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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

TradenameApplicantGeneric NamePatent NumberPatent Expiration
ALKERANGlaxosmithklinemelphalan hydrochloride4,997,651Nov 18, 2008
BREVIBLOCBaxter Hlthcare Corpesmolol hydrochloride5,017,609Nov 21, 2008
BUSPARBristol Myers Squibbbuspirone hydrochloride5,015,646Nov 14, 2008
COVERA-HSGd Searle Llcverapamil hydrochloride5,030,456Nov 7, 2008
DYNACIRC CRSmithkline Beechamisradipine5,030,456Nov 7, 2008
NEUROLITELantheus Medcltechnetium tc-99m bicisate kit5,279,811Nov 23, 2008
NEURONTINParke Davisgabapentin4,894,476Nov 2, 2008
NEURONTINPfizer Pharmsgabapentin4,894,476Nov 2, 2008
NUVIGILCephalonarmodafinil4,927,855Nov 22, 2008
PRELAYSankyotroglitazone4,572,912Nov 9, 2008
REZULINPfizer Pharmstroglitazone4,572,912Nov 9, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in October2008

*Drugs may be covered by multiple patents

TradenameApplicantGeneric NamePatent NumberPatent Expiration
CASODEXAstrazenecabicalutamide4,636,505Oct 1, 2008
CONDYLOXWatson Pharmspodofilox5,057,616Oct 15, 2008
COSOPTMerckdorzolamide hydrochloride; timolol maleate4,797,413Oct 28, 2008
ELIGARDQlt Usaleuprolide acetate4,938,763Oct 3, 2008
ELIGARDQlt Usaleuprolide acetate5,733,950Oct 3, 2008
ELIGARDQlt Usaleuprolide acetate5,739,176Oct 3, 2008
ELIGARDQlt Usaleuprolide acetateRE37950Oct 3, 2008
FERIDEX I.V.Amag Pharms Incferumoxides5,055,288Oct 8, 2008
GASTROMARKAmag Pharms Incferumoxsil5,055,288Oct 8, 2008
IONSYSAlzafentanyl hydrochloride5,232,438Oct 3, 2008
MIRCETTEDurameddesogestrel; ethinyl estradiolRE35724Oct 20, 2008
TRUSOPTMerckdorzolamide hydrochloride4,797,413Oct 28, 2008
ZEMURONOrganon Usa Incrocuronium bromide4,894,369Oct 13, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in September 2008

*Drugs may be covered by multiple patents

TradenameApplicantGeneric NamePatent NumberPatent Expiration
ANDRODERMWatson Labstestosterone4,855,294Sep 6, 2008
AVITAMylan Bertektretinoin5,045,317Sep 3, 2008
DDAVPSanofi Aventis Usdesmopressin acetate5,047,398Sep 10, 2008
OPANA EREndo Pharmsoxymorphone hydrochloride5,128,143Sep 19, 2008
RESCULAR Tech Ueno Ltdunoprostone isopropyl5,001,153Sep 19, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in August 2008

*Drugs may be covered by multiple patents

TradenameApplicantGeneric NamePatent NumberPatent Expiration
ADVAIR DISKUS 100/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate4,992,474Aug 12, 2008
ADVAIR DISKUS 100/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate5,126,375Aug 12, 2008
ADVAIR DISKUS 100/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate5,225,445Aug 12, 2008
ADVAIR DISKUS 250/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate4,992,474Aug 12, 2008
ADVAIR DISKUS 250/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate5,126,375Aug 12, 2008
ADVAIR DISKUS 250/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate5,225,445Aug 12, 2008
ADVAIR DISKUS 500/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate4,992,474Aug 12, 2008
ADVAIR DISKUS 500/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate5,126,375Aug 12, 2008
ADVAIR DISKUS 500/50Glaxosmithklinefluticasone propionate; salmeterol xinafoate5,225,445Aug 12, 2008
ADVAIR HFAGlaxosmithklinefluticasone propionate; salmeterol xinafoate4,992,474Aug 12, 2008
ADVAIR HFAGlaxosmithklinefluticasone propionate; salmeterol xinafoate5,126,375Aug 12, 2008
ADVAIR HFAGlaxosmithklinefluticasone propionate; salmeterol xinafoate5,225,445Aug 12, 2008
ETOPOPHOS PRESERVATIVE FREEBristol Myers Squibbetoposide phosphate5,041,424Aug 20, 2008
HECTOROLGenzymedoxercalciferol5,861,386Aug 2, 2008
HECTOROLGenzymedoxercalciferol5,869,473Aug 2, 2008
IMPLANONOrganon Usa Incetonogestrel4,957,119Aug 5, 2008
SEREVENTGlaxo Grp Ltdsalmeterol xinafoate4,992,474Aug 12, 2008
SEREVENTGlaxo Grp Ltdsalmeterol xinafoate5,126,375Aug 12, 2008
SEREVENTGlaxo Grp Ltdsalmeterol xinafoate5,225,445Aug 12, 2008
SEREVENTGlaxosmithklinesalmeterol xinafoate4,992,474Aug 12, 2008
SEREVENTGlaxosmithklinesalmeterol xinafoate5,126,375Aug 12, 2008
SEREVENTGlaxosmithklinesalmeterol xinafoate5,225,445Aug 12, 2008
TREXIMETGlaxosmithklinenaproxen sodium; sumatriptan succinate5,037,845Aug 6, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in July 2008

