News and Events - 19 Feb 2012

Human test of implanted medicine chips

NHS Choices

17.02.2012 21:25:00

BBC News says we are a step closer to microchips that can be “implanted under a patient’s skin to control the release of drugs”.

The news was based on a study that tested the use of advanced microchips containing tiny drug reservoirs that can be remotely triggered to release medication into the body. Creating workable drug-release chips has long been a goal of researchers, as it could help people take the correct dose of vital medicines such as insulin.

In this particular trial, reported to be the first of its kind, eight women were given the chips filled with a drug to combat osteoporosis. The drug, teriparatide, is normally delivered by daily injection, but researchers found that using the chips produced similar physical results to injections. Also, there were no toxic or adverse events, due to either the microchip or the drug, and all the patients reported that it did not impact on their quality of life.

This study throws up a range of possible uses for microchip-based drug delivery, which could one day be used for the treatment of wider conditions that require frequent, scheduled dosing, particularly where standard treatment is through injection.

However, much more testing of the technology will be needed to firmly establish its safety, and to see whether there could be wider applications. One key consideration though, would be whether the use of this advanced technology can actually prove better or cheaper than the use of injections.

 

Where did the story come from?

The study was carried out by researchers from MicroCHIPS, Inc, (a private company producing medical microchips ; the Harvard Medical School; Case Western Reserve University; On Demand Therapeutics, Inc, and the Massachusetts Institute of Technology. It was funded by MicroCHIPs, Inc.

The study was published in the peer-reviewed scientific journal Science Translational Medicine.

The results of this study have also been presented at the annual meeting of the American Association for the Advancement of Science (AAAS .

The story appeared on the BBC and a number of newspapers, including the Daily Mail, the Daily Mirror and The Independent.

Most of the coverage of the story was good. However, alongside The Independent’s main article the newspaper featured an opinion-based section discussing potential uses of the device, including allowing psychiatrists to trigger doses in schizophrenic patients when they resist injections of medication. There is a distinct difference between using medical devices to structure the delivery of medication and using them to force people to take medication against their will.

It seems unlikely that medical groups would find this theoretical use to be ethically acceptable, and it should be noted that the treatment of mental health problems was not assessed in the study or in other coverage.

The Independent also used a photograph of a distressed man huddled on the floor wearing no shoes, intended to illustrate schizophrenia. While the condition can certainly involve periods of acute problems and distress, it seems to a rather extreme and particularly negative depiction of someone with schizophrenia.

 

What kind of research was this?

This was a small cohort study of a drug delivery microchip, implanted under the skin. The microchip contains tiny drug reservoirs and can be programmed to wirelessly release discrete doses of a medication.

This particular study used the drug teriparatide, prescribed by specialists only for the treatment of severe osteoporosis (bone weakening . It is normally delivered by daily injection and given for a maximum treatment period of two years only.

The researchers aimed to see whether the drug released from the device had similar ‘pharmacokinetics’ (adsorption, distribution, metabolism and excretion and biological effect to the drug administered by standard injection. They also monitored how reliable and reproducible drug release from the microchip was, and if there were any side effects of the implant.

This was the first clinical trial of this microchip. As the researchers state, further development is required to ensure proper operation of implanted devices, and devices containing more reservoirs will be needed if the device were to provide regular doses over one or more years. In addition, before this technology becomes available, it will have to be tested in larger, controlled trials.

 

What did the research involve?

Eight women with osteoporosis, aged between 65 and 70, were recruited for the study. The drug delivery microchip was implanted under the skin, just under the waistline. The devices were implanted for four months. Eight weeks after implantation, the microchip started releasing daily doses of teriparatide for a period of 20 days. Blood samples were drawn regularly to monitor the pharmacokinetics and to determine levels of bone markers. A safety assessment was also performed.

After the 20 days of drug release from the device, the researchers administered the osteoporosis drug by injection, and again took blood samples, so that release from the microchip and from the injection could be compared.

 

What were the basic results?

In one patient, feedback from chip indicated that the drug was not being released. The results from this patient were excluded.

