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    In the pipeline: Drugs to watch in 2009

    Several blockbuster drugs will fight to hold onto their top spots in 2009 as new products come before FDA for marketing approval, reported Brian W. Kolling, PharmD, at a recent meeting of the Academy of Managed Care Pharmacy (AMCP) in Kansas City, Mo. Key therapies to watch as they move through the pipeline include medications for cardiovascular (CV) disorders, central nervous system (CNS) disorders, respiratory disease, and diabetes, he said.

    According to Keith Bradbury, executive director of drug information at Medco Health Solutions Inc., FDA has delayed approval of many NDAs while the agency struggles with implementing new regulations established by the 2007 FDA Amendment Act (FDAAA).

    “We are at a historic time in terms of the number of products the FDA has delayed or allowed the user end-date to pass and extended the review period,” Bradbury said.

    For this reason, he said, as many as 62 NDAs could be submitted in 2009. Of these, perhaps 25 will be approved. “There are about 40 to 45 drugs sitting at the FDA today waiting for action,” Bradbury said.

    According to Bradbury, a home run might occur in the CV field. Bradbury was referring to rivaroxaban (Bayer/Johnson & Johnson); if approved, this agent will be the first new anticoagulant oral drug to reach the market in more than 40 years, with the potential to replace warfarin.

    “This is potentially a multibillion-dollar drug. It looks very promising,” Bradbury said. The benefit of rivaroxaban is the potential elimination of the costly monitoring associated with warfarin.

    Another important CV agent in the pipeline is prasugrel (Daiichi Sankyo/Lilly), which, if approved, will compete with clopidogrel. The Cardiovascular and Renal Drugs Advisory Committee is scheduled to meet on February 3 to discuss prasugrel.

    “The $64,000 question is: Is the FDA going to be able to tease out from the data whether the drug is in the net beneficial and not harmful? If this happens, then [clopidogrel] is going to have some...competition,” Bradbury said.

    Although most of the new drugs expected to hit the market will inevitably carry hefty price tags, the introduction of several key generics should offset some of the medication costs consumers face. “It is our expectation that in 2009, about $11 billion of prescription drugs will be subject to generic competition,” Bradbury said.

    The following therapeutic areas are the ones to watch for emerging therapies.

    Cardiovascular
    During the next several years, generic products will continue to make inroads into the CV market as the top statin, angiotensin II receptor blocker (ARB), and antiplatelet drug all go off patent by 2012. There is also a full field of factor Xa inhibitors, several of which are now in phase 3 trials.

    Statins will still dominate cholesterol management, but combination products and several agents with new mechanisms of action are in development. New products to watch for include GlaxoSmithKline’s darapladib, which targets lipoprotein-associated phospholipase (Lp-PLA2), an enzyme linked to artery-clogging plaque, and Isis and Genzyme’s mipomersen, an apolipoprotein B100 antisense inhibitor designed as a lipid reducer for high-risk CV patients. Two new cholesteryl ester transfer protein (CETP) inhibitors, Merck’s anacetrapib and Roche’s dalcetrapib, are also on the horizon.

    There has been a push to develop new antiplatelet and antithrombotic agents to replace less effective and more costly products. As mentioned above, if approved, prasugrel, a platelet inhibitor used for the prevention of CV events in patients with acute coronary syndrome (ACS), could rival clopidogrel, which is set to see its patent expire in 2011. Clinical trials demonstrated that prasugrel may be more effective than clopidogrel in preventing CV death, nonfatal myocardial infarctions (MIs), and strokes, but also that it was more likely to cause serious bleeding. If FDA calls for additional clinical trials to study the bleeding issue, the drug’s approval would be delayed.

    SCH-530348 (Schering-Plough), an oral antiplatelet drug, would be the first in a new class of thrombin receptor antagonists. SCH-530348 prevents blood clots by inhibiting the action of thrombin, a key coagulation factor that converts fibrinogen into fibrin. This agent is in phase 2/3 trials.

    Another new antiplatelet formulation is ticagrelor, the first reversible oral adenosine diphosphate (ADP) receptor antagonist. Developed to reduce the risk of thrombotic events in ACS patients, ticagrelor inhibits platelet aggregation, which may reduce clot formation. Clinical benefits of reversibility are unclear; however, results of phase 2/3 trials now under way may shed light on the issue.

    With limited clinical choices for the prevention of thromboembolic disease, 2 new anticoagulants could meet the need for new products in this area: rivaroxaban, a once-daily direct Xa inhibitor being studied for the prevention of venous blood clots in adult patients undergoing elective hip- or knee-replacement surgery, and dabigatran etexilate (Boehringer Ingelheim), an oral reversible direct thrombin inhibitor being studied for acute venous thromboembolism (VTE) treatment and secondary prevention of VTE, as well as prevention of CV events in ACS.

    Dronedarone (Sanofi-Aventis), a multichannel blocker with antiadrenergic properties that is chemically similar to amiodarone, is being studied in patients with atrial fibrillation or atrial flutter. Clinical trial results indicate that this agent may be better tolerated than amiodarone.

