| Diane B. Williams |
|---|
| Cynthia Purcell |
|---|
| Chris Cook |
|---|
As health care moves into a changing marketplace, the roles of pharmacists will change. The past years already have brought major changes through mergers and cutbacks. Many institutions have been forced to cut their drug budgets, making it difficult to accommodate new drugs as they are requested, especially if their approval was not anticipated. The high cost of "doing business" has made the profession look with a more keen eye at all decisions that may affect the drug decision-making process. Pharmacists are in a unique position to help control cost and improve patient outcomes by fulfilling the roles of provider, management expert, educator, and drug information resource. To fulfill these roles, pharmacists must stay up to date on new drugs as they come to market, as well as prepare for new, high-cost drugs in development. Many of these agents will have a dramatic effect on pharmacy budgets; anticipating their approval allows time to consider their usefulness for patients.
FDA Drug Approval Process
The Food and Drug Administration has not escaped the wave of health care change. Many members of Congress and the pharmaceutical industry believe that the approval process is too long, despite major improvements during the past several years.1 Some have proposed that the drug approval process might be better handled by an independent group from the private sector, especially if the request is for additional indications of an already marketed drug. Potential new drugs-even ones that have been recommended for approval by FDA advisory committees for some time-still await final FDA approval before marketing efforts can begin. New drug applications have a 180-day statutory limit for action, but it is news if FDA even approaches this deadline.2
The question remains: Should the FDA drug-approval process be shortened? Many believe that shortening this process will lead to an onslaught of new drugs, many of which are "me-too" drugs. In fact, if the approval process were made less stringent, even more "me-too" drugs may be presented to FDA for review. Also, several newly approved drugs have had serious adverse effects not recognized in clinical trials. Would a shorter approval process increase the risk of even more of these potential adverse effects going unnoticed?
Table 1. Drug Development and Approval Process
| Phase | Period | Goal |
| Preclinical testing | Approx. 3.5 years | Laboratory and animal tests for activity against targeted disease and safety; investigational new drug filed with FDA |
| Phase I trial | Approx. 1 year | 20 to 80 normal, healthy volunteers tested for safety, dose, and pharmacokinetics |
| Phase II trial | Approx. 2 years | 100 to 300 volunteer patients with the targeted disease to assess effectiveness |
| Phase III trial | Approx. 3 years | 1,000 to 3,000 patients in controlled setting; patients monitored to determine efficacy and for adverse effects |
| Treatment investigational new drug | Promising new drugs made available before approval to patients with serious, life-threatening diseases for which no comparable therapy exists | |
| New drug application | All data gathered during Phases I-III filed with FDA trials submitted to FDA | |
| FDA reviewa | 6 months to 2.5 years | FDA approval |
| Phase IV | Postmarketing surveillance |
What the future holds for FDA is uncertain, but clearly, it will experience change in the not-so-distant future. Anticipating that change is in the air, FDA is working on a proposal that would streamline the approval process without compromising safety and efficacy. This would include eliminating special regulations required for insulin and antibiotics, eliminating most environmental assessments for drugs and biologics, exempting some devices from premarket review, changing reporting requirements for supplemental submissions, and evaluating the possibility of having a single, well-designed clinical trial instead of multiple clinical trials for an NDA.3
1995 Drug Approvals
This article focuses on the drug therapies that made the news during the past year. By being able to anticipate new drugs that will be approved, pharmacists are in a better position to prepare for the therapeutic and economic impact of those approvals. Table 1 defines the terms most commonly used when referring to the drug development and approval process. An understanding of these terms will help put into perspective the approval time frame for many of the new drugs discussed in this article. With 1995 came several new drug classes and new delivery systems, including protease inhibitors (saquinavir) for treating HIV, a light-activated agent (porfimer) for esophageal cancer palliation, and liposomal formulations (amphotericin and doxorubicin) for treating fungal infections and certain cancers, respectively.
Table 2. New Drugs Approved in 1995
| Agents (Brand Name, Manufacturer) | Indications |
| 1P Drugs (Priority Rating) | |
| Valacyclovir Hydrochloride (Valtrex, Glao Wellcome) | Herpes zoster and herpes simplex |
| Mycophenolate mofetil (Cellcept, Syntex/Roche) | Renal transplant rejection |
| Lamivudine (Epivir, GlaxoWellcome) | HIV |
| Amifostine (Ethyol, U.S. Bioscience) | Renal toxicity associated with cisplatin |
| Epoprostenol sodium (Flolan, GlaxoWellcome) | Treatment of pulmonary hypertension |
| Alendronate sodium (Fosamax, Merck) | Treatment of osteoporosis and Paget's disease |
| Saquinavir Mesylate(Invirase, Roche) | HIV |
| Porfimer sodium (Photofrin, QLT PhotoTherapeutics) | Phytotherapy of esophageal cancer |
| Riluzole (Rilutek, Rhone-Poulenc Rorer) | Amyotrophic Lateral Sclerosis |
| Dexrazoxane (Zinecard, Pharmacia) | Cardiomyopathy associated with doxorubicin |
| 1S Drugs (Standard Review) | |
| Glimepiride (Amaryl, Hoechst Marion Roussel) | Type II diabetes mellitus |
| Anastrozole (Arimidex, Zeneca) | Advanced breast cancer |
| Azelaic acid (Azelex, Allergan Herbert) | Acne vulgaris |
| Bicalutamide (Casodex, Zeneca) | Advanced prostate cancer |
| Ceftibutin (Cedax, Schering Laboratories) | Antibacterial |
| Carvedilol (Coreg, SmithKline Beecham) | Hypertension |
| Ibutilide Fumarate (Corvert, Pharmacia & Upjohn) | Atrial fibrillation/atrial flutter |
| Losartan potassium (Cozaar, Merck) | Hypertension |
| Dirithromycin (Dynabac, Bock Pharmacal) | Antibacterial |
| Ioxilan (Oxilan, Cook Imaging) | Contrast agent |
| Acarbose (Precose, Bayer) | NIDDM |
| Lansoprazole (Prevacid, TAP) | Active duodenal ulcer-GERD, PUD |
| Nalmefene (Revex, Ohmeda) | Opioid overdose |
| Nisoldipine (Sular, Zeneca) | Hypertension |
| Sevoflurane (Ultane, Abbott) | General anesthesia |
| Tramadol (Ultram, Ortho-McNeil) | Moderate to severe pain |
| Iopromide (Ultravist, Berlex) | Nonionic contrast agent |
| Moexipril (Univasc, Schwarz Pharma) | Hypertension |
| Cetirizine (Zyrtec, Pfizer) | Allergic rhinitis and chronic urticaria |
| Cisatracurium Besylate (Nimbex, Glaxo Wellcome) | Neuromuscular blockade |
| Tretinoin (Vesanoid, Roche) | Neuromuscular blockade |
Table 2 lists the new drugs approved in 1995. Liposomal drug delivery will continue to be evaluated for a variety of agents, especially those with toxic adverse effects, such as chemotherapy agents. Doxorubicin in a liposomal delivery system has reached approvable status and should be available in 1996 for treating Kaposi's sarcoma. Other amphotericin liposomal formulations may also be approved.
Drugs up for Approval in 1996 and Beyond
Table 3 provides the list of new drugs in various stages of development
in 1996. The list is long but by no means all-inclusive; rather,
it is a sample of some of the therapies that are newsworthy. The
drugs are divided into major categories, then listed alphabetically
by generic name. If known, trade name, manufacturer, drug type,
potential use, and approval status are included.
