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This is a student paper from the 2009 final projects in the NIH Foundation for Advanced Education in the Sciences’ TECH 366 — Biotechnology Management. The students were asked to tell a story based on the course lectures, and to expand with general lessons on biotechnology company management.

Discovering potential drug targets

Myung K. Kim

At the NIH, I am focusing on discovering potential drug targets in diseases associated with obesity and aging, and developing orally available, small molecule drugs against these targets with the potential to treat metabolic disorders such as obesity, type II diabetes and various aging-related disorders. The Tech 366 course helps to identify business/science issues for the future development of the compounds of our study.

Obesity is a major risk factor for developing Type 2 diabetes, heart disease, stroke, certain types of cancers and neurodegenerative conditions such as Alzheimer’s disease. The FDA now recognizes obesity as a disease. While there are many aging-associated diseases, aging per se is not considered a disease and one cannot get an FDA approval and validation for a treatment of a non-disease.

Exercise and calorie restriction (CR) produce many health benefits for the treatment and prevention of aging- and obesity-related illnesses, but most people do not exercise regularly and consume an excess of calories. Our drug candidates are thought to mimic certain beneficial health effects of exercise and CR at a low concentration, without requiring a change in exercise or eating habits, by activation of the kinase that we believe may control rate-limiting steps in the key pathways of the processes associated with aging and obesity.

Increased calorie intake and sedentary lifestyle have fueled the obesity epidemic in developed nations. Since 1980, the number of obese adults has doubled, and the number of obese children has tripled in the United States. Approximately 65% of Americans are now overweight or obese. One in three children born in the year 2000 will develop diabetes as a result of obesity. Another factor that affects obesity is age; an average American gains 1 lb per year starting from the second decade of life and the number of people 65 or older is rapidly rising throughout developed countries. The Centers for Disease Control and Prevention (CDC) estimate that by the year 2030, there will be 70 million elderly Americans, more than twice the current number. Additionally, the United Nations recently estimated that the world’s population over the age of 65 will reach two billion within 50 years. The aging and obesity in America and the rest of the world mean an increased demand for better compounds to combat those diseases and indications specific to the elderly or obese people.

One of the reasons for the lack of exercise in the elderly and obese people is that the capacity for exercise diminishes as age and obesity increase. Aging causes loss of mitochondria in skeletal muscles in lean and healthy individuals, the organelle that burns fat and produces energy, and loss of mitochondria increases abdominal fat accumulation and decreases physical stamina. As skeletal muscle loses mitochondrial function, the capacity to oxidize fat and generate energy during physical activity decreases, resulting in accumulation of fat, particularly abdominal fat. Therefore, a majority of people in developed countries is caught in a vicious cycle that is difficult to break; obesity and aging lead to a decline in physical fitness, which leads to physical inactivity, which further increases obesity. CR (calorie restriction), on the other hand, increases mitochondrial biogenesis and reverses many aging- and obesity-associated declines.

One of the hallmarks of aging is increased oxidative damage, including double-stranded breaks of nuclear DNA. We have found that the mitochondrial decline is driven, in part, by an enzyme that senses DNA-breaks. Our study proposes that this DNA-break sensing enzyme is responsible for aging and obesity in mammals, and that when used at a low concentration, the enzyme inhibitors reproduce many beneficial effects of exercise and CR such as induction of mitochondrial biogenesis in skeletal muscle and increase in insulin sensitivity in skeletal muscle and fat. The enzyme inhibitors also lower blood pressure and blood glucose level, reduce inflammatory signaling, improve memory and cognitive abilities and decrease anxiety/depression in mice. Overall, the enzyme inhibitors showed a reversal of obesity- and aging-associated loss of capacity in mice.

Because increased mitochondrial content could lead to increased oxidative damage, it is possible that repeated exercise may damage muscle and decrease endurance. This potential concern may not be a problem, because both the genetically modified mice deficient in this DNA-break sensing enzyme or mice treated with the enzyme inhibitors showed reduced serum lactate levels and increased endurance even after many days of repeated exercise, indicating that these muscles were not prone to damage by repeated exercise. Our work demonstrates that modulating this enzyme in muscle and fat could represent a novel strategy to increase exercise capacity and to reduce obesity-aging-related diseases.

