TCP presents its annual list of drugs in development and what their approval will mean to long-term care patients.
| L. Michael Posey |
| Jennifer T. Chang |
Following a year in which the Food and Drug Administration approved a record number of new drugs, the quantity of important new drugs in development has been depleted substantially. But many new agents still await federal action-or completion of clinical trials-and many of these agents will represent substantial improvements over currently marketed therapies.
In this article TCP presents compilations of drugs approved last year and agents that may be marketed in the United States over the next year or two. Readers aware of other new drugs are encouraged to contact TCP so additions may be included in future reports.
Table 1 provides readers with information about the investigational-drug and the drug-approval processes in the United States. An understanding of these terms will aid readers in understanding later descriptions of the status of investigational drugs as they move through the research and development pipeline.
Table 1. Drug-Development and Drug-Approval Process
| Phase | Time Period | Goal |
| Preclinical testing | Approximately 3.5 years | Laboratory and animal tests to test for activity against targeted disease and to test for safety. Investigational New Drug Application (IND) is filed with FDA |
| Phase I Trial | Approximately 1 year | 20-80 normal, healthy volunteers to test for safety, dose and pharmacokinetics |
| Phase II Trial | Approximately 2 years | 100-300 volunteer patients with the targeted disease to assess effectiveness |
| Phase III Trial | Approximately 3 years | 1,000-3,000 patients in controlled setting; patients monitored to determine efficacy and monitor for adverse effects |
| Treatment IND | - | Makes promising new drugs available to patients with serious, life-threatening diseases for which there is no comparable therapy before the drug is actually approved |
| New Drug Application | - | All data gathered during Phase I-III filed with FDA(NDA) trials submitted to FDA |
| FDA Review | 6 months-2.5 years | FDA Approval |
| Phase IV | - | Postmarketing surveillance |
1996 Drug Approvals
As FDA Commissioner David Kessler completed six activist years at the helm of FDA, reviewers of New Drug Applications apparently worked overtime so Kessler could proclaim to the world the efficiencies of the American system, 1990s style. But not only did these new agents boast success in numbers, some of the drugs also made immediate impacts on serious or common diseases, including HIV infection, the scourge of the late twentieth century.
Table 2 lists the new molecular entities approved by FDA during calendar year 1996. In addition to the 54 drugs listed here, FDA approved six new imaging agents and several new vaccines and other biologicals.
Table 2. New Molecular Entities Approved in 1996a
| 1P Drugs (Priority Rating) | Indication |
| Albendazole (Albenza, SKB) | Anthelmintic |
| Amlexanox (Aphthasol, Block Drug) | Aphthous ulcers |
| Atorvastatin (Lipitor, Warner-Lambert) | Hypercholesterolemia (HMG-CoA reductase inhibitor) |
| Betaine (Cystadane, Orphan) | Homocystinuria |
| Corticorelin (Acthrel, Ferring Labs) | Cushing's syndrome |
| Docetaxel (Taxotere, Rhone-Poulenc Rorer) | Breast cancer |
| Donepezil (Aricept, Pfizer/Eisai) | Alzheimer's disease |
| Gemcitabine (Gemzar, Lilly) | Pancreatic adenocarcinoma |
| Indinavir (Crixivan, Merck) | HIV/protease inhibitor |
| Insulin lispro (Humalog, Lilly) | Diabetes mellitus |
| Irinotecan (Camptosar, P&U) | Colorectal cancer |
| Ivermectin (Stromectol, Merck) | Strongyloidiasis/onchocerciasis |
| Latanoprost (Xalatan, P&U) | Open-angle glaucoma |
| Midodrine (ProAmatine, Roberts) | Orthostatic hypotension (alpha-1 agonist) |
| Nevirapine (Viramune, Boehringer Ingelheim) | HIV/non-nucleoside reverse transcriptase inhibitor |
| Ritonavir (Norvir, Abbott) | HIV/protease inhibitor |
| Sodium phenylbutyrate (Buphenyl, Ucyclyd) | Chronic urea cycle disorders |
| Topotecan (Hycamtin, SKB) | Ovarian carcinoma |
| 1S Drugs (Standard Review) | Indication |
| Adapalene (Differin, Galderma) | Acne vulgaris |
| Albendazole (Albenza, SKB) | Neurocysticercosis |
| Azelastine (Astelin, Carter-Wallace) | Allergic rhinitis |
| Bentoquatam (IvyBlock, EnviroDerm) | Skin protectant |
| Brimonidine (Alphagan, Allergan) | Open-angle glaucoma |
| Butenafine (Mentax, Penederm) | Fungal infections (topical) |
| Cabergoline (Dostinex, P&U) | Hyperprolactinemia |
| Cefepime (Maxipime, BMS) | Bacterial infections |
| Cidofovir (Vistide, Gilead) | Cytomegalovirus |
| Danaparoid (Orgaran, Organon) | Deep-vein thrombosis prophylaxis |
| Fexofenadine (Allegra, HMR) | Seasonal allergic rhinitis |
| Fosfomycin (Monurol, Forest/Zambon) | Uncomplicated UTIs |
| Fosphenytoin (Cerebyx, Warner-Lambert) | Epilepsy |
| Glatiramer (Copaxone, Teva) | Multiple sclerosis |
| Haemophilus b conjugate and hepatitis B vaccine (Comvax, Merck) | Infant infections |
| Interferon-beta-1a (Avonex, Biogen) | Multiple sclerosis |
| Irinotecan (Camptosar, P&U) | Colorectal cancer |
| Meropenem (Merrem I.V., Zeneca) | Infections (carbapenem antibiotic) |
| Mirtazapine (Remeron, Organon) | Antidepressant |
| Nilutamide (Nilandron, HMR) | Antiandrogen/metastatic prostate cancer |
| Olanzepine (Zyprexa, Lilly) | Psychosis |
| Olapatadine (Patanol, Alcon) | Allergic conjunctivitis |
| Penciclovir cream (Denavir, SKB) | Recurrent herpes labialis |
| Pentosan (Elmiron, Ivax) | Bladder pain |
| Porfimer (Photofrin, Quadra Logic) | Esophageal cancer |
| Remifentanil (Ultiva, Glaxo Wellcome) | Analgesic opioid |
| Reteplase (Retevase, Boehringer Mannheim) | Myocardial infarction |
| Ropivacaine (Naropin, Astra) | Local anesthetic |
| Selegiline (Carbex, Dupont Merck) | Parkinson's disease |
| Sparfloxacin (Zagam, Rhone-Poulenc Rorer) | Pneumonia/bronchitis |
| Tizanidine (Zanaflex, Athena Neurosciences) | Muscle spasticity |
| Topiramate (Topamax, J&J) | Partial onset seizures |
| Trandolapril (Mavik, Knoll) | ACE inhibitor/hypertension |
| Urea (13C; UBT breath test, Meretek) | H. pylori detection |
| Valsartan (Diovan, Novartis) | Hypertension (angiotensin II blocker) |
| Zafirlukast (Accolate, Zeneca) | Asthma |
| Zileuton (Zyflo, Abbott) | Asthma |
a Contrast media are not listed. SKB = SmithKline Beecham; P&U = Pharmacia & Upjohn; BMS = Bristol-Myers Squibb; HMR = Hoechst Marion Roussell; J&J = Johnson & Johnson.