Drug released from the microchip in the seven other patients had similar pharmacokinetics to drug administered by injection, and bone markers indicated that drug released from the microchip increased bone formation as expected. However, the effectiveness of medication released from the microchip was not compared to the effectiveness when given by injection.

There were no toxic or adverse events due to the device or drug. Patient response to the implant was also favourable, stating that it did not impact upon their quality of life.

 

How did the researchers interpret the results?

The researchers concluded that the programmable implant was able to deliver teriparatide at scheduled intervals, with pharmacokinetics similar to injections ‘without the pain and burden of daily injections’.

 

Conclusion

This study was a small clinical trial, performed in eight women, of an implantable microchip-based drug delivery device. It found that the microchip could deliver the osteoporosis drug teriparatide with similar pharmaceutical properties to injections, including adsorption, distribution, excretion and metabolism by the body. There were no toxic or adverse events due to either the microchip or the drug, and the patients all responded favourably to the implant, stating it did not affect quality of life.

Larger controlled trials comparing this device with conventional injected teriparatide would be needed to confirm the safety and efficacy findings. Furthermore, trials may need to assess use of the chip over a longer period - on prescription, teriparatide may be administered by daily injection for up to two years.

The findings also suggest that this microchip-based drug delivery device may have the potential to be used for the treatment of wider conditions that require frequent, scheduled dosing, particularly where standard treatment is through injection. However, much more testing of the technology will be needed to see whether there could be wider applications.

Analysis by Bazian

Links To The Headlines

Dawn of the age of wireless medicine. The Independent, February 17 2012

'Wireless medicine' helps solve one of doctors' biggest problems - getting patients to take drugs. The Independent, February 17 2012

New microchip will let doctor administer drugs into your body over the phone. Daily Mirror, February 17 2012

'Pharmacy on a chip' gets closer. BBC News, February 17 2012

Links To Science

Farra R, Sheppard NF, McCabe L, et al. First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip. Science Translational Medicine. Published online February 16 2012

feline toxoplasmosis article

18.02.2012 14:55:39

*Feline Toxoplasmosis and its Zoonotic Implications* *Introduction* The coccidian Toxoplasma gondii is an obligate intracellular parasite that can infect virtually all warm-blooded animals including humans. Members of the species Felidae, however, are the only known definitive hosts for the sexual stages of T. gondii and, thus, serve as the primary reservoir for the pareasite. Numerous other species are paratenic hosts and serve as intermediate hosts required for completion of the parasite’s life cycle but in which developmental changes do not occur. In the United States, the percentage of domestic cats seropositive for T. gondii is estimated to be between 16 - 43% based on regional variances.1,2 The high serological prevalence of toxoplasmosis and its zoonotic potential underscore the importance of veterinarians’ full understanding of both the disease course and the role of domestic cats in the T. gondii life cycle.3 *Epidemiology* T. gondii sporulated oocysts, bradyzoites, and tachyzoites may all cause infection.2 Cats, as obligate carnivores, primarily contract toxoplasmosis through ingestion of infected host tissue cysts. As definitive hosts, cats alone can complete the enteroepithelial life cycle. Extraintestinal cycling of T. gondii occurs in cats, as well, along with all other susceptible species that serve as intermediate hosts. In cats, the enteroepithelial and extraintestinal developmental cycles may occur simultaneously.4 *Enteroepithelial Life Cycle* Upon ingestion of tissue from infected hosts, proteolytic digestive enzymes degrade the tissue cysts and release the bradyzoites.2 These slowly dividing forms of the coccidian are capable of a sexual reproductive process called merogany that occurs only in cats.5 Through merogany, bradyzoites undergo repeated nuclear/cytoplasmic fission to yield microgamonts (‘male-like’ and macrogamonts (‘female-like’ .5 Microgamonts further divide to form microgametes which are then able to fertilize the macrogamont.5 A protective wall encapsulates fertilized macrogamonts to form the zygote-containing oocyst. Unsporulated oocysts are non-infective and are shed into the environment from the feces in most naïve cats, 10 days or less after tissue cyst ingestion.2,6 Oocyst sporulation to the infective form occurs approximately 1-5 days later, after exposure to ambient air and humidity.2 This is the period of most concern for exposure to pregnant women who may be cleaning the cat litter box. Each sporulated oocyst contains eight sporozoites that can survive in the environment for up to 18 months7, andinsects such as roaches and earthworms may function as transport hosts by dispersing oocysts from their initial shedding point .7 There are several reasons why cats who ingest oocysts or tachyzoites develop T. gondii infections less frequently (approximately 20% and exhibit a prolonged prepatent period when compared to those cats ingesting tissue cysts.6 Bradyzoites are able to serve as direct precursors to enteroepithelial cycling (and thus a shorter prepatent period whereas oocysts or tachyzoites must first develop to the bradyzoite stage.2, 5 Moreover, the decreased infection rate may be related to the fact that each tissue cyst contains a large number of bradyzoites whereas only eight sporozoites are within an oocyst.2 Finally, tachyzoite ingestion is less likely to result in patency as they are often destroyed by gastrointestinal digestive enzymes.2 *Extraintestinal Life Cycle* Ingested sporulated oocysts release sporozoites into the gastrointestinal tract of the host.6 Sporozoites enter cells of the intestine and lymph nodes where they undergo endodyogeny to form rapidly dividing tachyzoites that disemminate throughout the body through the blood and lymphatic vasculature.6 The tachyzoite tissue phase that develops within a host or is ingested may result in bradyzoite tissue cyst formation within the brain, skeletal muscle, and liver (see Figures 1,2 . These tissue cysts may persist for the life of the host,7 and the potential for recrudescence exists as tissue cysts rupture and release bradyzoites.2 Both ingested bradyzoites and those released through host cyst rupture are capable of asexual development to tachyzoites, thereby perpetuating the cycle.5

