 in every 40,000 births in the U.S.), inherited and often fatal disorder that affects the heart and muscles. It is caused by mutations in the gene that makes an enzyme called α-glucosidase (GAA) which is used by the body to break down glycogen. In Pompe’s disease, mutations in the GAA gene reduce or completely eliminate this essential enzyme. Excessive amounts of glycogen accumulate everywhere in the body, but the cells of the heart and skeletal muscles are the most seriously affected. Researchers have identified up to 70 different mutations in the GAA gene that cause the symptoms of Pompe’s disease, which can vary widely in terms of age of onset and severity. In April 2006, the European Commission approved Genzyme’s Myozyme^® (alglucosidase alfa) for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Pompe’s disease. The U.S. FDA issued its own approval of Myozyme just a month later, and was made available to patients soon thereafter. The product, which has orphan medicinal product designation in both markets, is the first treatment ever approved for this indication.

Hunter syndrome (also known as mucopolysaccharidosis II, or MPS II) is a lysosomal storage disorder in which the patient’s body produces insufficient quantities of the enzyme iduronate-2-sulfatase, which is re-quired to break down mucopolysaccharides, a kind of waste substance produced in the body. Symptoms of the disease, which is usually apparent by the age of 1-3 years, include growth delay, joint stiffness and coarsening of facial features. In severe cases, patients experience respiratory and cardiac problems, enlargement of the liver and spleen, neurological deficits and premature death. Last year the FDA approved the first product ever to treat this rare disorder, which is diagnosed in one out of every 65,000-132,000 births. The product, Shire’s idursulfase (Elaprase™), is a purified form of human iduronate-2-sulfatase and has orphan drug status in the U.S. It was launched in August. In October, the European Committee for Medicinal Products for Human Use (CHMP) recommended approval of Elaprase in the European Union.

Metabolic drugs

TREATMENT OF DRUG ABUSE AND DEPENDENCY

In May 2006 the FDA approved Pfizer’s novel antismoking pill, Chantix™ (varenicline tartrate), a nicotinic α₄β₂ partial agonist. Chantix, the first new prescription medication approved for smoking cessation in nearly a decade, received priority review because of its potential to be a significant therapeutic advance over existing therapies. Addiction to nicotine makes it very difficult for many smokers to quit. When smokers inhale smoke from a cigarette, nicotine reaches the brain within seconds and binds to nicotinic receptors, which activates the reward pathway in brain circuitry. This stimulates the pleasure center in the brain. The initial effects recede quickly, however, and a cycle of craving and withdrawal takes hold. Varenicline partially activates the nicotinic receptor and reduces the severity of craving for nicotine as well as withdrawal symptoms. Moreover, if a person smokes a cigarette while receiving treatment, varenicline may diminish the sense of satisfaction associated with smoking, helping to prevent the cycle of nicotine addiction. Pfizer began launching the product in Europe (under the name Champix) in December.

Treatment of drug abuse and dependency

DIAGNOSTIC AGENTS

Following E.U. marketing ap-proval in 2005, Vasovist^® (gadofosveset trisodium), Schering AG’s novel contrast agent for magnetic resonance angiography (MRA), was launched in April 2006 in The Netherlands, its first market. The innovative contrast agent is indicated for visualization of abdominal or limb vessels in patients with known or suspected vascular disease such as stenosis and aneurysms. Gadofosveset trisodium is a gadolinium-based magnetic resonance imaging (MRI) blood pool contrast agent optimized for prolonged vascular enhancement. After intravenous injection, it binds rever-sibly to human serum albumin in plasma, thus providing higher relaxivity and an extended imaging time window as compared with currently available contrast agents. Gadofosveset is designed to provide more flexibility and versatility, including high-resolution scans in the clinical practice of MRA. The product was discovered by and codeveloped with Epix Pharmaceuticals. Schering has worldwide marketing rights.