Drugs Up for Approval in 1997 and Beyond
Table 3 provides this year's list of new drugs in various stages of development. All investigational agents that have moved into clinical testing (Phases I, II, or III) are listed. Sources of information were trade press reports, previous years' new drugs articles in this journal, and news releases issued by pharmaceutical manufacturers.
TABLE 3. Potential New Drugs for 1997 and Beyond
| Drug Classes | Drug Type/Mechanism | Uses | Approval Status |
| Bone and Joint Disorders | |||
| Deflazacort (Hoechst Marion Roussel) | Bone-sparing steroid | Rheumatoid arthritis | Phase III |
| Droloxifene (Pfizer) | Estrogen antagonist/agonist | Osteoporosis | Phase II/III |
| Evista (Lilly) | Osteoporosis | Target NDA 1997 | |
| Kelixmab (SmithKline Beecham) | Anti-CD4 monoclonal antibody | Rheumatoid arthritis | Phase III |
| L-783,003 (Merck) | Arthritis | Phase II | |
| Leflunomide (HWA-486, Hoechst Marion Roussel) | Immunosuppressive agent | Rheumatoid arthritis | Target NDA late 1997 |
| MK-966 (Merck) | COX-2 inhibitor | Arthritis | Phase III |
| Oral type II collagen (Colloral, AutoImmune) | Adult and juvenile rheumatoid arthritis | Phase II | |
| Raloxifene (Lilly) | Estrogen receptor modulator | Osteoporosis | Phase III |
| Risedronate (Proctor & Gamble) | Bisphosphonate | Osteoporosis | Phase III |
| RS-66271 (Roche) | Parathyroid hormone- related peptide | Osteoporosis | Phase II |
| Sodium Fluoride (Mission Pharmacal) | Fluoride | Osteoporosis | NDA filed |
| Temoxicam (Tilcotil, Roche) | Rheumatoid arthritis | Phase III | |
| Tenidap (Enablex, Pfizer) | NSAID | Arthritis | Unfavorable |
| Tiludronate (Skelid, Sanofi) | Biphosphonate | Paget's disease | NDA filed |
| Cardiology | |||
| Acecainide (Parke-Davis) | Class III antiarrhythmic | Chronic sustained VT, PVC | Phase III |
| Alacepril (Cetapril, Dainippon) | ACE inhibitor | Mild-moderate HTN | Phase III |
| Arbutamine (GenESA, Gensia) | Dx of CAD | Phase III | |
| Bucindolol (Intracardial Astra Merck) | Beta blocker | CHF | Phase III |
| Cefenline (Cipralan, Roche, Glaxo Wellcome) | Imidazdine derivative | Arrhythmias | NDA filed |
| Celiprolol (Selecor, Rhone- Poulenc Rorer) | Beta blocker | HTN | NDA filed |
| Cetamolol (ICI) | Beta blocker | ||
| Citicoline (Interneuron) | Ischemic stroke | Phase III | |
| Clopidogrel (Bristol-Myers Squibb) | Platelet aggregation inhibitor | Atherosclerosis, stroke heart attack, PVD, | Phase III (target NDA 1997 |
| Dalvastatin (Rhone-Poulenc Rorer) | Hypercholesterolemia | Phase III | |
| Desirudin (Revasc, Ciba-Geigy) | Thrombin inhibitor | Acute MI | Phase III |
| Dofetilide (Pfizer) | Class III anti-arrhythmic | Atrial fib/flutter, PSVT, VT/VF | Phase III (Target NDA fourth quarter of 1997) |
| Duteplase (Prolysis, Glaxo Wellcome) | Tissue plasminogen activator | Acute MI | Phase III |
| Fenoldopam (Corlopam, Neurex) | Dopamine agonist | Hypertensive emergency, acute RF | NDA filed |
| Integrelin (Cor Therapeutics) | Glycoprotein IIb/IIIa inhibitor | Prevent complications after angioplasty | NDA filed |
| Irbesarban (Sanofi) | Angiotensin II antagonist | HTN | Target NDA 1997 |
| Lacidipine (Lacipil, Glaxo Wellcome) | Calcium antagonist | HTN | NDA filed |
| Lamifiban (Roche) | Acute coronary syndrome | Phase III | |
| Lemakalim (SmithKline Beecham) | Potassium channel agonist | HTN | |
| Mibefradil (Posicor, Roche) | Calcium antagonist | HTN, angina | NDA filed |
| Nicorandil (Ikorel, Upjohn) | Potassium channel agonist | Angina, CHF | |
| Pirmenol (Warner-Lambert) | Antiarrhythmic | PVC, SVT, supraventricular arrhythmias | Phase III |
| Ranolazine SR (CV Therapeutics) | Angina | Phase III | |
| Tasosartan (Wyeth-Ayerst) | Antgiotensin II antagonist | HTN | Target NDA 96/97 |
| Temocapril (Sankyo) | ACE inhibitor | HTN | Phase III |
| Teneten (SmithKline Beecham) | Angiotensin II inhibitor | HTN | Phase III |
| Tiamenidine (Symcor, Hoechst Marion Roussel) | Centrally acting agent | HTN, CHF | Phase III |
| Tirilazad (Freedox, Upjohn) | Lazaroid | SAH, stroke (Stroke studies stopped) | Phase III |
| Trandolapril (Mavik, Knoll) | ACE inhibitor | HTN | Approvable |
| Tirofiban (Aggrastat, Merck) | Unstable angina, decrease risk of cardiac events w/ angioplasty | Phase III (Target NDA second half of 1997) | |
| Vesnarinone (Arkin, Otsuka) | Phosphodiesterase inhibitor | CHF | Phase III |
| Xamoterol | Beta-1 partial agonist | HTN, CHF | NDA filed |
| Zofenopril (Zoprace, BMS) | ACE inhibitor | MI, HTN | Phase III |
| Dermatology | |||
| Acitretin (Soriatane, Roche) | Retinoid psoriasis | Recalcitrant psoriasis | Approvable |
| Anti-CD11a | Monoclonal antibody | Psoriasis | Phase II |
| Becaplermin (Regranex, Chiron) | Platelet growth factor | Wound healing | Phase III |
| CTLA4Ig (Bristol- Myers Squibb) | Immunomodulator | Psoriasis | Phase II |
| Graftskin (Sandoz) | Full thickness living skin equivalent | Chronic wounds, venous ulcers, diabetic ulcers, pressure sores, burns | NDA filed |