[TR] [TD]Image: http://www.vet.uga.edu/vpp/clerk/addante/fig01.jpg [/TD] [TD]Image: http://www.vet.uga.edu/vpp/clerk/addante/fig02.jpg [/TD] [/TR] [TR] [TD="width: 291"]*Figure 1*. Raccoon brain. Multiple Toxoplasma gondii tissue cysts (arrow within white matter. H&E stain, 40X.[/TD] [TD="width: 325"]*Figure 2*. Dog muscle. Myonecrosis and myositis with intralesional T. gondii tissue cysts (arrows containing developing bradyzoites. H&E stain, 40X.[/TD] [/TR] *Vertical and Iatrogenic Infections * Transplacental and transmammary transmission occurs in carnivores, omnivores, and herbivores as a result of naïve host infection during pregnancy.2,8 In congenital transmission, T. gondii replicates and infects placental tissue whereby it gains access to the fetus. Outcome in these cases is most severe (e.g. abortion, stillbirth when infection occurs during the first half of the pregnancy.2 Alternatively, when tachyzoites are shed in milk, transmammary transmission may occur and result in clinical illness of varying degrees in newborns.2 Additionally, although less commonly observed, infection is also possible in recipients of donor fluids or tissue thereby underscoring the importance of thoroughly screening donors asT. gondii can survive at 4°C for up to 50 days in stored blood products.9 *Clinical Disease* Although there is a high seroprevalence of T. gondii infection among Felidae, significant clinical disease in domestic cats is relatively infrequent. When disease does occur, it may be attributed to a primary infection in which an inadequate immune response failed to arrest invasive tachyzoites.1,2,4 Alternatively, disease may result from reactivation of subclinical infection in an immunocompromised individual with encysted bradyzoites which may then form rapidly multiplying tachyzoites.2 Such incidents are thought to relate directly to variables such as the age and sex of the host, presence of immunodeficient states (such as feline leukemia virus or feline immunodeficiency virus infection ,concomitant stress or illness, and organism load*.2 * Clinical illness appears to be most frequent among cats less than 2 years of age which may be due in part to an insufficient immune response by young cats.1,2,4 In one study involving 25 kittens experimentally infected with neonatal T. gondii infection, 3 kittens were stillborn.10 Among the 22 live kittens, approximately 95% exhibited proliferative interstitial pneumonia, necrotizing hepatitis, myocarditis, and skeletal myositis to the extent that euthanasia was necessary.10 Infected neonates also often develop central nervous system infections.2 Organism ingestion followed by initial enteroepithelial replication may lead to a self-limiting small bowel diarrhea that occurs due to an IgA response elicited by T. gondii resulting in increased intestinal secretions.2 Clinical illness may progress when naïve hosts are infected or when prior infections are reactivated. Extraintestinal spread of the parasite may occur as rapid multiplication of tachyzoites within host cells results in cell rupture, promoting organism dissemination and, ultimately, tissue necrosis.1,2,4 Disease onset may be sudden or insidious, and clinical signs are often multiple and varied as most types host cells are vulnerable to infection.11 Respiratory, CNS, hepatic, pancreatic, cardiac, and ocular tissues were among the most commonly affected tissues in a group of 100 adult cats with confirmed toxoplasmosis.7 Associated clinical signs included dyspnea, tachypnea, intermittent fever, icterus, vomiting, weight loss, hyperesthesia, shifting lame lameness, ataxia, dermatitis, and death.2 *Clinicopathologic Findings* Laboratory testing may detect several abnormal parameters in animals with acute systemic toxoplasmosis. A nonregenerative anemia may be detected with a concurrent neutrophilic leukocytosis, lymphocytosis, monocytosis, and