Diagnostic agents

In October, Daiichi Sankyo reported Japanese approval for the ultrasound contrast medium Sonazoid^® (perflubutane) for injection, a worldwide first. Perflubutane, which was developed in collaboration with licensor GE Healthcare, is a minimally invasive nonnuclear contrast medium characterized by prolonged ability to maintain its contrasting attributes. It will contribute to improving differential and presence diagnosis in diagnosing lesions associated with hepatic tumors as well as assessing the effectiveness of local treatment and posttreatment follow-ups in liver cancer patients. Sonazoid was launched in January 2006.

First-in-class targets-2006

Five of the new products launched in 2006 introduce novel mechanisms of action in the current therapeutic arsenal. The targets upon which these medicines act to exert their therapeutic effect is described in detail below. In addition to the figures shown here, subscribers to Integrity^®(http://integrity.prous.com) may access animated figures depicting these mechanisms of action in greater detail.

The ClC-2 channel, target of the gastrointestinal agent lubiprostone, is one of four voltage-gated ion channels that are expressed on several cell types in mammals including epithelial transport cells. The channel is activated in response to hyperpolarization, extracellular acidification and hypotonic cell swelling; however, the physiological role of the channel is not clearly understood. It has been implicated in the control of intracellular Cl^- in neurons expressing inhibitory GABA receptors and in epithelial transport. It is present on cells of the apical intestinal membrane and when activated, increases Cl^- and intestinal water absorption which results in softer stools, easier passage of stools and promotion of spontaneous bowel movements (Fig. 2). Thus, ClC-2 activators represent a potentially effective therapy for the treatment of constipation and constipation-predominant irritable bowel syndrome (IBS).^1-4

Fig. 2. Role of ClC-2 chloride channels in intestinal water absorption. ClC-2 is a voltage-gated chloride channel that has been suggested to play a role in water absorption in intestinal epithelium. ClC-2 is known to be activated by hyperpolarization and hypotonic conditions, resulting in secretion of chloride ions into the intestinal lumen. Accumulation of negatively charged chloride anions creates an electric potential that attracts sodium, pulling it into the lumen, apparently across tight junctions. The net result is secretion of NaCl, which creates an osmotic gradient across the tight junction, and water is drawn into the lumen. Increased intestinal water absorption results in softer stool, easier passage of stools and promotion of spontaneous bowel movements.

Rimonabant, another new product for 2006, is the first cannabinoid CB1 receptor antagonist. CB1 is a G-protein-coupled, 7-transmembrane-spanning receptor protein which together with CB2, has been identified as the receptor for cannabinoids. CB1 is preferentially expressed in brain where it mediates the psychoactivity of cannabinoids. High levels of CB1 receptors are found in the basal ganglia, hippocampus, cerebellum and cortical structures. CB1 receptors are coupled through the G_i/o family of proteins to signal transduction mechanisms that include inhibition of adenylyl cyclase and activation of mitogen- activated protein kinase (MAPK). Activation of presynaptic CB1 receptors inhibit N-type Ca²⁺ channel activity, which in turn reduces excitatory neurotransmitter release to the synaptic cleft, thus allowing the excitatory signals to activate the postsynaptic cell (Fig. 3). Endocannabinoids have been implicated in regulating food intake via both central and peripheral mechanisms with the CB1 receptor shown to modulate lipogenesis both in vitro in adipocytes and in animal models of obesity. Administration of CB1 receptor antagonists have been shown to inhibit food intake, stimulate energy expenditure (i.e., increase oxygen consumption) and increase in ambulatory activity in rats. Moreover, a study examining the frequency of a polymorphism of CB1 (1359G/A) in an Italian population found that while the CB1 polymorphism was significantly associated with a lower body mass index (BMI), the CB1 wild-type genotype was associated with an increase in BMI, and a direct relationship was found between the wild-type genotype, female gender, age, glycemia and triglycerides with both over-weight and obesity.^5-8 According to Integrity^®, at least four other drugs with this mechanism of action are in clinical trials and four more are under active development at the preclinical stage. During 2006, at least 40 basic patent applications claiming CB1 antagonists were published.