| Iamin (ProCyte) (Kynac, Sphinx) | Copper-based agent | Diabetic foot ulcer Psoriasis, eczema | Phase III |
| Mafenide acetate (Sulfamylon 5%, Mylan) | Antimicrobial | Burn wounds | NDA filed |
| Tazarotene topical gel (Zorac, Allergan) | Receptor-selective retinoid | Psoriasis and acne | Approvable |
| Tipredane (Bristol-Myers Squibb) | Atopic dermatitis, psoriasis | NDA filed | |
| Transforming Growth Factor Beta(Betakine, Celtrix) | Connective tissue growth stimulation, chronic ulcers, macular holes | ||
| Endocrinology | |||
| BRL49653 (SmithKline Beecham) | Insulin sensitizer | NIDDM | Phase III |
| Bromocriptine (Ergoset, Ergo Science) | Dopamine agonist | NIDDM | Phase III (Target NDA mid-1997) for approval |
| Englitazone (Pfizer) | Insulin sensitizer | NIDDM | |
| IGF-1 (Genentech) | Diabetes | Phase III | |
| Orlistat (Xenical, Roche) | Lipase inhibitor | Obesity | Phase III |
| Pimagedine (Alteon) | NIDDM | Phase III | |
| Pramlintide (Amylin Pharmaceuticals) | Amylin analog | NIDDM | Phase III |
| Pioglitazone (Takeda) | Insulin sensitizer | NIDDM | |
| Sibutramine (Meridia, Knoll) | Obesity | Approvable | |
| Tolrestat (Alredase, Wyeth Ayerst) | Aldose reductase inhibitor | Diabetic complications | Failed |
| Troglitazone (Rezulin, Warner Lambert) | Insulin sensitizer | NIDDM | Approved 1/29/97 (Launch March 1997) |
| Voglibose (Takeda) | Alpha-glucosidase inhibitor | NIDDM | |
| Gastroenterology | |||
| Alosetron (GlaxoWellcome) | 5HT3 receptor antagonist | Irritable bowel syndrome | Phase II |
| Balsalazide disodium(Colazide, Astra/Salix) | Ulcerative colitis | Phase III (Target NDA 1997) | |
| CDP-571 (Celltech) | Anti-TNF monoclonal antibody | Crohn's disease | Phase II |
| Darifenacin (Pfizer) | Irritable bowel syndrome & urinary incontinence | Phase III | |
| Didodesine (GlaxoWellcome) | Irritable bowel syndrome | Phase II | |
| Domperidone (Motilium, Janssen) | Prokinetic agent | Gastroparesis | |
| Enprostil (Gardin, Syntex) | Prostaglandin E2 analog | Peptic ulcers | NDA filed |
| Fedotazine | Irritable bowel syndrome | Phase III | |
| Ferriseltz (OncoMembrane) | MRI contrast agents | GI | NDA filed (Approvable) |
| Roxatidine (Roxin, Hoechst Marion Roussel) | H2 antagonist | Peptic ulcers | NDA filed |
| Saviprazole (Hoechst Marion Roussel) | Proton pump inhibitor | Peptic ulcers | |
| SB207266 (SmithKline Beecham) | 5-HT4 antagonist | Irritable bowel syndrome | Phase III |
| Tazofelone (Roberts) | Antioxidant and free radicals | Inflammatory Bowel disease scavenger | Completed phase II |
| Tropisetron (Navoban, Sandoz) | 5-HT3 antagonist | Chemotherapy-related nausea/vomiting | |
| Ursodeoxycholic acid (Urso, Axcan) | Bile acid | Primary biliary cirrhosis | NDA filed |
| Zamifenacine (Pfizer) | Irritable bowel syndrome | Phase III | |
| Zinc acetate (Galzin, Teva) | Wilson's disease | Approved 1/28/97(Available end of March) | |
| Infectious Disease | |||
| Cefdinir (Warner-Lambert) | Cephalosporin | Broad spectrum with good Staph coverage(may replace multiple drug regimens) | Phase III |
| Cefodizime (Fujisawa) | 3rd generation cephalosporin | NDA filed | |
| Cefpirome (Cefrom, Hoechst Marion Roussel) | 3rd-4th generation cephalosporin | Gram (+) and Gram (-)infections | Phase III |
| Ceftamet (Roche) | Upper respiratory infections in pediatrics | Phase III | |
| Clinafloxin (Warner-Lambert) | Quinolone | Hospital-acquired infections | Target NDA 6/98 |
| Delavirdine (Rescriptor, Pharmacia & Upjohn) | Non-nucleoside transcriptase inhibitor | HIV disease | NDA filed (Awaiting accelerated approval) |
| Cytolex (MSI-78, SmithKline Beecham) | Topical antibiotic cream | Diabetic foot ulcer | Phase III (Target NDA fourth quarter of 1997) |
| DMP 266 (DuPont/Merck) | Non-nucleoside transcriptase inhibitor | HIV disease | Phase II |
| Fleroxacin (Megalone, Roche) | Quinolone | Uncomplicated/ complicated UTI, uncomplicated cervical and urethral gonorrhea | Recommended approval (However, NDA withdrawn 1/96) |
| GV118819 (GlaxoWellcome) | Trinem class | Penicillin-resistant streptococci | Phase II |
| Inhaled tobramycin | Aminoglycoside | Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis | Target NDA second quarter 1997 |
| ISIS 2922 (Isis Pharmaceuticals) | CMV retinitis in AIDS patients | Phase III | |
| Levofloxacin (Levaquin, Ortho McNeil) | Quinolone | FDA cleared | |
| MSL-109 (Protovir, Protein Design Labs) | Monoclonal antibody | CMV | Phase II |
| Nelfinavir (Viracept, Agouron) | Protease inhibitor | HIV disease expanded access | Approved March 1997 |
| Neuprex (Xoma) | Bactericidal permeability- increasing protein | Gram-negative sepsis and hemorrhagic trauma | Phase II |
| Nitazoxanide (NTZ, Unimed Pharmaceuticals) | Cryptosporidium parvum in AIDS patients | Phase II | |
| Quinupristin-dalfopristin (Synercid, Rhone-Poulenc Rorer) | Streptogramin | Vancomycin resistant enterococcus faecium | Phase III (Available through emergency use program) |