eosinophilia.2 The biochemical profile of cats with chronic toxoplasmosis may demonstrate hyperglobulinemia due to chronic antigenic stimulation and immune response. Hepatocellular disease may result in elevated alanine aminotransferase (ALT enzyme activity, and muscle damage may cause an increase in aspartate aminotransferase (AST and creatine kinase (CK activity.2 Hyperbilirubinemia may occur in cats with cholangiohepatitis or hepatic lipidosis secondary to liver dysfunction.2 Histologically, lesions associated with toxoplasmosis are a result of cell death secondary to intracellular replication of T. gondii. The associated inflammatory reaction is primarily composed of macrophages in adult cats and neutrophils and macrophages (pyogranulomatous , with or without a lymphoplasmacytic component, in neonates.10,11 Tissue cysts often persist in the absence of host reaction. In the CNS, encephalitis may result from tachyzoites primarily infecting astrocytes.11 A resultant diffuse necrotizing and nonsuppurative lymphocytic infiltrate may develop in the brain and extend to the meninges.11 Necrotizing hepatitis with focal areas of coagulative lobular necrosis may be observed with the presence of few organisms.11 Other gross lesions include pulmonary edema and congestion with failure of lung collapse as well as multifocal areas of firm white, yellow, or gray discoloration in the pulmonary parenchyma.11 Toxoplasma organisms invade type 1 and 2 pneumocytes as well as pulmonary alveolar macrophages, fibroblasts, endothelial cells, and smooth muscle cells.11 The subsequent proliferative reaction in alveolar walls may resemble adenomatosis. Severe lymphadenopathy may occur.11 Pericardial effusion is occasionally reported and likely due to organisms invading the myocardium.2 Intestinal lymphatic tissue invasion may result in small bowel ulcerative disease.11 If the muscularis is involved, occasionally a chronic necrotizing process leads to large granulomatous nodules that can impede the transport of luminal contents and possible lymphangiectasia.2,11 Ocular lesions are frequent and may cause inflammation of the retina or anterior segment (anterior uveitis with granulomatous inflammation being the prominent cytologic feature.2 Placental lesions can include focal necrosis with or without foci of mineralization.7 *Diagnosis* Diagnosis of clinical toxoplasmosis in cats is challenging due to the high seroprevalence of the infection among non-affected cats as well as the many potential antibody responses that may occur in disease as well as in health. Sinceseroconversion also occurs in the absence of clinical disease, titers should be interpreted in conjuction with clinical signs consistent with toxoplasmosis. Accordingly, the exclusion of other causes of clinical disease paired with serologic evidence (such as a four-fold increase in titer and a positive response to appropriate therapy may be simultaneously employed in order to reach a tentative diagnosis.2 *Serology * Near 80% of cats are thought to develop IgM antibodies within 1-2 weeks after exposure. These antibodies may remain detectable for months to years.2 As a result, the presence of IgM antibody cannot reliably be used to predict recent infection and oocyst shedding. Similarly, IgG antibodies may not develop for 4-6 weeks and may peak in 2-3 weeks with some cats remaining high for several years.1,2,4 T. gondii titers may be by indirect fluorescent antibody testing, modified agglutination, enzyme-linked immunosorbent antibody assays, and Sabin-Feldman serologic testing.7 Because many cats have T. gondii antibodies from previous exposure, it is necessary to demonstrate either a four-fold rise in IgG titers over a 2-3 week period or a single high IgM titer (> 1:64 .1,2,4,7 Clinical signs may develop before seroconversion occurs in 1-2 weeks or not until after peak titers have developed.1,2,7 