Fig. 3. Role of cannabinoid CB1 receptor in body energy metabolism and brain reward function. CB1 receptors belong to the G_i/o family G-protein–coupled receptors and are found in the brain, liver and adipose tissue. After endocannabinoid (ECB) binding to CB1, β and γ subunits are released and the activated a subunit inhibits the enzyme adenylate cyclase (AC). This blocks cAMP production from ATP and subsequent PKA-associated signal transduction that is involved in lipogenesis, leptin and adiponectin biosynthesis. In neurons, G-β-γ dimer can activate G-protein–gated inwardly rectifying K+ channels (GIRK), thus regulating synaptic transmission. Moreover, activation of presynaptic CB1 receptors inhibits N-type Ca²⁺ channel activity, which in turn reduces GABA release. This is thought to play a role in brain reward function.

The launch last year of the first dipeptidyl peptidase IV (DPP IV) inhibitor, sitagliptin phosphate, was announced as a major advance for diabetes patients. DPP IV is an enzyme (EC 3.4.14.5) that removes N-terminal dipeptides from peptide hormones of the GRF superfamily, including incretins, glucagon, vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY). DPP IV plays a catalytic role in the processes of signal transduction during immune responses leading to type 2 diabetes. Incretins are a class of gut-derived insulin-releasing hormonal factors that potentiate glucose-induced insulin secretion when blood glucose levels are high. The major forms are gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP exerts insulinotropic activity. GLP-1 is proglucagon- derived peptide released in response to food intake that increases the synthesis and secretion of insulin, thereby controlling blood glucose levels. GLP-1 acts by enhancing the pancreatic expression of the transcription factor IDX-1. The biological functions of GLP-1 are mediated via the high affinity GLP-1 receptor (GLP-1R). Incretins are rapidly hydrolyzed by DPP IV into biologically inactive NH2-terminally truncated fragments (Fig. 4). The impaired secretion of GLP-1 and/or GIP could contribute to the pathogenesis of type 2 diabetes. Inhibition of DPP IV improves glucose tolerance by rescuing intact versions of the incretins GLP-1 and GIP, or by preventing their degradation.^9-12 According to Integrity^®, at least 15 DPP IV inhibitors are under active clinical development at this time, and another six are in preclinical testing. During 2006 more than 55 basic patent applications claiming DPP IV inhibitors were published.

Fig. 4. Insulinotropic signaling pathways associated with GLP-1 and DPP IV. Binding of glucagon-like peptide 1 (GLP-1) to its receptor (GLP-1R) on pancreatic b cells activates a stimulatory G-protein–coupled receptor (Gs family) that activates adenylate cyclase (AC). This favors cAMP production from ATP and subsequent PKA-associated signal transduction involved in the transcription of genes associated with the synthesis and secretion of insulin. GLP-1 is susceptible to hydrolyzation by dipeptidyl peptidase IV (DPP IV).

The antismoking agent varenicline targets the nicotinic α₄β₂ receptor. The nicotinic receptor class of acetylcholine (ACh) receptors are members of the Cys-loop superfamily of pentameric ligand-gated ion channels, which also includes GABA (A and C), serotonin and glycine receptors. They are activated by acetylcholine and the alkaloid nicotine (which imitates the effects of ACh) and thus distinguishes this class of ACh receptors from an unrelated group known as muscarinic ACh receptors. To date, 12 neuronal nAChR subunits have been identified (α_2-10 and β_2-4). They are generally grouped into α subunits containing two adjacent cysteine residues essential for ACh binding, and β subunits, which lack these residues. The majority of neuronal nAChRs either bind agonist with high affinity (nM) or a lower affinity (µM). Low-affinity re-ceptors are homomeric α7 receptors that are α-bungarotoxin-sensitive, while high-affinity nAChR include α₄β₂ in the brain. The receptors are linked to ion channels in the cell membrane and activation through ligand binding can result in depression or stimulation of autonomic ganglia and neuromuscular junctions. However, the role of these receptors in neurotransmission, signaling and behavior has not been completely elucidated. A role has been suggested for these receptors in nicotine addiction, and partial agonism of α₄β₂ may be an effective strategy for smoking cessation (Fig. 5).^13-16