With two-thirds of Americans said to be obese or overweight, a successful obesity drug could have huge sales. There is a need for better drugs because the existing ones are hampered by serious side effects. Anti-obesity drugs in the market operate through one or more of the following mechanisms; suppression of the appetite, increase of the body’s metabolism, or interference with the body’s ability to absorb specific nutrients in food. Some anti-obesity drugs have severe and often life-threatening side effects. These compounds carry a risk of severe psychiatric problems, high blood pressure, tachycardia, heart palpitations, closed-angle glaucoma, drug addiction, restlessness, agitation and insomnia. One of the drug targets for obesity is a serotonin-receptor affecting appetite. However, since eating and reproducing are absolute priorities in life, it is difficult to alter these pathways without causing serious side effects. Because of the safety concerns, developing a successful obesity drug appears to be a treacherous task. For example, Sanofi-Aventis, Merck and Pfizer all discontinued work on experimental obesity drugs last year because of concerns that the drugs, which all worked by similar mechanisms focusing on a serotonin-receptor, could contribute to depression and suicidal thinking.

The enzyme inhibitors in our study work by a different mechanism to induce weight loss and decrease anxiety/depression in mice showing no sign of psychiatric side effects. Also, there was no sign that the drug damages heart valves in mice. Mice treated with the compound ate more than the control group indicating that the compound would not induce a simple nausea which leads to weight loss.

Our initial goal is to get FDA approval of the enzyme inhibitors for the treatment of metabolic symptoms and abdominal obesity in overweight type II diabetics. If we take this out into the broad obese or overweight population which includes both pre-diabetics and diabetics as an anti-obesity drug, safety could become a problem once millions take this drug. We think that it would be better to start treating (abdominal) obesity and diabetes in overweight diabetics initially, which just about all type II diabetics are, to target a narrow segment of the population. This is based on our data that the enzyme inhibitors of our study improved all metabolic parameters in mice 1) by inducing weight loss; and 2) by directly increasing insulin signaling in skeletal muscle and fat.

Although there are many diabetes drugs on the market, there is no drug that can target both obesity and diabetes effectively. Weight loss is essential for the treatment of type II diabetes. Given that, the enzyme inhibitors of this study which can target both obesity and insulin resistance could provide an attractive treatment option. All diabetes drugs operate according to one of the following three mechanisms: stimulating insulin secretion from pancreatic beta cells, reducing glucose production in liver, or reducing insulin resistance in insulin-sensitive tissues (i.e., skeletal muscle, fat, liver). Among these, TZD  type drugs (rosiglitazone, pioglitazone), the insulin sensitizers, are known to induce a significant weight gain, because these drugs activate a transcription factor called PPARg that promotes fat cell formation. It is dangerous for diabetics to gain weight. Furthermore, when concerns were raised about the safety of rosiglitazone (Avandia, GlaxoSmithKline) in May 2007, many patients and doctors made the decision to discontinue use of the TZD type drugs. Rosiglitazone discontinuation left many diabetic patients without good control for their insulin resistance. For these reasons, we think that the enzyme inhibitors of our study can claim a distinct position even in the crowded diabetes drug market.

The trend in drug development suggests that one can sell something which does not cure a disease if one has a good enough argument that it can prevent a disease. For example, high cholesterol is not a disease, but six billion dollars is spent each year on cholesterol-lowering drugs. Obesity in general, abdominal obesity, in particular, is a major risk factor for many diseases such as type 2 diabetes, cancer and Alzheimer disease. Our hope is that we may be able to expand our trials to a broad obese population that includes pre-diabetics, based on the efficacy and toxicity data in the overweight type II diabetics. With an ever-increasing obese population, a successful obesity drug could have huge sales.

With these goals in mind, we are currently engaged in IND-oriented preclinical trials for the first-in-human studies. We are also treating animal models for Duchenne muscular dystrophy, which is an orphan disease, and are planning preclinical trials in various age-related diseases.

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in November 2008

*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
ALKERAN Glaxosmithkline melphalan hydrochloride 4,997,651 Nov 18, 2008
BREVIBLOC Baxter Hlthcare Corp esmolol hydrochloride 5,017,609 Nov 21, 2008
BUSPAR Bristol Myers Squibb buspirone hydrochloride 5,015,646 Nov 14, 2008
COVERA-HS Gd Searle Llc verapamil hydrochloride 5,030,456 Nov 7, 2008
DYNACIRC CR Smithkline Beecham isradipine 5,030,456 Nov 7, 2008
NEUROLITE Lantheus Medcl technetium tc-99m bicisate kit 5,279,811 Nov 23, 2008
NEURONTIN Parke Davis gabapentin 4,894,476 Nov 2, 2008
NEURONTIN Pfizer Pharms gabapentin 4,894,476 Nov 2, 2008
NUVIGIL Cephalon armodafinil 4,927,855 Nov 22, 2008
PRELAY Sankyo troglitazone 4,572,912 Nov 9, 2008
REZULIN Pfizer Pharms troglitazone 4,572,912 Nov 9, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in October2008