Table 3. Potential New Drugs for 1996 and Beyonda
| Drug Classes | Drug Type/Mechanism | Uses | Approval Status |
| Bone and Joint Disorders |   |   | |
| Deflazacort (Marion Merrell Dow) | Bone-sparing steroid | Rheumatoid arthritis | Phase III |
| Droloxifene (Pfizer) | Estrogen antagonist/agonist | Osteoporosis | Phase II/III |
| Raloxifene (Evista, Lilly) | Estrogen receptor modulator | Osteoporosis | Phase III |
| Risedronate (Proctor & Gamble) | Bisphosphonate | Osteoporosis | Phase III |
| Sodium fluoride (Mission Pharmacal) | Fluoride | Osteoporosis | NDA filed |
| Temoxicam (Tilcotil, Roche) | Rheumatoid arthritis | Phase III | |
| Tenidap (Enablex, Pfizer) | NSAID | Arthritis | NDA filed |
| Tiludronate (Skelid, Sanofi) | Biphosphonate | Osteoporosis | Phase III (target NDA 1997) |
| Cardiology |   |   | |
| Acecainide (Parke-Davis) | Class III antiarrhythmic | Chronic sustained VT, PVC | Phase III |
| Aggrastat (Merck) |   | Unstable angina, decrease Phase III risk of cardiac events with angioplasty |   |
| Alacepril (Cetapril, Dainippon) | ACE inhibitor | Mild to moderate HTN | Phase III |
| Arbutamine (GenESA, Gensia) | Dx of CAD |   | Phase III |
| Atorvastatin (Parke-Davis) | Synthetic HMG CoA reductase inhibitor | Moderate to severe hypercholesterolemia | Phase III (target NDA July 1996) |
| Bucindolol (Intracardial Astra Merck) | Beta blocker | CHF | Phase III |
| Cefenline (Cipralan, Roche, Glaxo) | Imidazoline derivative | Arrhythmias | NDA filed |
| Celiprolol (Selecor, Rhone- Poulenc Rorer) | Beta blocker | HTN | NDA filed |
| Cetamolol (ICI) | Beta blocker |   |   |
| Clopidogrel (Sterling Winthrop) | Ticlopidine analogue | Atherosclerosis, heart attack, PVD, stroke | Phase III |
| Dalvastatin (Rhone-Poulenc Rorer) | Hypercholesterolemia | Phase III | |
| Desirudin (Revasc, Ciba-Geigy) | Thrombin inhibitor | Acute MI | Phase III |
| Dofetilide (Pfizer) | Class III antiarrhythmic | Atrial fibrillation or flutter, PSVT, VT/VF | Phase III (target NDA 1997) |
| Duteplase (Prolysis, Glaxo Wellcome) | Tissue plasminogen activator | Acute MI | Phase III |
| Fenoldopam (Corlopam, SmithKline Beecham) | Dopamine agonist | Hypertensive emergency, acute renal failure | Phase III |
| Integrelin (Cor Therapeutics) | Glycoprotein IIb/IIIa inhibitor | Prevent complications after angioplasty | Phase III |
| Lacidipine (Lacipil, Glaxo) | Calcium antagonist | HTN | NDA filed |
| Lemakalim (SmithKline Beecham) | Potassium channel agonist | HTN |   |
| Mibefradil (Posicor, Roche) | Calcium antagonist | HTN, angina, CHF | Phase III |
| Nicorandil (Ikorel, Upjohn) | Potassium channel agonist | Angina, CHF |   |
| Pirmenol (Warner-Lambert) | Antiarrhythmic | PVC, SVT, supraven- tricular arrhythmias | Phase III |
| Reteplase | Direct plasminogen activator | Myocardial infarction | Phase III |
| Tasosartan (Wyeth-Ayerst) | Antgiotensin II | HTN | Target NDA 1996-97 |
| Temocapril (Sankyo) | ACE inhibitor | HTN | Phase III |
| Tiamenidine (Symcor, Hoechst-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 |
| Vesnarinone (Arkin, Otsuka) | Phosphodiesterase inhibitor | CHF | Phase III |
| Xamoterol |   | HTN, CHF | NDA filed |
| Zofenopril (Zoprace, Bristol-Myers Squibb) | ACE inhibitor | MI, HTN | Phase III |
| Dermatology |   |   | |
| Acitretin (Soriatane, Roche) | Retinoid | Recalcitrant psoriasis | Approvable |
| Becaplermin (Regranex, Chiron) | Platelet growth factor | Wound healing | Phase III |
| Graftskin (Sandoz) | Full thickness living skin equivalent | Chronic wounds, venous ulcers, diabetic ulcers, pressure sores, burns | NDA filed |
| Iamin (ProCyte) | Copper-based agent | Diabetic foot ulcer | Phase III |
| (Kynac, Sphinx) |   | Psoriasis, eczema |   |
| Tipredane (Bristol-Myers Squibb) | Atopic dermatitis, psoriasis | NDA filed | |
| Transforming Growth Factor Beta (Betakine, Celtrix) |   | Connective tissue growth stimulation, chronic ulcers, macular holes |   |
| Endocrinology |   |   |   |
| Dexfenfluramine (Redux, Interneuron) | Alters serotonin levels | Obesity | Recommended for approval |
| Englitazone (Pfizer) | Insulin sensitizer | NIDDM |   |
| Glimepiride (Amaryl, Hoechst Marion Roussel) | Sulfonylurea | NIDDM | Approved (launch 1996) |
| Insulin, modified human (Humulog , Lilly) | Human insulin analogue | Type I DM | NDA filed |
| Miglitol (Bayer) | Alpha-glucosidase inhibitor | NIDDM |   |
| Orilipiastat (Orlistat, Roche) | Lipase inhibitor | Obesity | Phase III |
| Pramlintide (Amylin Pharmaceuticals) | Amylin analogue | NIDDM | Phase III |
| Pimagedine (Alteon) |   | NIDDM | Phase III |
| Pioglitazone (Takeda) | Insulin sensitizer | NIDDM |   |
| Sibutramine (Meridia, Knoll) | Obesity | NDA filed | |
| Tolrestat (Alredase, Wyeth Ayerst) | Aldose reductase inhibitor | Diabetic complications | Phase III |
| Troglitazone (Warner Lambert) | Insulin sensitizer | NIDDM | Phase III (target NDA December 1996) |
| Voglibose (Takeda) | Alpha-glucosidase inhibitor | NIDDM |   |
| Gastroenterology |   |   |   |
| Alosetron (Glaxo Wellcome) | 5-HT3 receptor antagonist | Irritable bowel syndrome | Phase II |
| CDP-571 (Celltech) | Anti-TNF monoclonal antibody | Crohn's disease | Phase II |
| Darifenacin (Pfizer) | Irritable bowel syndrome and urinary incontinence |   | Phase III |
| Didodesine (Glaxo Wellcome) | Irritable bowel syndrome | Phase II | |
| Domperidone (Motilium, Janssen) | Prokinetic agent | Gastroparesis |   |
| Enprostil (Gardin, Syntex) | Prostaglandin E2 analogue | Peptic ulcers | NDA filed |
| Fedotazine |   | Irritable bowel syndrome | Phase III |
| Roxatidine (Roxin, Hoechst Marion Roussel) | H2 antagonist | Peptic ulcers | NDA filed |
| Saviprazole (Hoechst-Roussel) | Proton pump inhibitor | Peptic ulcers |   |
| Tropisetron (Navoban, Sandoz) | 5-HT3 antagonist | Chemotherapy-related nausea and vomiting |   |
| Zamifenacine (Pfizer) |   | Irritable bowel syndrome | Phase III |
| Infectious Disease |   |   | |
| Amphotericin B, liposomal (AMBisome, NeXstar/Fujisawa) | Antifungal | Cryptococcal meningitis | Phase III |
| Cefdinir (Warner-Lambert) | Cephalosporin | Broad spectrum with good Staphylococcus coverage | Target NDA June 1996 (may replace multiple drug regimens) |
| Cefipime (Maxipime, Bristol-Myers Squibb) | Fourth-generation cephalosporin | Uncomplicated and complicated UTIs, uncomplicated skin and skin structure infections, pneumonia | Approved (available second quarter 1996) |
| Cefodizime (Fujisawa) | Third-generation cephalosporin |   | NDA filed |
| Cefpirome (Cefrom, Hoechst Marion Roussel) | Third- and fourth-generation cephalosporin | Gram-positive and -negative infections | Phase III |
| Ceftamet (Roche) |   | Upper respiratory infections in pediatrics | Phase III |