| Remune (Immune Response) | Immunogen | HIV | Phase III (Available via expanded access program) |
| Roxithromycin (Rulid, Hoechst Marion Roussel) | Macrolide antibiotic | Nongonorrheal urethritis, Lyme disease, otitis media, respiratory infections | Phase III |
| Sorivudine (Bravavir, Bristol-Myers Squibb) | Thymidine analog | Varicella zoster in AIDS patients | NDA filed |
| Subgingival doxycycline(Atridox, Block Drug) | Antibiotic | Periodontal disease delivery system | Phase III (Target NDA1997) |
| Teicoplanin (Targocid,Hoechst Marion Roussel) | Glycopeptidase | Gram positive antibacterial infections | NDA filed |
| Trospectomycin (Spexil, Pharmacia & Upjohn) | Community-acquired pneumonia, STDs | Phase III | |
| Trovafloxacin (Pfizer) | Quinolone | Phase III | |
| VX-478 (141W94, Glaxo/Vertex) | Protease inhibitor | HIV | Phase II |
| Zintevir (Aronex) | HIV-1 integrase inhibitor | HIV | Phase I |
| (Betafectin, Alpha-Beta) | Beta-glycan polymer antibacterial | Post-operative infections | Phase III |
| (Provir, Shaman) | Plant-derived antiviral | Secretory diarrhea | Phase II |
| Nephrology | |||
| Anaritide (Auriculin, Scios Nova) | Atrial natriuretic peptide | Oliguric acute renal failure | Phase III |
| Dacliximab (Zenapax, Roche) | Monoclonal antibody immunosuppressant | Prevention of acute transplant rejection | Completed Phase III(Target NDA 1997) |
| Neurology | |||
| Acetyl-l-carnitine (Alcar, Roche) | Naturally occurring substance related to acetylcholine | Alzheimer's disease | Phase III |
| AF 102B (Forest) | Muscarinic agonist | Alzheimer's disease | Phase III |
| Aptiganel (Cerestat, Neuroscience)Cambridge | Ion-channel blocker | Stroke | Phase II |
| Brain-derived factor (Amgen) | neurotrophic | ALS | Phase III |
| BMS-204756 (Bristol-Myers Squibb) | Dopamine reuptake inhibitor | Parkinson's disease | Phase II |
| Citicoline (Interneuron Pharmaceuticals) | Stroke | Phase II/III | |
| Dacliximab (SMART, Protein Design Labs) | Humanized anti-TAC | Relapsing-remitting MS monoclonal antibody | Phase III |
| Dextrorphan (Roche) | NMDA antagonist | Stroke | |
| Dizocilpine (Neurogard, Merck) | NMDA antagonist | Stroke | |
| Dolasetron (Anzemet, Hoechst Marion Roussel) | 5-HT3 receptor antagonist | Nausea | NDA filed |
| Ebiratide (Hoechst Marion Roussel) | Alzheimer's disease | ||
| Eletriptan (Pfizer) | Migraine | Phase III | |
| Entacapone (Sandoz) | Peripheral COMT inhibitor | Parkinson's | Phase III |
| Exelon (ENA-713, Novartis) | Cholinesterase inhibitor | Alzheimer's disease | Phase III |
| Flupirtine (Katadolon, Carter-Wallace) | Non-narcotic analgesic | NDA filed | |
| Galanthamine (Janssen) | Acetylcholin-esterase inhibitor | Alzheimer's disease | Phase III |
| Idebenone (Avan, TAP) | Nootropic | Alzheimer's disease | |
| Lazabenide (Roche) | MAO-B inhibitor | Parkinson's disease | Phase III |
| Levobupicaine (Chiroscience) | Local anesthetic | Surgery/Pain | Phase III (Target NDA 1998) |
| Linomide (Kabi) | Multiple sclerosis | Phase III | |
| Linopirdine (Avia, Merck) | Alzheimer's disease | Phase III | |
| Lornoxicam (IVAX) | NSAID | Moderately severe pain | NDA filed |
| Lubeluzole | Ischemic stroke | ||
| Mecasermin (Myotrophin, Cephalon) | ALS | NDA filed | |
| Memric (SmithKline Beecham) | Muscarinic M1 partial agonist | Alzheimer's disease | Phase III |
| Metrifonate (Bayer) | Acetylcholin-esterase inhibitor | Alzheimer's disease | Phase III |
| Milameline (Warner- Lambert/Roussel Uclaf) | Muscarinic M1 agonist | Alzheimer's disease | Phase III |
| Modafinil (Provigil, Cephalon) | Narcolepsy | NDA filed | |
| Naratriptan (GlaxoWellcome) | 5HT receptor agonist | Migraines | Phase III |
| Nerve Growth Factor (Genentech) | Peripheral neuropathy in diabetic patients | Phase III | |
| Oxcarbazepine (Ciba-Geigy) | Epilepsy | NDA filed | |
| Oxiracetam (SmithKline Beecham) | Nootropic | Alzheimer's disease | |
| Pegorgotein (Sanofi Winthrop) (formally known as PEG-SOD) | Free radical scavenger | Brain trauma | Phase III |
| Physostigmine Salicylate(Synapton, Forest) | Acetylcholinesterase inhibitor | Alzheimer's disease | Phase III (Target NDA in 1997) |
| Pramipexole (Mirapex, Pharmacia & Upjohn) | Dopamine agonist | Parkinson's disease | Approvable |
| Propentofylline (HWA-285 Hoechst Marion Roussel) | Alzheimer's and vascular dementia | Phase III | |
| Propiram (Dirame, Roberts) | Moderate-severe pain | Phase III | |
| Rizatriptan (Maxalt, Merck) | Migraine | Target NDA first half of 1997 | |
| Ropinirole (Requip, Smith Kline Beecham) | Dopamine D2 agonist | Parkinson's disease | Approvable |
| Sabeluzole (Janssen) | Axonal transport enhancer | Alzheimer's disease | Phase III |
| SB209509 (SmithKline Beecham, Vanguard) | 5HT-1D receptor partial agonist | Migraine | Phase II |
| SB220453 (SmithKline Beecham) | 5-HT1 agonist | Migraine | Phase III |
| SNX-111 (Neurex) | Neuron-specific calcium channel blocker | Chronic pain | Phase III |