For these reasons, antibody titers may be difficult to interpret and single antibody titers are often insufficient for definitive diagnosis.2 *Cytology* Definitive diagnosis for T. gondii is possible through identification of the organisms in body tissue or fluids (see Figures 3,4 . In acute illness, tachyzoites may be present in large numbers in body fluids such as abdominal and pleural effusions.2 Peripheral blood smears, cerebrospinal fluid (CSF , fine needle aspirates of tissues, and airway washings are less likely to provide direct organism detection.2 Such biologic samples can be used for bioassays in mice, tissue cultures, or PCR to demonstrate the presence of T. gondii organisms.2,7 [TR] [TD]Image: http://www.vet.uga.edu/vpp/clerk/addante/fig03.jpg [/TD] [TD]Image: http://www.vet.uga.edu/vpp/clerk/addante/fig04.jpg [/TD] [/TR] [TR] [TD="width: 316"]*Figure 3*. Transtracheal washing from a cat. A large binucleate phagocytic cell contains intracytoplasmic Toxoplasma tachyzoites (arrow . Wrights stain, 50X.[/TD] [TD="width: 325"]*Figure 4*. Fine needle aspirate from cat lung. A ruptured large mononuclear cell with multiple Toxoplasma tachyzoites. Wrights stain, 100X.[/TD] [/TR] Fecal samples may also be examined for the presence of T. gondii oocysts but are relatively insensitive and nonspecific. Clinical signs usually do not develop until after oocyst shedding has ceased, and oocyst shedding may occur in the absence of clinical toxoplasmosis.1,2,7 Furthermore, the microscopic appearance of T. gondii oocysts is indistinguishable from the oocysts of other coccidians such as Hammondia and Besnoitia that may also infect cats.2,7 *CNS and Aqueous Humor Analysis* Diagnosis of toxoplasmosis-induced uveitis or encephalitis is also possible through antibody testing and subsequent calculation of Goldman-Witmer coefficients.2, 7 Antibody measurements for T. gondii and another agent-specific-antibody (ASA in aqueous humor or CSF must be compared to the same measurements obtained for serum.2,7 The ASA should be from an agent that is expected to have a high serum titer but does not cause CNS disease. Calicivirus antibody has been used for this purpose in cats.2 This procedure allows for higher antibody levels occurring simply due to increased vascular permeability that may result from inflammation of any cause.2 To calculate the coefficient, the ratio of the T. gondii antibody level in the aqueous or CSF over the T. gondii antibody level in the serum is multiplied by the ratio of the ASA level in body fluids (i.e. in the aqueous or CSF over the serum ASA level.2,7 A coefficient greater than 1 is significant, and a result greater than 8 is considered compatible with T. gondii infection.2,7 *Treatment* [TR] [TD="bgcolor: #990000"]Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol. [/TD] [/TR] Clindamycin at 10-12mg/kg every 8-12 hours for 4 weeks, by oral or parenteral route, is often used for treatment of cats with clinical toxoplasmosis.2,7 Resolution of clinical signs may begin within 24 to 48 hours of instituting therapy.2 Clindamycin doses necessary to treat toxoplasmosis in cats may lead to such adverse reactions as anorexia, vomiting, and diarrhea.12 If clindamycin cannot be tolerated at the recommended dose, pyrimethamine or trimethoprim may be combined with a sulfonamide for treatment. However, the risk of anti-folate drug related bone marrow suppression necessitates frequent monitoring for hematologic abnormalities.2,7 Dietary supplementation with folic acid (5mg/day or yeast (100 mg/kg may aide in correcting hematopoietic disruption.2,7 The prognosis for cats with toxoplasmosis is guarded, as available drugs are unable to completely eliminate the parasite and the risk for relapse of clinical disease is possible.2 Recurrence is particularly common in immunocompromised cats.2,7 *Zoonotic Potential* An estimated 30-50% of the