*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
CASODEX Astrazeneca bicalutamide 4,636,505 Oct 1, 2008
CONDYLOX Watson Pharms podofilox 5,057,616 Oct 15, 2008
COSOPT Merck dorzolamide hydrochloride; timolol maleate 4,797,413 Oct 28, 2008
ELIGARD Qlt Usa leuprolide acetate 4,938,763 Oct 3, 2008
ELIGARD Qlt Usa leuprolide acetate 5,733,950 Oct 3, 2008
ELIGARD Qlt Usa leuprolide acetate 5,739,176 Oct 3, 2008
ELIGARD Qlt Usa leuprolide acetate RE37950 Oct 3, 2008
FERIDEX I.V. Amag Pharms Inc ferumoxides 5,055,288 Oct 8, 2008
GASTROMARK Amag Pharms Inc ferumoxsil 5,055,288 Oct 8, 2008
IONSYS Alza fentanyl hydrochloride 5,232,438 Oct 3, 2008
MIRCETTE Duramed desogestrel; ethinyl estradiol RE35724 Oct 20, 2008
TRUSOPT Merck dorzolamide hydrochloride 4,797,413 Oct 28, 2008
ZEMURON Organon Usa Inc rocuronium bromide 4,894,369 Oct 13, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in September 2008

*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
ANDRODERM Watson Labs testosterone 4,855,294 Sep 6, 2008
AVITA Mylan Bertek tretinoin 5,045,317 Sep 3, 2008
DDAVP Sanofi Aventis Us desmopressin acetate 5,047,398 Sep 10, 2008
OPANA ER Endo Pharms oxymorphone hydrochloride 5,128,143 Sep 19, 2008
RESCULA R Tech Ueno Ltd unoprostone isopropyl 5,001,153 Sep 19, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in August 2008

*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
ADVAIR DISKUS 100/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 4,992,474 Aug 12, 2008
ADVAIR DISKUS 100/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,126,375 Aug 12, 2008
ADVAIR DISKUS 100/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,225,445 Aug 12, 2008
ADVAIR DISKUS 250/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 4,992,474 Aug 12, 2008
ADVAIR DISKUS 250/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,126,375 Aug 12, 2008
ADVAIR DISKUS 250/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,225,445 Aug 12, 2008
ADVAIR DISKUS 500/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 4,992,474 Aug 12, 2008
ADVAIR DISKUS 500/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,126,375 Aug 12, 2008
ADVAIR DISKUS 500/50 Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,225,445 Aug 12, 2008
ADVAIR HFA Glaxosmithkline fluticasone propionate; salmeterol xinafoate 4,992,474 Aug 12, 2008
ADVAIR HFA Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,126,375 Aug 12, 2008
ADVAIR HFA Glaxosmithkline fluticasone propionate; salmeterol xinafoate 5,225,445 Aug 12, 2008
ETOPOPHOS PRESERVATIVE FREE Bristol Myers Squibb etoposide phosphate 5,041,424 Aug 20, 2008
HECTOROL Genzyme doxercalciferol 5,861,386 Aug 2, 2008
HECTOROL Genzyme doxercalciferol 5,869,473 Aug 2, 2008
IMPLANON Organon Usa Inc etonogestrel 4,957,119 Aug 5, 2008
SEREVENT Glaxo Grp Ltd salmeterol xinafoate 4,992,474 Aug 12, 2008
SEREVENT Glaxo Grp Ltd salmeterol xinafoate 5,126,375 Aug 12, 2008
SEREVENT Glaxo Grp Ltd salmeterol xinafoate 5,225,445 Aug 12, 2008
SEREVENT Glaxosmithkline salmeterol xinafoate 4,992,474 Aug 12, 2008
SEREVENT Glaxosmithkline salmeterol xinafoate 5,126,375 Aug 12, 2008
SEREVENT Glaxosmithkline salmeterol xinafoate 5,225,445 Aug 12, 2008
TREXIMET Glaxosmithkline naproxen sodium; sumatriptan succinate 5,037,845 Aug 6, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in July 2008