Fig. 5. Role of brain nicotinic α4β2 acetylcholine receptor in neurotransmission and nicotine addiction. The arrival of an action potential in the presynaptic nerve terminal results in the opening of voltage-activated calcium channels. Calcium enters and binds to synaptotagmin, which then interacts with SNARE proteins and membranes to cause the fusion of the synaptic vesicle with the plasma membrane, thereby releasing the neurotransmitter acetylcholine (ACh) into the synaptic cleft. Released ACh binds to the α4β2 receptor, the most common nicotinic ACh receptor subtype in the brain, causing a positively charged ions flow inwards that results in excitation of the neuron. In the brain, ACh plays a role in euphoria, pleasure, mood, appetite and alertness, nicotine having high affinity for α4β2 receptors.

Vorinostat, the first histone deacetyltransferase (HDAC) inhibitor, was also launched in 2006. Histone is a highly conserved protein found in the nuclei of all eukaryotic cells where it is complexed to DNA in chromatin and chromosomes. It is a protein of relatively low molecular weight and is basic with a high arginine/lysine content. Two copies of H2A, H2B, H3 and H4 bind to about 200 base pairs of DNA to form the repeating structure of chromatin known as the nucleosome; H1 binds to the linker sequence. It can act as a nonspecific repressor of gene transcription, and histone acetylation in particular is one mechanism that regulates chromatin structure and its transcription. Histone acetyltransferase (HAT) is the enzyme responsible for addition of the acetyl group on histones. HDAC is the enzyme that removes an acetyl group from histones allowing them to bind DNA and inhibit gene transcription. Because human tumors commonly exhibit changes in DNA methylation and histone modifications, researchers have focused on identification of epigenetic agents such as HDAC inhibitors as potential anticancer agents. Inhibitors of HDAC are thought to transcriptionally reactivate dormant tumor-suppressor genes (Fig. 6). They also possess cell-cycle arrest and apoptotic properties and induce chromatin remodeling and loss of fidelity during mitosis.^17-19 Interest in HDAC inhibitors has been increasing steadily in recent years: 62 new basic patent applications claiming HDAC inhibitors were published in 2006, up from 51 in 2005 and 38 in 2004, according to Integrity^®. At least 20 products with this mechanism of action are in active preclinical and clinical development.

Fig. 6. Modulation of transcriptional activation by histone acetylation and deacetylation. In the absence of ligands, nuclear receptors recruit histone deactylase (HDAC) in a corepressor complex. Deacetylation of the histone proteins leads to chromatin compaction and transcriptional repression (gene silencing). Signal-mediated ligand binding to nuclear receptors causes the release of the corepressor complex and the recruitment of coactivators that exert histone acetyltransferase (HAT) activity. Acetylation establishes a structure that permits remodeling of chromatin to open promoters, recruit transcription factors (TF) and RNA polymerase II (RNA pol II) to initiate gene transcription.

Market for the year’s new drugs and biologics

Last year’s new drugs and biologics entered a market dominated by the products shown in Table A: Estimated pharmaceutical market in Appendix at the end of this issue and in the web version of this article at journals.prous.com, which serves to illustrate the potential market for new medicines launched in 2006. Together these drugs reaped sales of more than USD 40 billion in the year 2006. Products in Table A are listed in the order in which they are cited in this article. The data in this table reflects sales reported by the companies in their quarterly and year-end financial reports. Data on sales by individual product, as obtained from company financial reports, are available from Integrity^®.

The life spans of drugs and biologics

We believe that new or unconventional information is necessary to provide a more accurate picture of the discovery and development of new drugs and biologic therapeutics. For this reason, this year we introduce a new section in our annual review dealing with an analysis of the discovery and development periods for selected new medicines introduced in 2006, from patent application to drug approval to patent expiration and subsequent generic status. This information provides a framework to visually understand the relationship between the many processes that occur during the life of a drug or biologic. The life span of drugs and biologics is one of the parameters being used by the Prous Institute in the development of the Reality^® project.