| Somatomedin-C (Myotrophin, Cephalon) | ALS | Phase III (Target NDA 1996) | |
| Stiripentol | Absence seizures | Phase III | |
| Suronacrine (Hoechst Marion Roussel) | Cholinesterase inhibitor | Alzheimer's disease | |
| Tiagabine (Tibex, Abbott) | Inhibits GABA uptake | Adjunctive anti-seizure therapy | Phase III |
| Tolcapone (Tasmar, Roche) | COMT inhibitor | Parkinson's disease | NDA filed |
| Velnacrine (Mentane, Hoechst Marion Roussel Roussel) | Cholinesterase inhibitor | Alzheimer's disease | NDA filed |
| Vigabatrin (Sabril, Hoechst Marion Roussel) | GABA analog | Adjunctive therapy for refractory seizures | Phase III(NDA filed 4/94) |
| Xanomeline (Lilly) | Muscarinic receptor agonist | Alzheimer's disease | Phase II |
| Zaleplon (Wyeth-Ayerst) | GABA agonist | Insomnia | Phase III (Target NDA mid-1997) |
| Zanomeline (Lilly) | Muscarinic M1 agonist | Alzheimer's disease | Phase III |
| Zomig (311C, Zeneca) | Migraine | Target NDA 1997 | |
| Zonisamide (Excegran, Dainippon/ Warner Lambert) | Seizures | Phase III | |
| Zopiclone (Imovane, Rorer) | Nonbenzodiazepine hypnotic | Short-term treatment of insomnia | |
| Oncology/Hematology | |||
| 131-l-anti-B1 (Coulter Pharmaceuticals) | Anti-CD20 monoclonal antibody | B-cell lymphoma | Target NDA 1997 |
| AG-337 (Thymitaq, Agouron) | Thymidylate synthetase inhibitor | Solid malignant tumors | Phase II/III |
| ALRT 1057 (Allergan) | 9-cis retinoic acid | Acute promyelocytic leukemia | Phase I/II |
| Amsacrine (Amsidyl, Parke-Davis) | Acute leukemia | NDA filed | |
| Anagrelide (Agrylin, Roberts | Platelet inhibitor | Thrombocythemia | Approvable |
| Annamycin (Aronex) | Anthracycline | Breast cancer | Phase I/II |
| Anti-HER2 (Genentech) | Monoconal antibody | Breast cancer | Phase III |
| AR-102 (Aronex) | Methylxanthine analog | Non-small cell lung cancer | Phase III |
| Bropirimine (Remisar, Pharmacia & Upjohn) | Pyrimidinone derivitive | Bladder carcinoma | Phase III |
| Broxuridine (BUdR, Neo-Pharm) | Radiosensitizer | Brain cancer and diagnostic in breast cancer | Target NDA 1997 |
| Carbomustine (Gliadel, Guilford) | Polymer wafer containing carbomustine | Brain cancer | Phase III (Available under treatment IND) |
| Crisnatol (Ilex) | Glioblastoma | Phase III | |
| Daunorubicin, liposomal(DaunXome, NeXstar) | Advanced Kaposi's sarcoma | Approvable | |
| Diaziquone (Schein) | Glioma | Phase III | |
| Droloxifene (Pfizer) | Estrogen antagonist/agonist | Breast cancer | Phase III |
| Enloplatin (American Home Products) | Platinum analog | Solid tumors | |
| Epirubacin (Pharmorubicin, Pharmacia & Upjohn) | Anthracycline | Advanced breast, lung, and ovarian cancers | Phase III |
| Fadrozole (Ciba-Geigy) | Armotase inhibitor | Breast cancer | Phase III |
| Fenretinide (McNeil) | Retinoid | Cancer chemotherapy | Phase III |
| Floxuridine (Roche) | Brain/hepatic cancer | Phase III | |
| Hu23F2G (Icos) | Recombinant humanized monoclonal antibody | Hemorrhagic shock | Phase II |
| ICI 182,780 (Zeneca) | Antiestrogen | Breast cancer | Phase II |
| IDEC-C2B8 MAb | B-cell lymphoma | Non-Hodgkin's | Phase III |
| Linomide (Kabi) | Acute myelocytic leukemia | Phase III | |
| Melanoma theraccine (Melacine, ImmunoChem Research) | Disseminated melanoma | Phase III | |
| Mitoguazone (Sanofi) | Refractory or relapsed AIDS-related lymphoma | Target NDA 1997 | |
| Piritrexim (Ilex) | Bladder cancer | Phase II | |
| Piroxantrone (Oxantrazole, Warner-Lambert) | Anthrapyrazole | ||
| PIXY-321 (Pixykine, Lederle) | GM-CSF/IL-3 | Chemotherapy-induced neutropenia/thrombo- cytopenia | Phase III |
| Porfiromycin (Vion) | Alkylating agent | Head and neck cancer | Phase III |
| Rapamycin, Sirolimus (Rapamune, Wyeth-Ayerst) | Immunosuppressant | Prevention of transplant rejection | Phase III |
| ReothRx (CyRx) | Sickle cell crisis | Phase II | |
| Samarium-153-EDTMP (Quadramet, Cytogen/DuPont Merck) | Pain associated with bone cancer | NDA filed | |
| SnET2 (Pharmacia) | Skin cancer | Phase III | |
| Suramin (Warner-Lambert) | Prostate cancer | Target NDA 12/97 | |
| Talc, sterile aerosol(Sclerosol, Bryan) | Malignant pleural effusions | Recommended for approval | |
| Tauromustine (Tauricyt, Pharmacia & Upjohn | Phase III | ||
| Temozolomide (Schering) | Malignant glioma | ||
| Thyrogen (Genzyme) | Thyroid cancer | Phase III (Target NDA 1997) | |
| Tirapazamine (Tirazone, Sanofi) | Radiation and chemotherapy enhancer | Non-small cell lung cancer | Phase III(Target NDA in 1997) |
| Toremifene (Fareston, Schering-Plough) | Antiestrogen | Advanced breast cancer in post menopausal women | Approved |
| Tretinoin LF (Aronex) | All-trans retinoic acid | Acute promyelcytic leukemia | Phase II |
| (Panorex, Centocor/Glaxo) | Monoclonal antibody | Colorectal carcinoma | Phase III |
| ZD-1694 (Tomudex, Zeneca) | Thymidylate synthetase inhibitor | Colorectal cancer | Phase III |
| Ophthalmology | |||