| Cidofovir (Vistide, Gilead Sciences) | Nucleoside analogue | Relapsing CMV retinitis | Phase III (available under treatment IND) |
| Clinafloxin (Warner-Lambert) | Quinolone | Hospital-acquired infections | Target NDA June 1998 |
| Delavirdine (Rescriptor Pharmacia & Upjohn), | Antiretroviral | HIV | Phase III (available via expanded access program) |
| Fosfomycin (Monurol, Forest) | Antibiotic | Uncomplicated UTI | NDA filed |
| Fleroxacin (Megalone, Roche) | Quinolone | Uncomplicated and complicated UTI, uncomplicated cervical and urethral gonorrhea | Recommended for approval, but NDA withdrawn January 1996 |
| Ganciclovir (Vitrasert, Chiron) | Antiviral | CMV retinitis | Recommended for approval |
| GV118819 (Glaxo Wellcome) | Trinem class | Penicillin-resistant streptococci | Phase II |
| Indinavir (Crixivan, Merck) | Protease inhibitor | HIV disease | Approved March 1996 |
| ISIS 2922 (Isis Pharmaceuticals) |   | CMV retinitis in AIDS patients | Phase III |
| Levofloxacin (Ortho McNeil) | Quinolone |   |   |
| Meropenem (Merrem, Zeneca) | Carbapenem | Community-acquired skin and soft tissue infections | NDA filed |
| Nevirapine (Viramune, Boehringer Ingelheim) | Nonnucleoside reverse transcriptase inhibitor | HIV disease | Target NDA first quarter1996 (available via expanded access program) |
| Nitazoxanide (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) |
| Ritonavir (Norvir, Abbott) | Protease inhibitor | HIV | Approved March 1996 |
| Roxithromycin (Rulid, Hoechst Marion Roussel) | Macrolide antibiotic | Nongonorrheal urethritis, Lyme disease, otitis media, respiratory infections | Phase III |
| Sorivudine (Bravavir, Bristol-Myers Squibb) | Thymidine analogue | Varicella zoster in AIDS patients |   |
| Sparfloxacin (Zagam, Rhone-Poulenc Rorer) | Quinolone |   | Phase III |
| Teicoplanin (Targocid, Marion Merrell Dow) | Glycopeptidase antibacterial | Gram-positive infections | NDA filed |
| Trospectomycin (Spexil, Upjohn) |   | Community-acquired pneumonia, STDs | Phase III |
| Trovafloxacin (Pfizer) | Quinolone |   | Phase III (target NDA 1996) |
| (Virend, Shaman) |   | Genital herpes | Phase II |
| (Pharmacia & Upjohn) | Oxazolidinone | Resistant microbes | Phase II |
| (Betafectin, Alpha-Beta) | Beta-glycan polymer antibacterial | Postoperative infections | Phase III |
| (Provir, Shaman) | Plant-derived antiviral | Secretory diarrhea | Phase II |
| Nephrology |   |   |   |
| Anaritide (Auriculin, Scios Nova) | Atrial natriuretic peptide | Acute renal failure | Phase III |
| Lisofylline (Cell Therapeutics) | Immunomodulator | Hemorrhagic shock | Phase III |
| Smar Humanized Anti-Tac (Zenapax, Roche) | Monoclonal antibody immunosuppressant | Prevention of acute transplant rejection | Phase III |
| Neurology |   |   |   |
| Brain-derived neurotrophic factor (Amgen) |   | ALS | Phase III |
| BMS-204756 (Bristol-Myers Squibb) | Dopamine reuptake inhibitor | Parkinson's disease | Phase II |
| Cerestat (Cambridge Neuroscience) | Ion-channel blocker | Stroke | Phase II |
| Citicoline (Interneuron Pharmaceuticals) |   | Stroke | Phase II/III |
| Copolymer I (Copaxone, Teva) |   | Relapsing-remitting MS | NDA filed |
| Dacliximab (SMART, Protein Design Labs) | Humanized anti-Tac monoclonal antibody | Relapsing-remitting MS | Phase III |
| Dextrorphan (Roche) | NMDA antagonist | Stroke |   |
| Dizocilpine (Neurogard, Merck) | NMDA antagonist | Stroke |   |
| Flupirtine (Katadolon, Carter-Wallace) | Nonnarcotic analgesic | Pain | NDA filed |
| Fosphenytoin (Parke-Davis) | Phentoin prodrug | Epilepsy |   |
| Interferon beta-1a (Avonex, Biogen) |   | MS | Recommended for approval |
| Lazabenide (Roche) | MAO-B inhibitor | Parkinson's disease | Phase III |
| Linomide (Kabi) |   | Multiple sclerosis | Phase III |
| Lornoxicam (IvAX) | NSAID | Moderately severe pain | NDA filed |
| Lubeluzole |   | Ischemic stroke |   |
| Modafinil (Provigil, Cephalon) |   | Narcolepsy | Phase III (target NDA 1996) |
| Naratriptan (Glaxo Wellcome) | 5-HT receptor agonist | Migraines | Phase III |
| Oxcarbazepine (Ciba-Geigy) |   | Epilepsy | NDA filed |
| Pegorgotein (Sterling Winthrop; formally known as PEG-SOD) | Free radical scavenger | Brain trauma | Phase III |
| Pramipexole (Pharmacia & Upjohn) | Dopamine agonist | Parkinson's disease | Phase III (NDA filed January 1996) |
| Propiram (Dirame, Roberts) |   | Moderate to severe pain | Phase III |
| Ropinirole (Ziatrol, SmithKline Beecham) |   | Parkinson's disease | Phase III |
| Sabeluzole | Axonal transport enhancer | Alzheimer's disease | Phase III |
| SB209509 (SmithKline Beecham & Vanguard) | 5-HT-1D receptor partial agonist | Migraine | Phase II |
| Somatomedin-C (Myotrophin, Cephalon) |   | ALS | Phase III (target NDA 1996) |
| Stiripentol |   | Absence seizures | Phase III |
| Tiagabine (Tibex, Abbott) | GABA uptake inhibitor | Adjunctive antiseizure therapy | Phase III |
| Tizanidine (Zanaflex, Athena) | Alpha-2 agonist | MS | NDA filed |
| Topiramate (Topamax, McNeil) |   | Epilepsy | Approvable |
| Vigabatrin (Sabril, Hoechst Marion Roussel) | GABA analogue | Adjunctive therapy for refractory seizures | Phase III (NDA filed April 1994) |
| Zonisamide (Excegran, Dainippon/ Warner Lambert) |   | Seizures | Phase III |
| Oncology/hematology |   |   |   |
| AG-337 (Thymitaq, Agouron Pharmaceuticals) | Thymidylate synthetase inhibitor | Solid malignant tumors | Phase II |
| Amsacrine (Amsidyl, Parke-Davis) |   | Acute leukemia | NDA filed |
| Anagrelide (Agrelin, Bristol-Myers Squibb) | Platelet inhibitor | Thrombocythemia | NDA filed |
| 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 |
| Docetaxel (Taxotere, Rhone-Poulenc Rorer) | Taxane | Refractory breast cancer | Approvable |
| Droloxifene (Pfizer) | Extrogen antagonist/agonist | Breast cancer | Phase III |
| Enloplatin (American Home Products) | Platinum analogue | Solid tumors |   |
| Epirubacin (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 |
| Gemcitabine (Gemzar, Lilly) | Pyrimidine antimetabolite | Pancreatic cancer | Recommended for approval |
| ICI 182,780 (Zeneca) | Antiestrogen | Breast cancer | Phase II |
| Irinotecan (Upjohn) | Topoisomerase-1 inhibitor | Refractory cervical and colon cancer | Phase II |
| Linomide (Kabi) |   | Acute myelocytic leukemia | Phase III |
| Melanoma theraccine (Melacine, ImmunoChem Research) |   | Disseminated melanoma | Phase III |
| Mitoguazone (Sanofi-Winthrop) |   | Refractory or relapsed AIDS-related lymphoma | Phase II (target NDA 1996) |
| Nilutamide (Nilandron, Roussel-Uclaf) | Androgen blocker | Prostate cancer | Approvable |
| Nofetumomab Merpentan Tc-99M (Verluma, NeoRx) | Imaging agent | Small-lung-cell imaging agent | Recommended for approval |
| Piritrexim (Ilex) |   | Bladder cancer | Phase II |
| Piroxantrone (Oxantrazole, Warner-Lambert) | Anthrapyrazole |   |   |