Repositioning of new drugs and biologics

The life of a drug has the following main periods: drug discovery, drug development, marketing and line extensions.

The drug discovery period lasts until a specific compound is identified as a candidate drug to undergo clinical development. The drug development period includes advanced laboratory, preclinical and all clinical studies and technical development. In order to have a reference date we consider that the development period begins around the date of patent application. After a period of some 10 years, a small portion of drugs that enter the development pipeline actually reach the stage of regulatory approval and marketing. At the time a drug reaches the market, approximately 10 years of patent protection remain for the product-an insufficient time period, in many cases, to recover the investment made to develop the drug in the first place. For this reason the development of new formulations, new indications and new combinations (known as line extensions or repositioning) has emerged as an important strategy for extending the life span of a new product and reaping further financial benefits.

An analysis of the pharmaceutical pipeline in the context of the products considered in this article, based on information from Integrity^®, confirms the importance of repositioning both in present and future terms.

The present: Drug repositioning has a significant impact on market introductions, with line extensions (new formulations, new indications and/or new combinations of previously marketed products) accounting for more than 20 of the new medicines launched in 2006.

The future: Nearly 100 line extensions (new indications, combinations and formulations) are reported to be under clinical evaluation for 17 of the new drugs and biologics that were launched for the first time in 2006 (see Table B: Drugs and biologics repositioning in the Appendix and in the web version of this article.

In addition, at least one combination product incorporating a new molecular entity from 2006 is in active development: Merck & Co. has filed in the U.S. for marketing approval of Janumet^TM, a fixed-dose combination product incorporating sitagliptin phosphate and metformin for the treatment of type 2 diabetes.

After the discovery period (coinciding approximately with the priority date of patents), an IND plan is established and filed, and clinical studies are initiated. Phase I clinical trials focus on safety and last about one year. Phase II focuses on effectiveness in the expected indication(s) and lasts anywhere from 2 to 5 years. Phase III confirms the results of earlier studies in a large patient population and requires between 2 and 4 years.

Life span periods for selected new drugs and biologics introduced in 2006 are depicted in Figure 7. Additional information on patent life spans is presented in Table C: Patent lifespan, in the Appendix and on the web version of this article.

Fig. 7. Estimated life spans of selected drugs and biologics introduced in 2006, from patent priority to patent expiration (Source: Integrity® and Orange Book). *Data presented in this figure (current as of December 31, 2006) are susceptible to change. **New formulation. ***First patent for the approved use.

As can be seen in Table D: Regulatory approval times, in the Appendix and on the web version of this article, approval times are typically shorter and a greater number of new medicines are approved by U.S. regulators as compared with those in the European Union, Japan and other countries.

Generic drug launches, 2006

The rising number of blockbuster drugs that face patent expiration, combined with increasing healthcare expenditures, portends significant growth of the generic drug industry in the coming years. A cycle has been established: pharma innovation → patent expiration → generics. Costing up to 60% less than branded drugs, generics now account for approximately half of all prescription drug sales in the U.S. Generic penetration in other global markets is also increasing, with substantial growth forecasted in the coming years in Europe, Japan and Canada, while growth in the U.S. is expected to decelerate.

It is expected that by the year 2012, drugs worth more than USD 50 billion in sales will go generic. Generic drugs are also discussed in “Overcoming the Challenges in the Pharma/Biotech Industry” (see p. 58). Pharmaceutical companies such as Novartis and Merck KGaA have responded to this challenge by establishing successful generic subsidiaries of their own. Other companies have elected to produce lower-cost generic versions of their own best-selling drugs, as is the case with Pfizer’s antidepressant Zoloft (sertraline) or Merck & Co.’s Zocor (simvastatin) following recent patent expirations. This could be an alternative new strategy for facing competition from generic companies.

The provisions of the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Amendments) that govern the generic drug approval process give 180 days of marketing exclusivity to certain generic drug applicants. The 180-day generic drug exclusivity provision is one component of the complex patent listing and certification process, which also provides for a 30-month stay on generic drug approvals while certain patent infringement issues are litigated.