*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
CARDIOLITE Bristol Myers Squibb technetium tc-99m sestamibi kit 4,988,827 Jul 29, 2008
DEPAKOTE Abbott divalproex sodium 4,988,731 Jul 29, 2008
DEPAKOTE Abbott divalproex sodium 5,212,326 Jul 29, 2008
DEPAKOTE CP Abbott divalproex sodium 4,988,731 Jul 29, 2008
DEPAKOTE CP Abbott divalproex sodium 5,212,326 Jul 29, 2008
DEPAKOTE ER Abbott divalproex sodium 4,988,731 Jul 29, 2008
DEPAKOTE ER Abbott divalproex sodium 5,212,326 Jul 29, 2008
GLUCOTROL XL Pfizer glipizide 5,545,413 Jul 2, 2008
HIVID Roche zalcitabine 5,028,595 Jul 2, 2008
RESTORIL Tyco Hlthcare temazepam 5,030,632 Jul 9, 2008
RESTORIL Tyco Hlthcare temazepam 5,326,758 Jul 9, 2008
UVADEX Therakos methoxsalen 5,036,102 Jul 30, 2008
VEXOL Alcon rimexolone 4,686,214 Jul 22, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in June 2008

*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
ADALAT CC Bayer Pharms nifedipine 4,892,741 Jun 8, 2008
CAVERJECT IMPULSE Pharmacia And Upjohn alprostadil 4,968,299 Jun 28, 2008
EFFEXOR Wyeth Pharms Inc venlafaxine hydrochloride 4,535,186 Jun 13, 2008
EFFEXOR XR Wyeth Pharms Inc venlafaxine hydrochloride 4,535,186 Jun 13, 2008
GENOTROPIN Pharmacia And Upjohn somatropin recombinant 4,968,299 Jun 28, 2008
GENOTROPIN PRESERVATIVE FREE Pharmacia And Upjohn somatropin recombinant 4,968,299 Jun 28, 2008
NICODERM CQ Sanofi Aventis Us nicotine 5,004,610 Jun 14, 2008
NICODERM CQ Sanofi Aventis Us nicotine 5,342,623 Jun 14, 2008
NICODERM CQ Sanofi Aventis Us nicotine 5,344,656 Jun 14, 2008
NICODERM CQ Sanofi Aventis Us nicotine 5,364,630 Jun 14, 2008
NICODERM CQ Sanofi Aventis Us nicotine 5,462,745 Jun 14, 2008
NICODERM CQ Sanofi Aventis Us nicotine 5,633,008 Jun 14, 2008
NICODERM CQ Sanofi Aventis Us nicotine 6,165,497 Jun 14, 2008
PREVACID Tap Pharm lansoprazole 5,026,560 Jun 25, 2008
RISPERDAL Janssen Pharma risperidone 4,804,663 Jun 29, 2008
RISPERDAL CONSTA Janssen Pharma risperidone 4,804,663 Jun 29, 2008
SONATA King Pharms zaleplon 4,626,538 Jun 6, 2008
SULAR Sciele Pharma Inc nisoldipine 4,892,741 Jun 8, 2008
TESTIM Auxilium Pharms testosterone 5,023,252 Jun 11, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in May 2008
*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
HABITROL Novartis nicotine 5,016,652 May 21, 2008
REQUIP Glaxosmithkline ropinirole hydrochloride 4,824,860 May 19, 2008
SARAFEM Lilly fluoxetine hydrochloride 4,971,998 May 20, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in April 2008
*Drugs may be covered by multiple patents

Tradename Applicant Generic Name Patent Number Patent Expiration
ACTINEX Univ Az Cancer Ctr masoprocol 4,695,590 APR 17,2008
ACTINEX Univ Az Cancer Ctr masoprocol 5,008,294 APR 15,2008
ESTROSTEP 21 Warner Chilcott ethinyl estradiol; norethindrone acetate 5,010,070 APR 23,2008
ESTROSTEP FE Warner Chilcott ethinyl estradiol; norethindrone acetate 5,010,070 APR 23,2008
FEMPATCH Parke Davis estradiol 5,006,342 APR 09,2008
LODINE XL Wyeth Pharms Inc etodolac 4,966,768 APR 30,2008
ORFADIN Swedish Orphan nitisinone 5,006,158 APR 09,2008
ZEMURON Organon Usa Inc rocuronium bromide 4,894,369 APR 13,2008

Courtesy of DrugPatentWatch.com