| PIXY-321 (Pixykine, Lederle) | GM-CSF/IL-3 | Chemotherapy-induced neutropenia/ thrombocytopenia | Phase III |
| Porfimer (Photofrin, Quadra Logic) | Photosensitizer | Esophageal cancer | Approved December 1995 (launch second quarter of 1996) |
| 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 December 1997 |
| Talc, sterile aerosol (Sclerosol, Bryan) |   | Malignant pleural effusions | Recommended for approval |
| Tauromustine (Tauricyt, Pharmacia) |   |   | Phase III |
| Temozolomide (Schering) |   | Malignant glioma | Phase III (target NDA 1997) |
| Tirapazamine (Tirazone, Sanofi) | Radiation and chemotherapy enhancer | Non-small-cell lung cancer |   |
| Topotecan (SmithKline Beecham) | Topoisomerase inhibitor | Colorectal, ovarian, breast, or lung cancer | Phase III |
| Toremifene (Fareston, Schering-Plough) | Antiestrogen | Advanced breast cancer in post-menopausal women | Approvable |
| Panorex (Centocor/Glaxo) | Monoclonal antibody | Colorectal carcinoma | Phase III |
| 20-1694 (Tomudex, Zeneca) | Thymidylate synthetase inhibitor | Colorectal cancer | Phase III |
| Ophthalmology |   |   |   |
| Dorzolamide/Timolol (Cosopt, Merck) | Carbonic anhydrase inhibitor/beta blocker | Glaucoma |   |
| Latanoprost (Xalatan, Pharmacia) | Topical prostaglandin | Open-angle glaucoma | Recommended for approval |
| Loteprednol (Lotemax, Pharmos Corps, Bausch & Lomb) |   | Uveitis and other forms of ocular inflammation | Launch late 1996 |
| GM-6001 (Galardin, Ligand) | Matrix metalloproteinase inhibitor | Corneal ulcers | Phase III |
| Psychiatry |   |   |   |
| Acetyl-l-carnitine (Alcar, Roche) | Naturally occurring substance related to acetylcholine | Alzheimer's disease | Phase III |
| Citralopram (Cipramil, Lundbec) | Serotonin receptor inhibitor | Depression, Alzheimer's disease | Phase III |
| Duloxetine (Lilly) | Norepinephrine/serotonin uptake inhibitor | Depression | Phase II |
| E202 (Pfizer) | Acetylcholinesterase inhibitor | Alzheimer's disease | Phase III |
| Ebiratide (Hoechst Marion Roussel) |   | Alzheimer's disease |   |
| ENA 713 (Sandoz) | Cholinesterase inhibitor | Alzheimer's disease | Phase III |
| Flesinoxan (Solvay) | Serotonin-1a receptor agonist |   |   |
| Gepirone (Fabre & Kramer) | Serotonin-1a receptor agonist | Depression/anxiety | Phase III |
| ICI 204,636 (Seroquel, Zeneca) | Dibenzothiapine | Schizophrenia | Phase III (target NDA 1996) |
| Idebenone (Avan, TAP) | Nootropic | Alzheimer's disease |   |
| Ipsapirone (Bayer) |   | Depression and anxiety | Phase III |
| Linopirdine (Avia, Merck) |   | Alzheimer's disease | Phase III |
| Mianserin (Bolvidon, Organon) |   | Depression | Phase III |
| Mirtazapine (Remeron, Organon) | Alpha-2 receptor antagonist | Depression | Recommended for approval |
| Olanzepine (Zyprex, Lilly) | Serotonin/dopamine antagonist | Schizophrenia | Phase III (NDA filed September 1995) |
| Oxiracetam (SmithKline Beecham) | Nootropic | Alzheimer's disease |   |
| Pazinaclone (TAP) |   | Anxiety | Phase III |
| Physostigmine Salicylate (Synapton, Forest) | Acetylcholinesterase inhibitor | Alzheimer's disease | Target NDA 1996 |
| Sertindole (Abbott) | Serotonin/dopamine antagonist | Schizophrenia | Phase III (NDA filed October 1995) |
| Suronacrine (Hoechst-Marion Roussel) | Cholinesterase inhibitor | Alzheimer's disease |   |
| Velnacrine (Mentane, Hoechst Marion Roussel) | Cholinesterase inhibitor | Alzheimer's disease | NDA filed |
| Xanomeline (Lilly) | Muscarinic receptor agonist | Alzheimer's disease | Phase II |
| Ziprasidone (Pfizer) | Antipsychotic |   | Target NDA 1997 |
| Zopiclone (Imovane, Rorer) | Nonbenzodiazepine hypnotic | Short-term treatment of insomnia |   |
| Respiratory |   |   |   |
| Azelastine (Astelin, Carter-Wallace) | Antihistamine | Seasonal allergic rhinitis | Approved 2/96 |
| Doxofylline (Maxivent, Robert) |   | Asthma | Phase III |
| Ebastine (Rhone-Poulenc Rorer) | Antihistamine |   | Phase II/III |
| Emedastine | Antihistamine |   | Phase II/III |
| Epinastine | Antihistamine |   | Phase II/III |
| Fexfenadine | Antihistamine | Allergic rhinoconjunctivitis | Phase III |
| Formoterol (Astra) | Beta agonist | Asthma | Phase III |
| Icatibant (Hoechst-Roussel) | Bradykinin antagonist | Asthma | Phase III |
| Ketotifen (Zaditen, Sandoz) | Mast cell stabilizer | Allergies, asthma | NDA filed |
| Lisofylline (Cell Therapeutics) |   | ARDS | Phase II |
| Mizolastine | Antihistamine |   |   |
| Montelukast (Singulair, Merck) | Leukotriene inhibitor | Asthma |   |
| Pranlukast (SmithKline Beecham) | Leukotriene inhibitor | Asthma |   |
| Procaterol (Pro-air, Otsuka) | Beta agonist | Asthma | NDA filed |
| Setastine | Antihistamine |   |   |
| Zafirlukast (Accolate, Zeneca) | Leukotriene inhibitor | Asthma | NDA filed |
| Zileuton (Leutrol, Abbott) | Leukotriene inhibitor | Asthma | Recommended for approval |
| Urogenital diseases |   |   |   |
| Duloxetine (Lilly) uptake inhibitor | Norepinephrine/serotonin | Urinary incontinence | Phase II |
| Epristeride (SmithKline Beecham) | 5-Alpha reductase inhibitor | Benign prostatic hypertrophy | Phase III |
| Sildenafil (Pfizer) |   | Male erectile dysfunction | Phase III |
| 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 |   |
| Herpes simplex vaccine (Aviron) |   | Herpes simplex | Target IND during second quarter 1996 |
| HIV vaccine (Wyeth-Ayerst/Apollon) |   | HIV | Phase I/II |
| Influenza nasal spray vaccine (Aviron) |   | Influenza |   |
| Lyme disease vaccine (Lymex, Connaught) | Lyme disease |   |   |
| Malaria vaccine (Chiron, SmithKline Beecham) | Malaria prevention |   |   |
a Abbreviations used: NDA = New drug application; NSAID = Nonsteriodal
anti-inflammatory drug; VT = Ventricular tachycardia; PVC = Premature
ventricular contraction; ACE = Angiotensin-converting enzyme;
HTN = Hypertension; CAD = Coronary artery disease; CHF = Congestive
heart failure; PVD = Peripheral vascular disease; MI = Myocardial
infarction; PSVT = Paroxysmal supraventricular tachycardia; VT/VF
= Ventricular tachycardia/flutter; SVT = Supraventricular ventricular
tachycardia; SAH = Subarachnoid hemmorrage; NIDDM = Non-insulin-dependent
diabetes mellitus; DM = Diabetes mellitus; 5-HT3 = 5-hydroxytryptophan
(serotonin);
TNF = Tissue necrosis factor; UTI = Urinary-tract infection; CMV
= Cytomegalovirus; IND = Investigational new drug; HIV = Human
immunodeficiency virus;
AIDS = Acquired immunodeficiency syndrome; STD = Sexually transmitted
disease; ALS = Amyotrophic lateral sclerosis; MS = Multiple sclerosis;
Tac =; NMDA = N-methyl-D-aspartate; MAO = Monoamine oxidase; GABA = gamma-aminobutyric;
GM-CSF/IL-3 = Granulocyte-macrophage colony-stimulating factor/interleukin-3;
ARDS = Acute respiratory distress syndrome.