Several significant patent expirations for blockbuster branded pharmaceuticals took place in 2006, including Zoloft (sertraline) and Bristol-Myers Squibb’s Pravachol (pravastatin). In 2005 Zoloft was the sixth highest-selling brand name drug in the U.S.

The market for statins was about USD 22 billion at the end of 2006. In 2006 both Zocor (the second most widely prescribed statin) and Pravachol lost patent protection. Generic substitution of Zocor and Pravachol is predicted to decrease current sales of all branded statins by as much as USD 8-9 billion in the next

5 years, when atorvastatin (Lipitor) goes generic as well. The relatively few new products currently in the pipeline (according to Integrity^®, only two new statins are in clinical testing at this time) are not expected to make up the difference felt by existing statins’ loss of dominance.

Also in 2006, the FDA issued the first tentative approval for a three-ingredient fixed-dose tablet for use as a stand-alone antiretroviral treatment for HIV-1 infection in adults. The product, a lamivudine/zidovudine/nevirapine tablet, contains the active ingredients in the widely used antiretroviral drugs Epivir (lamivudine), Retrovir (zidovudine) and Viramune (nevirapine). This was the first NDA generic approval in the world for an antiretroviral three-drug combination. The agency’s tentative approval means that although existing patents and/or exclusivity prevent approval of this product in the U.S., it meets all of the FDA’s manufacturing quality and clinical safety and efficacy standards required for marketing in the U.S. The fixed-dose combination tablet, manufactured by Aurobindo Pharma, will be available for purchase and distribution in 15 other countries under the President’s Emergency Plan for AIDS Relief (PEPFAR).

In some cases generic approvals granted by the FDA are later reversed in court. One such case was that of escitalopram (Lexapro), for which a generic approval was granted by the agency in May 2006. Product manufacturers Lundbeck and Forest took the generic manufacturer (Teva) to court over patent rights, and in July a U.S. district court ruled in favor of the former. Lexapro patents do not expire until 2012. In a similar story, Bristol-Myers Squibb is attempting to recover patent exclusivity for Plavix (clopidogrel), which faced a brief but fierce competition from a generic version introduced last year by Apotex. The generic company has been temporarily barred from selling the drug, while the case is being decided in the U.S. district court in New York.

Table III shows major first-time generic approvals issued by the Food and Drug Administration last year, together with their estimated annual sales while still under patent protection. Together these drugs generated sales of about USD 14 billion in 2006.

What’s next? Outlook for 2007 and beyond

Which drugs will be next to market? Which therapeutic groups could incorporate the greatest number of new members in 2007/2008? In the changing world of drug development, no one can answer these and related questions with complete certainty.

At present nearly 80 drugs and biologics are awaiting approval by regulatory authorities. Some of these new medicines will be introduced in the next 2 years. Based on a careful analysis of company communications, clinical studies and other parameters, we can predict with some confidence which new medicines could be expected to be included in future editions of this yearly article. Of course some of these drugs may not reach the market, and others that we have not selected may be approved.

One interesting new product is retapamulin, expected to become the first in a new class of antibiotics called pleuromutilins. The product has been filed for approval in the U.S. and Europe by GlaxoSmithKline for the topical treatment of secondarily infected traumatic lesions (SITL), and in December 2006, GlaxoSmithKline received an approvable letter from FDA.

Novartis’ DPP IV inhibitor vilda-gliptin (Galvus^®), awaiting approval as a new oral once-daily therapy for patients with type 2 diabetes, was issued a 3-month review process extension in November 2006 by the FDA. Results from recent clinical trials were submitted to the FDA involving an additional 1,000 patient-years of treatment experience. The data further support the proposed once-daily dosing regimen and indications. The product is also under review in the E.U.

In December 2006 New River Pharmaceuticals and Shire received a second approvable letter from the FDA regarding Vyvanse™ (lisdexamfetamine dimesylate) for the treatment of attention deficit-hyperactivity disorder. A first approvable letter was received in October, to which New River immediately submitted a complete response. No additional studies have been requested as a condition for approval. The data requested are routine, and their provision to the FDA is not expected to delay the product launch, anticipated by the companies in the second quarter of 2007.