    Central nervous system
    Researchers are aggressively working to develop new products that will eliminate some of the undesirable side effects associated with many currently available CNS drugs. Several new migraine treatments are under investigation, as are new fibromyalgia agents. The CNS market will also see several top drugs going off patent in 2010 and 2011.

    Existing antidepressants often have negative side effects, efficacy problems, and poor patient compliance. One new drug in the pipeline is saredutant (Sanofi-Aventis), a neurokinin-2 receptor antagonist with a mechanism of action different from any employed by existing drugs. It blocks the effects of neurokinin-2, thereby preventing the neurochemical changes induced by stressful conditions in various brain regions.

    Melatonin receptor agonists are also in the pipeline, with one of the lead compounds, agomelatine (Novartis), now in phase 3 trials. Compared with existing antidepressants, agomelatine is the first melatonergic agent to demonstrate favorable results in its effect on sleep, weight, and sexual function.

    Although antipsychotic drugs are the mainstay of schizophrenia treatment, common side effects such as metabolic disturbances, sexual dysfunction, hyperprolactinemia, and cardiotoxicity lead to poor long-term adherence. As a result, researchers are working to develop a third generation of antipsychotics that may provide broader efficacy, reduced side effects, and improved tolerability. Several NDAs have been submitted, among them applications for sertindole (Lundbeck), which is associated with less sedation when used to treat schizophrenia, and asenapine (Schering-Plough), a new 5-HT2A/D2 receptor antagonist for treatment of schizophrenia and bipolar mania disorder. FDA issued a complete response letter for asenapine earlier this month; the letter asked for supplemental data but not for additional clinical trials.

    Two migraine treatments are in late-stage development: telcagepant (Merck), an oral calcitonin gene-related peptide (CGRP) receptor antagonist, and botulinum toxin A (Botox; Allergan), which is injected every 12 weeks in trials. Both agents are in phase 3 trials, and the manufacturers hope to file for FDA approval in 2009.

    Milnacipran (Savella, Forest/Cypress), a selective norepinephrine serotonin reuptake inhibitor (NSRI), was approved earlier this month for the management of fibromyalgia. [S,S]-reboxetine (Pfizer), a norepinephrine reuptake inhibitor, is also in development for this indication. Reboxetine is in phase 3 clinical trials.

    The sleep-disorder market may see the arrival of 2 new insomnia drugs: doxepin (Somaxon) and eplivanserin (Sanofi-Aventis). Unlike existing sleep aids, doxepin selectively blocks the neurotransmitter histamine and may improve insomnia symptoms without serious adverse effects. The PDUFA date for the doxepin NDA was recently extended to February 29, 2009. Eplivanserin, a selective 5HT2A receptor antagonist, is in phase 3 trials. Zolpidem tartrate extended release (Ambien CR; Sanofi-Aventis) is scheduled to go off patent in March 2009.

    Respiratory agents
    Respiratory drug development is focused on a wide range of potential combination therapies. A new class of drugs is not likely to be available for at least 3 to 5 years.

    Novartis is developing indacaterol, an ultra-long-acting beta agonist inhaler, for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. An NDA for aclidinium bromide (Forest/Almirall), an inhaled muscarinic antagonist for COPD, is expected to be filed in the fourth quarter of 2009 or the first quarter of 2010.

    Tadalafil (Cialis, Lilly) has demonstrated promising results for the treatment of pulmonary hypertension. An NDA for inhaled treprostinil (United Therapeutics) for the treatment of pulmonary arterial hypertension was submitted in June 2008. Pfizer is awaiting FDA approval for sitaxsentan, an endothelin receptor antagonist for pulmonary arterial hypertension treatment.

    Diabetes treatments
    Few patients with diabetes achieve their target goals for blood glucose, cholesterol, and blood pressure, and many of these patients are undertreated. Drugs are being developed to meet the needs of this population as the incidence of diabetes assumes epidemic proportions.

    Two new dipeptidyl peptidase (DPP-4) products, alogliptin (Takeda) and saxagliptin (Bristol-Myers Squibb/AstraZeneca), have demonstrated favorable results in patients not adequately controlled with existing insulin products. Alogliptin is pending FDA approval; the PDUFA date for this NDA was recently extended to June 26, 2009. An NDA was submitted for saxagliptin on June 30, 2008.

    Novo Nordisk’s liraglutide, a GLP-1 analog, has demonstrated a risk of hypoglycemia much lower than that connected with many existing drugs. In phase 3 trials, more than half of the participating patients achieved a glycosylated hemoglobin A1c (HbA1c) of
    Dapagliflozin (Bristol-Myers Squibb/Astra-Zeneca), a highly selective inhibitor of sodium glucose cotransporter 2 (SGLT2), has a dose-dependent effect on HbA1c levels and fasting plasma glucose (FPG). In clinical trials, the drug produced slight weight loss but was also associated with a higher incidence of urinary tract infections.

    In a field of failed attempts to market inhaled insulin, MannKind is hoping to gain approval for a delivery system that administers a dry-powder insulin formulation through a palm-sized inhaler. Phase 3 trial data comparing this powder formulation with injected insulin have demonstrated similar efficacy between the 2 formulations.