Some of the drugs listed in Phase III already may have had a New Drug Application submitted to FDA.
Following are some of the major considerations surrounding advances expected in therapy that might be of interest to consultant pharmacists.
Bones and Joints
Approximately 20 million people in the United States suffer from osteoporosis. It is especially common in postmenopausal women and is responsible for approximately 1.3 million fractures per year. Newer agents in development for osteoporosis include raloxifene, which works like estrogen in the bone but blocks estrogen effects in other parts of the body. This allows patients to have the bone-protective properties of estrogens without the associated risks. Slow-release sodium fluoride is another agent being evaluated for treating osteoporosis. Although fluoride is known to increase bone mass, its use has been limited because of adverse effects, especially at higher doses. The sodium fluoride product being reviewed is in a "honeycomb wax" tablet, which retains the drug as it passes through the stomach and into the intestines, thus avoiding gastrointestinal problems.
Tenidap has been shown to be useful for treating osteoarthritis and rheumatoid arthritis. Recent information suggests that tenidap may slow the progression of rheumatoid arthritis. This may result in part from the drug's ability to inhibit the production of prostaglandins, as well as inflammatory cytokines such as the interleukins IL-6, IL-1, and tissue necrosis factor (TNF-alpha).
Cardiology
Research in cardiology continues to produce therapeutic advances. Approximately 20 percent of the new molecular entities approved during 1995 were cardiovascular agents. One area of interest is the continued research for drugs that decrease the risk of atherosclerosis. For more than 21 years, researchers have been searching for the "good cholesterol" receptor. Scientists recently isolated high-density lipoprotein receptors (named SR-B1) in the liver, adrenal gland, and ovary tissue. This potential breakthrough coincides with an exciting new, synthetic HMG-CoA reductase inhibitor, atrovastatin, which is available under a Treatment IND for patients with homozygous familial hypercholesterolemia. Atrovastatin is reported to demonstrate greater potency in decreasing low-density lipoproteins and triglycerides while increasing HDLs compared with currently available drugs in this class.4, 5 The new HMG-CoA reductase inhibitor has been shown to lower cholesterol by approximately 60 percent, with a 30 to 40 percent decrease in triglycerides. Most of the other HMG-CoA reductase inhibitors are capable of lowering cholesterol only by about 40 percent. Atrovastatin may offer an advantage to those patients requiring combination therapy to achieve higher reductions in cholesterol levels.
The platelet aggregation cascade is another popular research topic. Several new compounds should strengthen the arsenal soon. To join the company of dalteparin and enoxaparin, five other low-molecular-weight heparin products are in development. Hirudin is a thrombin inhibitor that never made it to market after promising early results; however, the findings of desirudin, another thrombin inhibitor, are encouraging. The manufacturer of desirudin is seeking approval for use in patients who have had acute myocardial infarction. Abciximab will also be encountering some competition from another glycoprotein IIb/IIIa receptor inhibitor. The glycoprotein IIb/IIIa receptor is the key receptor that allows the matrix of a thrombus to be formed by interlinking platelets through a fibrin connector.6 The manufacturer of integrelin is seeking approval for use in preventing complications following angioplasty. As with abciximab, bleeding complications appear to be the main side effect.7 A potent ticlopidine analogue, clopidogrel also is expected to join the class of platelet inhibitors soon, as it is in Phase III trials. Clopidogrel has been shown to significantly reduce the occlusive thrombosis at the site of vessel wall injury.8, 9
A new direct plasminogen activator is in Phase III trials for treating myocardial infarction. Reteplase (r-PA) appears to be effective in improving patency rates, and the incidence of stroke is comparable with that of other thrombolytic agents. Reteplase has the advantage of not having to be dosed on a weight-adjusted basis. The indications for plasminogen activators are increasing. The available tissue plasminogen activator, activase (t-PA), is being evaluated for its effects in stroke patients. Data suggest that patients given activase within three hours of onset of stroke symptoms may see improvement of neurologic function by as much as 30 percent.
Tirilazad, a lazaroid, is in Phase III clinical trials for treating subarachnoid hemorrhage. This compound has a potent capability to interrupt cell membrane peroxidative mechanisms. This capability may block the pathophysiology of central nervous system trauma and facilitate the functional recovery and survival of patients with CNS injury. This mechanism may also be of benefit in chronic neuro-degenerative diseases such as Parkinson's disease and Alzheimer's disease, as well as demyelination disorders such as multiple sclerosis.10, 11
Several new antiarrhythmics are gaining attention. Ibutilide recently was approved as an alternative to cardioconversion for patients requiring conversion of atrial arrhythmias to normal sinus rhythm. In trials, ibutilide demonstrated a 70 percent cardioversion from atrial fibrillation of atrial flutter within 30 minutes. Dofetilide is a class III antiarrhythmic (potassium channel blocker) that appears to be useful in treating paroxysmal atrial fibrillation and flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation.12 Although dofetilide appears to be safer than amiodarone, torsades de pointe has been reported with this agent.
The first angiotensin converting enzyme inhibitor, captopril, was introduced in 1981. Since then, we have seen a host of new ACE inhibitors. Many of the newer agents have focused on improving duration of action or improving cost effectiveness. Because ACE inhibitors are used widely for managing hypertension, especially in the elderly, having an agent that is eliminated primarily in the bile so that renal adjustment is not a problem may be beneficial. Temocapril is a new ACE inhibitor likely to reach the market, and it is excreted primarily in the bile.13 It is a prodrug that is rapidly converted to its active form by the liver carboxylesterases. But the next ACE inhibitor likely to reach the market is trandolapril. It has reached approvable status for treating hypertension and is also being studied for patients with left ventricular dysfunction after myocardial infarction. Zofenopril is another ACE inhibitor in Phase III trials, and it too appears useful in hypertension and in patients with left ventricular dysfunction after myocardial infarction.
Several renin antagonists, potassium channel blockers, and atriopeptidase inhibitors are also working their way through clinical trials.
Endocrinology
Several exciting new products to manage patients with diabetes mellitus are likely to be approved. The recent additions of metformin, acarbose, and glimepiride in the battle to control noninsulin-dependent diabetes mellitus (NIDDM) is an indication of new treatment options to come. Miglitol and voglibose are two new alpha-glucosidase inhibitors being developed to rival acarbose.