| Dorzolamide/Timolol (Cosopt, Merck) | Carbonic anhydrase inhibitor/beta blocker | Glaucoma | Target NDA 1997 |
| GM-6001 (Galardin, Ligand) | Matrix metalloproteinase inhibitor | Corneal ulcers | Phase III |
| Psychiatry | |||
| Citalopram (Forest) | SSRI | Depression | Phase III |
| Duloxetine (Lilly) | Norepinephrine/serotonin uptake inhibitor | Depression | Phase II |
| Fansanserin (Rhone-Poulenc Rorer) | Serotonin/Dopamine antagonist | Schizophrenia | Phase II |
| Flesinoxan (Solvay) | Serotonin-1a receptor agonist | Depression | Phase III |
| Gepirone (Fabre & Kramer) | Serotonin-1a receptor agonist | Depression/anxiety | Completed Phase III (Target NDA 1997) |
| ICI 204, 636 (Seroquel, Zeneca) | Dibenzothiapine | Schizophrenia | Phase III (Target NDA 1997) |
| Ipsapirone (Bayer) | Depression/anxiety | Phase III | |
| MDL100,907 (Hoechst Marion Roussel) | 5-HT2A antagonist | Schizophrenia | Phase IIb |
| Mianserin (Bolvidon, Organon) | Depression | Phase III | |
| Pagoclone (Interneuron) | Panic disorders | Phase II/III | |
| Pazinaclone (TAP) | Anxiety | Phase III | |
| Quetiapine (Seroquel, Zeneca) | Antipsychotic | Schizophrenia | NDA filed |
| Sertindole (Serlect, Abbott) | Serotonin/dopamine antagonist | Schizophrenia | Approvable |
| YKP10A (Yukong) | Serotonin reuptake inhibitor | Depression | Phase I |
| Ziprasidone (Pfizer) | Antipsychotic | Target NDA in 1997 | |
| Respiratory | |||
| APC-366 (Arris) | Tryptase inhibitor | Asthma | Phase IIB |
| Doxofylline (Maxivent, Roberts) | Asthma | Phase III | |
| Ebastine (Kestine, Rhone-Poulenc Rorer) | Antihistamine | Seasonal and perennial allergic rhinitis, chronic urticaria | Phase III (Target NDA 1997) |
| Emedastine | Antihistamine | Phase II/III | |
| Epinastine | Antihistamine | Phase II/III | |
| Formoterol (Astra) | Beta agonist | Asthma | Phase III |
| Icatibant (Hoechst-Roussel) | Bradykinin antagonist | Asthma | Phase III |
| Infasurf (Forest) | Lung surfactant | Respiratory distress in premature infants | Approvable |
| Ketotifen (Zaditen, Sandoz) | Mast cell stabilizer | Allergies, asthma | NDA filed |
| Lisofylline (Cell Therapeutics) | ARDS | Phase II | |
| Mizolastine | Antihistamine | ||
| Mometasone furoate nasal spray (Nasonex, Schering) | Corticosteroid | Seasonal allergic rhinitis and perennial rhinitis | NDA filed |
| Montelukast (Singulair, Merck) | Leukotriene inhibitor | Asthma | Target NDA first quarter of 1997 |
| Oxothiazolide carboxylate(Procysteine, Transcend Therapeutics) | Reactive oxygen neutralizer | Acute respiratory distress | Phase II |
| Perflubron (LiquiVent, Hoechst Marion Roussel) | Oxygen carrying liquid | Acute hypoxemic respiratory distress | Target NDA 1997 |
| Pranlukast (Ultair, Smith-Kline Beecham) | Leukotriene inhibitor | Asthma | Target NDA 1997 |
| Procaterol (Pro-air, Otsuka) | Beta agonist | Asthma | NDA filed |
| Setastine | Antihistamine | ||
| Zafirlukast (Accolate, Zeneca) | Leukotriene inhibitor | Asthma | NDA filed |
| Urogenital Diseases | |||
| Duloxetine (Lilly) | Norepinephrine/serotonin uptake inhibitor | Urinary incontinence | Phase II |
| Epristeride (SmithKline Beecham) | 5-alpha reductase inhibitor | Benign prostatic hypertrophy | Phase III |
| Sildenafil (Viagra, Pfizer) | Male erectile dysfunction | Target NDA fourth quarter of 1997 | |
| Tamsulosin (Yamanouchi/ Boehringer Ingelheim) | Selective alpha-1 adrenoreceptor antagonist | Benign prostatic hyperplasia | Phase III |
| Testosterone gel (Androgel, Unimed) | Testosterone | Hypogonadism | Phase III |
| Tolterodine (Detrusitol, Pharmacia & Upjohn) | Urinary incontinence | Target NDA 1997 | |
| Vaccines | |||
| Arthritis vaccine (Immune Response) | Rheumatoid arthritis | Phase II | |
| Arthritis vaccine (Anervax, Anergen) | DR4/1-peptide | Rheumatoid arthritis | Phase I |
| Cat vaccine (Catvax, Immunologic) | Cat allergy vaccine | Cat allergy | |
| Group B streptotoccus conjugate vaccine (North American Vaccine) | Prophylaxis in women of child-bearing age | Phase II | |
| Herpes simplex vaccine (Smith- Kline Beecham) | Herpes simplex | Phase III | |
| HIV vaccine (Wyeth-Ayerst/Apollon) | HIV disease | Phase I/II | |
| Influenza nasal spray vaccine (Aviron) | Influenza | ||
| Lyme disease vaccine (Smith- | Kline Beecham) | Lyme disease | Phase III |
| Malaria vaccine (Chiron, SmithKline Beecham) | Malaria prevention | ||
| Pediatric pneumococcal vaccine (Merck) | Prevention of middle ear infection, meningitis, and pneumonia | Phase III | |
| Finasteride (Propecia, Merck) | 5-alpha reductase inhibitor | Male pattern baldness | NDA filed |
| Nalmefene (Cervene, Ivax) | Ischemic stroke and narcotic antagonism | Phase III (Target NDA 1997) | |
The drugs in the table are divided into major categories and then listed alphabetically by generic name. When known, trade name, manufacturer, drug type, potential use, and approval status are also listed. Some drugs listed as being in Phase III may have already had an NDA submitted to FDA.