Eprodisate sodium (Kiacta™), an antiamyloidogenic agent, is under review in the U.S. and E.U. for the treatment of secondary amyloid A (AA) amyloidosis. In August 2006, Neurochem received an approvable letter from the FDA for the NDA, which had been granted priority review in April 2006. In Europe the Marketing Authorization Application for eprodisate has been validated by the EMEA, which confirmed that the regulatory review has started; Neurochem expects to receive a decision from the FDA in the first half of 2007 and from the EMEA in the second half of the year.

Other promising new drugs and biologics that we forecast could be granted regulatory approval in the near future include the protein kinase C β inhibitor ruboxistaurin mesilate hydrate (Arxxant; Lilly), under review at the FDA for the treatment of diabetic retinopathy; the pandemic influenza vaccine Daronrix^® (GlaxoSmithKline), which received a positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) in December 2006; the CCR5 antagonist miraviroc (Pfizer), a promising new anti-HIV agent under review with fast-track status at the FDA and with accelerated review status in Europe; and Roche’s Mircera^®, the first continuous erythropoietin receptor activator for the treatment of anemia in patients with chronic kidney disease. Regulatory filings for this product occurred in the U.S. and E.U. in April of last year. In December Roche submitted additional data to the FDA to support its BLA for Mircera, and the FDA subsequently granted Roche a 3-month extension to the review period. Another human papillomavirus vaccine, Merck & Co.’s Cervarix^®, is also under regulatory review in Europe and could reach the market in the coming year or two, as could the topical antifungal agent abafungin (Abasol™; York Pharma). A prospective new addition to the armamentarium of oncolytic drugs is Novartis’s nilotinib (Tasigna^®), a signal transduction inhibitor under review at the FDA for the treatment of chronic myeloid leukemia. A re-lated drug, the ErB-1/ErB-2 dual kinase inhibitor lapatinib (Tykerb; GlaxoSmithKline), is under review at the FDA, where it has fast-track status for the treatment of breast cancer. Other drugs that are expected to soon emerge from the pipeline are armodafinil (Nuvigil; Cephalon), an α1-adrenoceptor antagonist for the treatment of excessive daytime sleepiness associated with narcolepsy and other sleep disorders; GlaxoSmithKline fluticasone furoate (Allermist), a glucocorticoid receptor agonist for the treatment of allergic rhinitis; and the selective estrogen receptor modulator (SERM) bazedoxifene acetate (Viviant; Wyeth/Ligand), a prospective treatment for osteoporosis. Assuming that regulatory reviewers view these prospective new medicines in a favorable light, they could soon provide new therapeutic options for the treatment of a range of human diseases.

References

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13.  Saccone, S.F., Hinrichs, A.L., Saccone, N.L. et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3,713 SNPs. Hum Mol Genet 2007, 16: 36-49.

14.  Nashmi, R., Lester, H.A. CNS localization of neuronal nicotinic receptors. J Mol Neurosci 2006, 30: 181-4.

15.  Rollema, H., Chambers, L.K., Coe, J.W. et al. Pharmacological profile of the alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neurophar-macology 2006, Dec 6; [Epub ahead of print].

16.  Reus, V.I., Obach, R.S., Coe, J.W. et al. Varenicline: New treatment with efficacy in smoking cessation. Drugs Today 2007, 43(2): in press.

17.  Hodges-Gallagher, L., Valentine, C.D., Bader, S.E. et al. Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res Treat 2006, Advance Publication.

18.  Kim, H.R., Kim, E.J., Yang, S.H. et al. Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway? Exp Mol Med 2006, 38: 616-24.

19.  O’Connor, O.A. Clinical experience with the novel histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in patients with relapsed lymphoma. Br J Cancer 2006, 95(Suppl 1): S7-12.

Drug News & Perspectives Vol. 20, No. 1, 2007, pp. 17-44
ISSN 0214-0934 Copyright 2007 Prous Science, S.A. CCC: 0214 0934/2007 http://www.prous.com

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