Also in development is a new class of agents called insulin sensitizers. Pioglitazone is thought to increase insulin sensitivity by activating insulin receptor kinase.14 Other insulin sensitizers in the pipeline include englitazone and troglitazone. Troglitazone has been shown to improve insulin resistance, reduce insulinemia, lower hepatic glucose production, and improve both fasting and postprandial glycemia.15, 16
Aldose reductase inhibitors were once thought to be the next great advancement in treating and preventing diabetic complications. However, only one of these promising agents remains under investigation. Problems with toxicity and efficacy have left only tolrestat as a viable candidate. Improvements in paresthesia and neuropathy have been slight to moderate, but no improvement in pain symptoms has been realized.17 Current Phase III trials should determine whether tolrestat becomes available. Another promising diabetes treatment, Humulog, is an analogue of human insulin. Its quicker peak action allows patients to take insulin at mealtime instead of the 30 to 60 minutes before meals required with insulin. In addition, Humulog is removed quickly, which means there is less risk of hypoglycemia after meals.
One of the hot topics for 1996 is obesity drugs. More than 15 years have passed since a new drug has been approved for treating obesity, but proposed changes in FDA guidelines for evaluating obesity drugs may shorten the approval time. It now takes two years of human testing to prove that patients lose weight and decrease risks associated with obesity, such as heart disease.18 Olestra recently was approved as a fat substitute in food. It is a synthetic fat with large molecules that are not broken down and, therefore, pass through the digestive tract without being absorbed. This controversial agent has been linked to adverse effects such as diarrhea and electrolyte abnormalities. Critics claim that the fat substitute will reduce serum carotenoid concentrations, which may increase the risk of developing cancer, heart disease, stroke, and blindness.
Investigational drugs being evaluated for treating obesity include dexfenfluramine and orilipiastat. Dexfenfluramine, the dextro isomer of fenfluramine, inhibits the reuptake of serotonin and promotes its release. It is selective for serotonin and does not possess antidopaminergic properties.19 As many as 40 percent of patients have lost as much as 10 percent of their body weight while on the drug because it makes them feel full even when they eat less. Dexfenfluramine has been found to be effective in reducing the intake of carbohydrates and fats. Hypertension has been reported in some patients during clinical trials, and further studies are needed to assess risk of drug-induced neurotoxicity. This agent recently was recommended for approval by an FDA advisory committee.
Orilipiastat is an inhibitor of gastric, carboxyester, and pancreatic lipase. It decreases the absorption of dietary fat secondary to inhibition of triglyceride hydrolysis. The only side effects were gastrointestinal in nature, and those were reported as mild and transient.20
An investigational new drug application has been filed with FDA for testing another agent used to treat obesity. The drug, NGD 95-1, is one of the first compounds tested to treat eating disorders by the mediation of receptor subtype of neuropeptide Y, a neurotransmitter that possibly causes the desire to eat.21
Gastroenterology
With the discovery of Helicobacter pylori as a causative agent for peptic ulcer disease, many new treatment options are expected to emerge. One promising therapy includes the use of proton pump inhibitors with the macrolide antibiotic clarithromycin. Other therapies include a novel, nonantibiotic, antibacterial formulation designed to kill this pathogenic bacteria rapidly on contact. Phase I clinical trial results have been submitted to FDA for this new nonantibiotic agent, and additional clinical trials were expected to begin in early 1996. Also, a new one-step, whole blood finger-stick test for H. pylori is being investigated. Sent back for more data was a breath test that uses carbon-14 to detect the presence of H. pylori urease in patients' stomachs.
Expanded FDA approval has been sought for access to the orphan drug Synovir (thalidomide) for treating AIDS patients suffering from mouthulcers, cachexia, and severe weight loss. The use of thalidomide was banned in the United States during the 1960s because of birth defects in children whose mothers took the drug during pregnancy to relieve nausea.22 FDA has allowed doctors who have the permission of their affiliated hospitals to enroll their AIDS patients in the study of thalidomide. A new method for making high-purity thalidomide is being researched by the manufacturers of Synovir.23
Infectious Disease
During the past several years, antibiotic resistance has emerged as a significant and serious clinical problem. The bacterial resistance has been exacerbated by the improper overuse of antibiotics and social problems related to the increased number of immunosuppressed patients. Hospitals have seen an increased incidence of methicillin-resistant Staphylococcus aureus (MRSA), beta-lactam-resistant streptococci, and vancomycin-resistant enterococci. Infectious disease research has begun to search for new antibiotics that can protect against these resistant organisms.
One of the most exciting antibiotics we can expect soon is in a new class called streptogramins. This class of antibiotics was first developed by fermentation from different organisms from soil samples. Two major streptogramins are in production: pristinamycin and virginiamycin. These compounds comprise two components of streptogramins that work in synergy. Quinupristin/dalfopristin is a new semisynthetic streptogramin derived from pristinamycin IA and IIB combination. The two components of quinupristin/dalfopristin synergistically bind to different sites on the 50s subunit of bacterial ribosomes, causing inhibition similar to that of aminoglycosides. The synergism occurs by dalfopristin's alteration of the ribosome's conformation, causing an increased affinity for quinupristin, inhibiting protein synthesis.24 Quinupristin/dalfopristin is in Phase III trials and has been available through an emergency use program since June 1993. It is especially useful in resistant gram-positive infections in hospitalized patients, especially those with Enterococcus faecium and MRSA. It also is useful in treating infections caused by coagulase-negative staphlococci, streptococci, and most gram-positive and gram-negative anaerobic organisms. Because a number of other antibiotics already cover these organisms, it has been suggested that quinupristin/dalfopristin be reserved for gram-positive infections that result from resistant strains of Staph. aureus and E. faecium or in patients intolerant of or refractory to more conventional therapies such as vancomycin.
Another new class of antibiotics showing promise against resistant organisms is the oxazolidinones. These agents, in Phase I/II clinical trials, inhibit protein synthesis early in microbes' growth cycles.
Carbapenem antibiotics have a broad spectrum of activity against gram-positive and -negative aerobes and anaerobic bacteria. Meropenem is a new carbapenem with some advantages over its forerunner, imipenem/cilastatin. This new agent has a similar efficacy and tolerability profile; however, it has a low incidence of associated seizures, increasing its potential for use in bacterial meningitis resistant to penicillins and third-generation cephalosporins.25 It also appears useful in treating intra-abdominal infections; however, it should not be used as monotherapy if MRSA is suspected. Also, meropenem does not require the coadministration of a renal dehydropeptidase inhibitor (cilastatin) that imipenem requires.26 Recommendations for specific guidelines for use with meropenem are important (as with any other broad-spectrum antibiotic) to decrease the chance of creating bacterial resistance.
Flerfloxacin is a new once-daily quinolone antibiotic recommended for approval. With its long half-life and better drug interaction profile, flerfloxacin seemed promising in treating a variety of infections, including complicated and uncomplicated urinary tract infections and sexually transmitted diseases. However, because of a large number of quinolones on the U.S. market, the NDA for flerfloxacin was withdrawn. Other potential quinolones include levofloxacin, trovafloxacin, and sparfloxacin. Quinolones have been coupled with beta-lactams to yield a new class of drugs known as quinalactams. Research with these compounds is in the early stages.
The use of antifungals has increased with the increased number of immunocompromised patients,27 but most antifungals have unpleasant side effects. A new antifungal class called pneumocandins has been developed. They are a natural lipopeptide product of echinocandins. The pneumocandins inhibit the synthesis of 1,3-b-D-glucan, causing inhibition of cell wall synthesis of susceptible fungi. Because of the lack of the 1,3-b-D-glucan synthesis pathway in humans, this class has minimal side effects when used in systemic fungal infections. A new pneumocandin Bo derivative (L-733-560) has demonstrated an increased potency and wider antifungal spectrum than natural products.