Presented in the text of this article are brief discussions of some of the more important agents in development for diseases of various organ systems. When available, information focuses on the unique needs of typical long-term care facility residents.
Bone and Joint
While the 1995 approval of alendronate represented an important advance in the treatment of osteoporosis, gastrointestinal problems associated with the drug's administration have greatly compromised its successful use. Two other bisphosphonates are under development, and initial findings indicate less severe gastrointestinal problems associated with their use.
Other potential approaches to osteoporosis include use of slow-release sodium fluoride, estrogen-receptor modulators, and parathyroid hormone-related peptide. The sodium fluoride product currently under review is in a "honeycomb wax" tablet, which retains the drug as it passes through the stomach into the intestines, thus avoiding gastrointestinal problems.1
As reported last year,1 the NSAID tenidap was viewed as very useful for treatment of osteoarthritis and rheumatoid arthritis. However, an unfavorable FDA advisory committee ruling last May has left its future in doubt.
Cardiology
Among the most talked about cardiovascular drugs of 1996 were the "statins," hypercholesterolemia agents that drug companies are salivating over. Statin use is exploding, with the retail market estimated at $2.8 billion and growing by 20 percent each year. Warner-Lambert launched atorvastatin (Lipitor), and studies showed that statin use could prevent first heart attacks. More HMG-CoA reductase inhibitors are in development, as companies strive to carve out some portion of the lucrative statin market for themselves.
Reteplase is another important new drug approved last year; it is now reaching the market. This plasminogen activator improves patency rates in patients with myocardial infarction. Reteplase has been significantly better than alteplase (tPA) for perfusion rates and acute interventions, with a comparable safety profile. The drug is as effective as other thrombolytic agents in protecting against stroke, and a major advantage is that rPA can be given in bolus doses. Morbidity and mortality data will be available when results of the GUSTO-3 trial come out this spring,2 but initial reports from March's American College of Cardiology Meeting were equivocal about reteplase in comparison with alteplase. Researchers continue to investigate the early use of thrombolytics in patients with stroke symptoms.
Research is also focusing on the platelet-aggregation crusade, dysrhythmias, and ACE inhibition. Several new drugs may alter therapy of several cardiovascular disorders, depending on study results.
Endocrinology
New drugs continue to improve therapy for diabetes mellitus. In addition to the previous introduction of agents such as metformin, acarbose, glimepiride, insulin analogue, and miglitol into the U.S. market, several other new approaches are being reviewed for use in diabetes mellitus, including insulin sensitizers and dopamine agonists.
Approved on January 29 and launched in March was the insulin sensitizer troglitazone. Troglitazone is indicated for use in patients with type II diabetes currently on insulin whose hyperglycemia is inadequately controlled (HbA1c > 8.5%) despite insulin therapy of more than 30 units/day in multiple injections. In insulin-taking patients with type II diabetes, troglitazone decreases serum glucose, plasma insulin, and hemoglobin A1c. The drug is effective only in the presence of insulin (either endogenous or injected).
The first new agent in 20 years indicated for obesity was marketed during 1996. Dexfenfluramine, the dextro isomer of fenfluramine, inhibits the reuptake of serotonin and promotes its release. Dexfenfluramine is effective in reducing the intake of carbohydrates as well as fats.
Gastroenterology
With the increased attention on eradication of Helicobacter pylori in patients with ulcer disease, efforts in the field of gastroenterology are turning more to refinements than to new drugs. Nevertheless, several important agents could reach the U.S. market in 1997. Hoechst Marion Roussel has both an H2 antagonist and a proton-pump inhibitor under investigation.
Crohn's disease and other irritable bowel syndromes continue to be difficult to manage with existing therapies, and several agents that promise hope are under investigation (Table 3). Zinc acetate was approved in late January for treatment of Wilson's disease.
Infectious Disease
Clearly the most important new drugs of 1996 were the protease inhibitors, which, when combined with two other anti-HIV therapies, put the first chink in the armor of the virus that causes AIDS. But at the same time, microbial resistance to powerful antibiotics and anti-infective agents has created fear in the hearts of many patients and doubt in the minds of health care providers.
Protease inhibitors have been hailed as a breakthrough in HIV treatment, but high prices and distribution problems caused consternation in providers and patients alike. The non-nucleoside transcriptase inhibitors will be the next agents to be incorporated into practice, with agents now reaching the market or the final stages of testing. At least one HIV-1 integrase inhibitor (zintevir) has begun clinical testing.
Immunology offers many new approaches to the treatment of infectious diseases, and these therapies will likely become more common and more complicated. Such therapies could well end many of the resistance problems that plague traditional anti-infective agents, but their administration often requires creativity in drug-delivery systems.
Neurology
Clinicians eagerly await results from widespread use of donepezil, the second agent approved for Alzheimer's disease in the United States. Preliminary results have encouraged families and caregivers alike, and the chance to offer some hope to patients with this tragic disease has raised expectations even further.