*Drugs may be covered by multiple patents

TradenameApplicantGeneric NamePatent NumberPatent Expiration
CARDIOLITEBristol Myers Squibbtechnetium tc-99m sestamibi kit4,988,827Jul 29, 2008
DEPAKOTEAbbottdivalproex sodium4,988,731Jul 29, 2008
DEPAKOTEAbbottdivalproex sodium5,212,326Jul 29, 2008
DEPAKOTE CPAbbottdivalproex sodium4,988,731Jul 29, 2008
DEPAKOTE CPAbbottdivalproex sodium5,212,326Jul 29, 2008
DEPAKOTE ERAbbottdivalproex sodium4,988,731Jul 29, 2008
DEPAKOTE ERAbbottdivalproex sodium5,212,326Jul 29, 2008
GLUCOTROL XLPfizerglipizide5,545,413Jul 2, 2008
HIVIDRochezalcitabine5,028,595Jul 2, 2008
RESTORILTyco Hlthcaretemazepam5,030,632Jul 9, 2008
RESTORILTyco Hlthcaretemazepam5,326,758Jul 9, 2008
UVADEXTherakosmethoxsalen5,036,102Jul 30, 2008
VEXOLAlconrimexolone4,686,214Jul 22, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

Drug Patent Expirations in June 2008

*Drugs may be covered by multiple patents

TradenameApplicantGeneric NamePatent NumberPatent Expiration
ADALAT CCBayer Pharmsnifedipine4,892,741Jun 8, 2008
CAVERJECT IMPULSEPharmacia And Upjohnalprostadil4,968,299Jun 28, 2008
EFFEXORWyeth Pharms Incvenlafaxine hydrochloride4,535,186Jun 13, 2008
EFFEXOR XRWyeth Pharms Incvenlafaxine hydrochloride4,535,186Jun 13, 2008
GENOTROPINPharmacia And Upjohnsomatropin recombinant4,968,299Jun 28, 2008
GENOTROPIN PRESERVATIVE FREEPharmacia And Upjohnsomatropin recombinant4,968,299Jun 28, 2008
NICODERM CQSanofi Aventis Usnicotine5,004,610Jun 14, 2008
NICODERM CQSanofi Aventis Usnicotine5,342,623Jun 14, 2008
NICODERM CQSanofi Aventis Usnicotine5,344,656Jun 14, 2008
NICODERM CQSanofi Aventis Usnicotine5,364,630Jun 14, 2008
NICODERM CQSanofi Aventis Usnicotine5,462,745Jun 14, 2008
NICODERM CQSanofi Aventis Usnicotine5,633,008Jun 14, 2008
NICODERM CQSanofi Aventis Usnicotine6,165,497Jun 14, 2008
PREVACIDTap Pharmlansoprazole5,026,560Jun 25, 2008
RISPERDALJanssen Pharmarisperidone4,804,663Jun 29, 2008
RISPERDAL CONSTAJanssen Pharmarisperidone4,804,663Jun 29, 2008
SONATAKing Pharmszaleplon4,626,538Jun 6, 2008
SULARSciele Pharma Incnisoldipine4,892,741Jun 8, 2008
TESTIMAuxilium Pharmstestosterone5,023,252Jun 11, 2008

Courtesy of DrugPatentWatch.com

Courtesy of DrugPatentWatch.com:

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

TradenameApplicantGeneric NamePatent NumberPatent Expiration
ACTINEXUniv Az Cancer Ctrmasoprocol4,695,590APR 17,2008
ACTINEXUniv Az Cancer Ctrmasoprocol5,008,294APR 15,2008
ESTROSTEP 21Warner Chilcottethinyl estradiol; norethindrone acetate5,010,070APR 23,2008
ESTROSTEP FEWarner Chilcottethinyl estradiol; norethindrone acetate5,010,070APR 23,2008
FEMPATCHParke Davisestradiol5,006,342APR 09,2008
LODINE XLWyeth Pharms Incetodolac4,966,768APR 30,2008
ORFADINSwedish Orphannitisinone5,006,158APR 09,2008
ZEMURONOrganon Usa Incrocuronium bromide4,894,369APR 13,2008

Courtesy of DrugPatentWatch.com