Ongoing research for the treatment of HIV continues to produce new advances. The standard of care with reverse transcriptase inhibitors continues to be pursued with the production of new drugs in this class, such as lamivudine. However, this class of drugs is limited by the rapid selection of inhibitor-resistant viral variants.28 Therefore, researchers have shifted their focus to other mechanisms of attacking HIV. One of the most promising is the inhibition of the HIV enzyme protease. This enzyme is required by the virus to continue replication in the final processing of viral proteins. Its inhibition prevents the production of infectious viral particles. Saquinavir and indinavir, both recently approved, have been available for compassionate use for some time. A third protease inhibitor, ritonavir, is making its way through Phase III trials. The most significant discovery that has come with the production of protease inhibitors is that a combination of the two classes of antivirals (thymidine synthetase inhibitors and protease inhibitors) may be the best treatment strategy for patients with HIV. The combination of the two classes (e.g., zidovudine and saquinavir) has produced a more potent antiviral effect, resulting in higher CD4 cell counts than those produced with either agent alone.29
Recent data suggest that patient viral load is a good predictor of clinical progress. Delavirdine is a new antiretroviral agent shown to decrease circulating viruses by as much as 68 percent for as many as 60 weeks in HIV-positive patients. This agent may be available soon under an accelerated approval process.
Cidofovir is an acyclic cytosine nucleotide analogue for relapsing cytomegalovirus (CMV) retinitis in AIDS patients. It offers a broad spectrum of activity against herpes viruses and is available under a treatment IND. This intravenous therapy offers an alternative to those patients who progress on approved therapies or who cannot tolerate those therapies. Ocular implants and combination therapy also are being evaluated for managing patients with CMV retinitis.
Neurology
Lou Gehrig's disease, amyotrophic lateral sclerosis, affects approximately 30,000 people in the United States. It is a disease of unknown etiology that deteriorates the motor neurons with a mean survival of only three to four years from the time of diagnosis.30 Until recently, no treatments were available for this disorder; however, much progress has been made in treating this progressive, degenerative disease. "Excitotoxicity" caused by an accumulation of glutamate, an excitatory neurotransmitter, is thought to lead to neuronal injury or death. Riluzole, recently approved for use in ALS, inhibits glutamate release and has shown to prolong life by about three months. However, riluzole has not been shown to slow the deterioration of the motor neurons or reduce symptoms.
Other drugs in the pipeline may offer some help for ALS. Brain-derived neurotrophic factor is being evaluated for use in treating pulmonary symptoms seen in patients with ALS. Somatomedin-C is also being evaluated for its ability to slow the progression of muscle deterioration in patients with ALS. An insulin-like growth factor-1 (IGF-1), it is a naturally occurring protein found in muscle and other tissue. IGF-1 may promote the regeneration of damaged motor neurons and enlargement of muscle cells. However, questions about increased mortality have prevented expanded testing with this agent. Although no cure has been discovered, progress is being made toward slowing disease progression.
Achievements also have been made in the search for treatment for multiple sclerosis. In MS, the demyelination of neurons and the inflammatory response cause development of plaques in the CNS. These plaques disrupt the transmission of nerve impulses.31 Another immunoregulator recently was approved for controlling the symptoms of MS. Interferon beta-1a significantly delays progression of disability among subjects. It is glycosolated and differs from Betaseron by one amino acid.
Also on the horizon for the treatment of MS are copolymer-1 and tizanidine. Copolymer-1 has been shown to decrease relapses in as many as 33 percent of patients, while tizanidine has demonstrated reduction in spasm and clonus. The mechanism of action in copolmyer-1 is not yet fully understood, while tizanidine appears to inhibit alpha-2 receptors in the CNS. Tizanidine is similar to clonidine in structure, but its cardiovascular effects are fewer and more transient.32, 33
One exciting product is the free-radical scavenger agent pegorgotein (formally known as PEG-SOD), which is in Phase III trials for treating closed head injury. Pegorgotein decreases brain damage and the incidence of acute respiratory distress syndrome by decreasing metabolic and pathologic consequences of reperfusion injury, such as edema, metabolic dysfunction, and ischemia.34 Tirilizad, which initially looked promising for head injury, has not shown consistent treatment effects. Further studies in head-injury patients for this lazaroid compound have been put on hold. Study with tirilizad continues for managing subarachnoid hemorrhage.
The prevalence of Parkinson's disease is 90 to 100 cases per 100,000 people, and the major site of pathologic involvement is the substantia nigra.35 The deficiency of dopamine in relation to acetylcholine leads to various movement disorders. Several mechanisms are being explored to correct the imbalance. The dopamine agonist pramipexole is in Phase III trials for treating Parkinson's disease.36 An NDA was filed with FDA at the end of December 1995 for pramipexole. Ropinirole is another dopamine agonist being studied. The class of N-methyl-D-aspartate antagonists is being developed as neuroprotectants aimed at several degenerative neuronal disorders. However, different subtypes of NMDA classes mediate different behaviors. Concern for safety and tolerability has slowed the progress of this class. Several compounds are in trials, but none is ready for immediate release.
The host of new antiepileptic agents approved during the past several years brought an end to the 15-year lag since valproic acid became available in 1978. Several more antiepileptics are in clinical trials, some of which focus on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA is thought to play a role in seizure control. One such agent, vigabatrin, is a GABA analogue with low protein binding and high renal elimination. This agent offers the advantage of fewer drug interactions over most available antiepileptics37 and has a favorable adverse effect profile. Another agent, tiagabine, is progressing through clinical trials and appears promising as adjunctive therapy in patients with complex partial seizures. It too affects GABA by inhibiting reuptake.38
The approval of fosphenytoin, a water-soluble prodrug of phenytoin, is likely to have an impact in the coming year. Unlike phenytoin, it does not contain propylene glycol and therefore is well tolerated when given I.M. or I.V. It is compatible with most I.V. solutions and can be given approximately four times faster than phenytoin. Converting a patient from phenytoin to fosphenytoin is not a direct conversion. The ratio of phenytoin to fosphenytoin is 1:1.5. The major disadvantage is the increased cost, which is expected to be significantly more than phenytoin. Parke-Davis plans to withdraw I.V. Dilantin from the market approximately six months or more after fosphenytoin becomes available. Finally, topiramate is a potent anticonvulsant that recently reached approvable status from FDA. It initially will be used as add-on therapy for adult patients with partial seizures.
Oncology/Hematology
Cancer is the second leading cause of death in the United States. Some predict that cancer soon will surpass cardiovascular disease and become the leading cause of death in the United States.40 In 1995, some 98 companies were developing cancer medications. This number has doubled since 1993. These companies have more than 200 cancer-related drugs in development; however, only about one of every 14 new chemotherapy compounds that show success in animal studies is considered for human testing.39 Approximately 20 percent of the new molecular entities approved in 1995 were oncologic agents. Four new oncologic drugs have reached approvable status; these agents include docetaxel and toremifene for breast cancer, liposomal daunorubicin for Kaposi's sarcoma, and nilutamide for prostate cancer.
One of the most promising new drug classes includes the topoisomerase I inhibitors. This class is structurally related to the natural compound camptothecin, which is derived from the Chinese Camptotheca acuminata plant.40 Topoisomerase I inhibitors differ from topoisomerase II inhibitors, such as etoposide, in that they bind to the topoisomerase-DNA complex; cell death ensues when the DNA helix cannot rebuild after uncoiling.41 The two most promising compounds in this class are irinotecan and topotecan; in Phase II trials, they have shown activity against a variety of cancers, including colorectal cancer. The success of topotecan in patients with previously treated small-cell lung cancer (response rate of as high as 39 percent) and ovarian cancer (response rate as high as 61 percent) has increased interest in Phase III trials with this drug.41
Breast cancer treatment advanced significantly in 1993 with the approval of the novel antineoplastic agent, paclitaxel, a compound obtained from the bark of the Pacific yew tree.42 A new taxane derivative, docetaxel, has been developed. It is semisynthetized from an inactive precursor found in the needles and twigs of different species of the yew tree. Docetaxel's mechanism of action is like that of paclitaxel; however, its activity and formulation allow for shorter infusion times.43 Also, docetaxel has been proven to be 2.5 times more potent than its precursor.44 Docetaxel also differs in that it causes a fluid retention syndrome; this side effect seems to be significantly reduced with the use of dexamethasone. Prospective trials are being conducted to compare the two taxane derivatives.45 The major activity of docetaxel has been noted in breast cancer and non-small cell lung cancer. It recently received approvable status for treating breast cancer.