Investigational drugs aimed at Alzheimer's disease use a multiplicity of mechanisms to attack the identified aberrations that form the bases of the many theories of causation (Table 3). Research has focused on five theories on the cause of Alzheimer's, but more research is needed to move treatment to the next level.
William Simonson of Oregon
State University told TCP that for Alzheimer's disease, clinical research will include muscarinic agonists. Blocking formation of beta-amyloid protein will be another therapeutic approach sure to draw researchers' interest.
Interest is also growing in anti-inflammatory therapies for Alzheimer's disease. Based on studies of nonsteroidal agents' effects on the neuropathology produced by the condition, trials of prednisone are beginning. Also, the Women's Health Initiative has added an arm to its research that looks at the effects of estrogens on incidence of Alzheimer's disease.
Lou Gehrig's disease, or amyo-trophic lateral sclerosis, is also a focus for research. Brain-derived neurotrophic factor is now in Phase III trials, and this biotechnology option is high on many experts' lists of possible therapeutic advances.
Approved last year for multiple sclerosis was interferon beta-1a. Promising agents under development include copolymer-1 and tizanidine. Simonson says that immunotherapy may continue to be a focus of therapy for multiple sclerosis. However, childhood inoculations will be investigated because some evidence indicates a possible viral etiology for the condition.
Parkinson's disease is under further investigation, but changes in therapy will more likely involve already-marketed agents than investigational drugs. On the research side, neuroprotectants are of interest, as are dopamine agonists.
Fosphenytoin is now on the U.S. market, and some pharmacists are still upset with Parke-Davis over the simultaneous withdrawal of injectable Dilantin from commerce. They feel the company has substituted a much more expensive agent with minimal clinical advantages for an agent whose safety and efficacy have been proven for many years.
Other new antiepileptic agents include the GABA analogue vigabatrin and an adjunctive agent, tiagabine.
Oncology/Hematology
The results of 50 years of research into molecular biology and the resulting biotechnology movement have unquestionably revolutionized the diagnosis and treatment of oncologic and hematologic disorders. Just a glance at that section of Table 3 leaves most pharmacists marveling at how unfamiliar many names and mechanisms are.
Certainly, one important milestone was passed when gemcitabine was approved for treatment of pancreatic cancer. Indicated for locally advanced or metastatic adenocarcinoma, the new drug is the first indicated for pancreatic cancer.
Other new drugs, as shown in Table 3, are aimed at other difficult-to-treat cancers, including cancers of the breasts, lungs, and ovaries. Among adjunctive therapies, one recently approved agent, PIXY-321, is sure to generate a lot of attention. A cytokine, it stimulates production of both neutrophils and platelets.
Psychiatry
Among the psychiatric disorders, only schizophrenia and other psychoses are affected by emerging new drugs. The marketing of olanzapine last fall boosted interest in the antipsychotic class, and real-world results appear to be confirming the product's usefulness.
Sertindole should also come onto the market presently, and this serotonin-dopamine antagonist will make waves similar to those of olanzapine. The agent is expected to be approved for schizophrenia.
Most new antidepressants are a few years away from marketing, and none of them will create the kind of excitement the selective serotonin reuptake inhibitors have. Likewise, most agents for anxiety disorders do not represent substantial advances over existing therapies.
Respiratory
Asthma therapy is undergoing substantial change as new drugs come onto the market and new guidelines are released for practitioners to consider.
Final text of the new guidelines is due out in April. Preliminary drafts, released earlier, reclassify asthma into four stages: mild intermittent, mild persistent, moderate persistent, and severe persistent. The guidelines specify which drugs should be used in each type of asthma. They emphasize regular use of inhaled corticosteroids and p.r.n. inhaled beta-2 agonists for exacerbations (see this month's "Assisted Living Forum" for more details).
Zileutin and zafirlukast are the new drugs on the market. Both antileukotriene agents, they inhibit contraction of airway smooth muscle, vasodilatation, and migration of eosinophils into the airways.
The move toward elimination of freon as a propellant in metered-dose inhalers also continues. FDA approved the first non-CFC inhaler last August (Proventil HFA), and international treaties require that CFC products be banned as new alternatives become available. In March FDA proposed banning CFC-containing products after three non-CFC products containing two different active ingredients are on the U.S. market for one year. Commercial production of CFC is already banned for all uses other than essential medical products.3
Possible removal of terfenadine from the U.S. market is also shaking up therapy of allergic conditions. Seldane, marketed in 1985, has been plagued with problems since the 1992 discovery of a life-threatening interaction with erythromycin or ketoconazole in patients with hepatic disease. An aggressive educational campaign has targeted physicians, pharmacists, and other health professionals since that time. FDA acknowledged that the efforts had reduced inappropriate prescribing and dispensing of terfenadine with interacting drugs, but the agency said that such events have not been-and almost certainly cannot be-eliminated.
An antihistamine nasal spray, approved by FDA last November, became commercially available in March. Azelastine is available in a strength of 137 mcg and is indicated for relief of symptoms of seasonal allergic rhinitis in adults and children over 12 years old. It can be used with erythromycin and ketoconazole and given to patients with concomitant asthma.4
Conclusion
As information experts on drug therapy, pharmacists must be aware
of the advances in therapeutics. By monitoring the research and
development pipeline-and understanding the roles new drugs are
playing in the clinical setting-pharmacists are well-positioned
for their roles with patients, colleagues, family, and friends.
References
1. Williams DB, Purcell C, Cook C. New drugs for 1996. Consult Pharm 1996; 11:326-63.
2. Anonymous. Reteplase: changing the way MIs are treated. PNN Pharmother Line 1996(Dec. 11); 3(233):1.
3. Anonymous. FDA proposes Seldane withdrawal from market. PNN Pharmacother Line 1997(Jan. 14); 4(7):1.
4. Anonymous. Azelastine nasal spray hits the U.S. market. PNN Pharmacother Line 1997(Feb. 27); 4(37):1.
L. Michael Posey is Academics Editor.
Jennifer T. Chang, PharmD, is Pharmacy Resident, Valley Medical Center, Renton, Washington.
Copyright © 1997, American Society of Consultant Pharmacists,
Inc. All rights reserved.