A new synthetic pyrimidine antimetabolite, gemcitabine, recently was approved for treating pancreatic cancer.46 This prodrug is structurally related to cytarabine and works to inhibit DNA synthesis and repair. The drug requires intracellular metabolic activation but has the capability to enhance its own activity. The dose-limiting side effects of lethargy (flu-like symptoms) and myelosuppression are dependent upon the schedule of administration.45
Fluorouracil (5-FU) is a well-established antineoplastic drug used to treat a variety of tumors, especially colorectal cancer.40 This drug is activated by several biochemical pathways that produce different cytotoxic metabolites. One of the most important metabolites is fluorodexoyuridine monophosphate (FdUMP). Its cytotoxicity occurs by inhibiting the enzyme thymidylate synthetase. The development of drugs that enhance the action of 5-FU is ongoing. A new class of agents, TS inhibitors, enhances the inhibition of thymidylate synthetase. The most promising agent in this class is tomudex, which competes with reduced folates to inhibit TS. Phase III trials will compare tomudex with the standard 5-FU/leucovorin regimen for colorectal cancer patients.
An innovative new technology using photoactivation has been approved for the fight against cancer. This new technology is composed of a drug that can pinpoint its target (such as a tumor) by activation through light.46 This first photosensitive agent, porfimer, is prepared from a haematoporphyrin derivative; when injected into a patient, it accumulates mainly in abnormally active tissues, including neoplasms. However, this drug has no effect until it is activated by a light source such as a laser.47 Illumination causes a photochemical reaction, which results in the production of oxygen and leads to cell damage and death by oxidation. This allows for the cancer to be treated without systemic side effects. Porfimer's activity has been tested successfully in lung, bladder, and esophageal cancers.
Other potential candidates include anastrozole, toremifene, and suramin. Anastrozole appears useful for treating breast cancer in postmenopausal women whose disease progresses while receiving tamoxifen. Toremifene has received approvable status for treating postmenopausal women with estrogen receptor-positive or estrogen receptor-unknown advanced breast cancer. Suramin is being investigated for prostate cancer. It decreases prostate-specific antigens, a specific marker for the disease.
Psychiatry
Several agents are being evaluated for their effectiveness in improving cognitive function in the nearly 5 million patients suffering from Alzheimer's disease. Effective treatments aimed at slowing progression or reversing this neurodegenerative disease have been, for the most part, unsuccessful. Agents investigated include acetylcholine agonists, acetylcholine precursors, vasodilators, metabolic enhancers, antioxidants, and psychostimulants.48 Conjugated estrogens and estradiol have been evaluated for their capability to improve mental functioning in women with Alzheimer's disease who also were receiving estrogen-replacement therapy. Nicotine also is being studied because of its capability to stimulate the release of acetylcholine in the cerebral cortex. However, because of the risks associated with nicotine use, whether the benefits seen in Alzheimer's patients outweigh these risks remains questionable. Newer agents include xanomeline, a potent, selective M-1 receptor agonist in Phase II clinical trials.
Mirtazapine is an alpha-2 receptor antagonist that has been recommended for approval by FDA advisory committees for treating depression.
Sertindole and olanzapine are ahead of at least three other antipsychotic agents in development. Sertindole is in Phase III trials for treating schizophrenia. It does not appear to cause extrapyramidal side effects to the same extent as does haloperidol. Olanzapine has shown to be more effective than haloperidol in treating both the positive and negative symptoms of schizophrenia.
Respiratory
Approximately 5 percent of the U.S. population suffers from asthma, and it is becoming more prevalent. A new direction for research related to asthma treatment may lead to expanded options for this illness. The development of asthma drugs with different mechanisms of action enables clinicians to better individualize treatment for their patients. Current research has led to a better understanding of the causes of inflammation in asthma attacks. This, in turn, has led to new classes of drugs that can selectively inhibit the inflammatory chemicals.
One of these new agents is a 5-lipoxygenase inhibitor, zileutin. This agent was recommended for approval by the FDA's Pulmonary-Allergy Drugs Advisory Committee for maintenance therapy of chronic asthma in patients 18 years and older.49 The 5-lipoxygenase enzyme is important in the process of leukotriene formation. By blocking this enzyme, contraction of airway smooth muscle, vasodilatation, and migration of eosinophils into the airway are inhibited. Zileutin has demonstrated an additive bronchodilatory action with beta agonists.50 One study demonstrated an 80-percent decrease in the use of corticosteroids and a greater reduction of corticosteroid rescue with zileutin, when compared with theophylline therapy. The 5-lipoxygenase inhibitor also may decrease the amount of beta agonists required, which may have a positive economic effect. Although the drug seems to be effective, concerns of hepatotoxicity and hematologic effects have been raised. FDA recommended that the use of this drug require at least a 10-day follow-up visit to evaluate the potential for liver toxicity.49
Another novel drug being developed as a result of the research findings on leukotrienes is zafirlukast.50 This drug also interferes with the inflammatory and bronchospasm responses; however, it does so by blocking the leukotriene receptors. Zafirlukast demonstrates anti-inflammatory activity in patients with mild to moderate asthma and reduces the use of beta agonists without demonstrating serious adverse effects. Pranlukast is another leukotriene inhibitor being investigated.
A ban on freon-containing propellants is inevitable as concern for our environment increases. Therefore, one of the focuses of asthma research is on new dose forms for MDI inhalers.51 The beta agonist eformaterol has been formulated into a dry powder for use with a dry powder inhaler called an aerolizer. The new form of eformoterol has been shown to be safe and have a rapid onset of 1 minute with a 12-24 mg dose. This new inhaler requires less patient coordination and decreases the potential for an overdose, as compared with the available MDI inhalers.
Several new antihistamines are also in clinical trials this year. Of the new antihistamines in Phase II and III trials, fexofenadine, a compound closely related to terfenadine, seems to be the closest to market. Phase III trials have demonstrated the drug's effectiveness for allergic rhinoconjunctivitis and showed no evidence of adverse CNS or cardiovascular events at doses 14 times greater than the recommended 60mg dose given twice daily.
Conclusion
As pharmacists brace for the onslaught of changes in health care, keeping abreast of drugs in development is crucial. With many institutions having to cut drug expenditures, anticipating which drugs will become available in 1996 allows pharmacists to prepare for decisions about these drugs and to position themselves in the most cost-effective, rational manner.
References
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2. Anonymous. FDA understaffed, approval process too slow. Hosp Formul 1995; 30:57-8.
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23. America Online. Neurogen Corporation; Pfizer Inc.; Schering-Plough Corporation. Connecticut, New Jersey.
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37. Campbell, MM. Focus on vigabatrin: a second generation antiepileptic agent for treatment of refractory seizure disorders. Hosp Formul 1995; 30:143-7.
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39. Anonymous. Cancer update. Pharm Pract News 1995 (Aug):52-63.
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42. Anonymous. Paclitaxel. A promising addition to the antineoplastic armamentarium. Drugs Ther Persp 1995; 5(3):1-5.
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44. Cassidy J, Kaye SB. New drugs in clinical development in Europe. Hematol Oncol Clin North Am 1994; 8:289-303.
45. Anonymous. New drugs/drug news. P&T 1995; 20:668.
46. Anonymous. Porfimer sodium in the photodynamic therapy of cancer. Drugs Ther Persp 1995; 5(6):8-9.
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49. Anonymous. New drugs/drug news. P&T 1995; 20:456.
50. Barnes N. Investigational asthma drugs with novel routes of action may expand Rx options. Pharm Pract News 1995 (September):7-9.
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