human population is currently infected with Toxoplasma in the asymptomatic cyst form.3 In immunocompromised patients, the cyst form may potentially lead to serious disease.3,13 Because of the potential for disastrous outcomes in infections that occur during pregnancy, women planning to become pregnant may opt for T. gondii antibody testing.13 Positive antibody detection indicates previous infection and suggests that the likelihood of congenital transmission upon re-exposure to the parasite during pregnancy is limited.13 Conversely, antibody-negative women are at far greater risk of transmitting Toxoplasma to the fetus if they should become infected during pregnancy.13 This risk becomes magnified as 70 million domestic cats are kept as pets in American households, making them the most numerous in the nation among domestic companion species.14 Clearly, it is vital to clarify the role of cats in the transmission of Toxoplasma to humans. The primary means by which most humans are infected with T. gondii are through oocyst-contaminated soil and eating undercooked infected meat such as lamb and pork.3 People who own cats are not at a significantly higher risk for T. gondii infection than those who do not.7 Since oocysts are highly resistant to environmental conditions, exposure can be minimized by wearing rubber gloves during contact and washing hands thoroughly after possible exposure to potentially contaminated soil.1,3,13 Areas such as sandboxes should be kept covered to avoid oocyst contamination. 1,3,13 Meat should routinely be cooked to an internal temperature of 70°C (158°F for at least 15 to 30 minutes in order to destroy tissue cysts.13 Restricting the access of pet cats to hunting and disallowing the ingestion of uncooked meat may prevent cats exposure to T. gondii. When they are exposed. most healthy cats will shed oocysts only during acute infection.1,2,7,13 As the infected cat develops an immune response, oocyst shedding is halted, and the development of tachyzoites is arrested with the resultant formation of bradyzoites (slowly replicating forms of the organism conyained within tissue cysts.2 Cats previously unexposed to T. gondii usually begin shedding oocysts between 3 and 10 days after ingestion of infected tissue and continue shedding for 10-14 days, during which time many millions of oocysts may be produced.1,2,7,13 However, once a cat has developed an immune response, further shedding of oocysts is extremely rare.1,2,7,13 In the few cats that do re-excrete oocysts after another exposure to Toxoplasma, the number of oocysts shed is lower and may even be insufficient to transmit the parasite effectively.2,7 An antibody-negative cat, particularly a kitten, is most susceptible to infection and will shed oocysts for one to two weeks post-exposure to T. gondii.2 In a healthy cat, positive antibody titers are suggestive that the cat is immune, not excreting oocysts, and an unlikely source of infection.2 In any case, daily cleaning of feces from litter boxes, paired with regular disinfection of the boxes, will prevent any oocysts that are shed from sporulating to the infective form.1,2,7,13 It is still recommended, however, that women who are or may become pregnant avoid cleaning the litter box.

Rensselaer web scientists to help lead conference on computation in healthcare and life sciences

17.02.2012 8:00:00

(Rensselaer Polytechnic Institute Web scientist and Research Associate Professor Joanne Luciano in the Tetherless World Constellation at Rensselaer Polytechnic Institute is co-chairing the 2012 Semantics in Healthcare and Life Sciences conference Feb. 22-24 in Boston, Mass. The conference is focused on the use of semantic web technologies in the pharmaceutical industry and academic research labs. The conference is open to any interested scientist.

Corcept Therapeutics Incorporated Announces FDA Approval of Korlym™ (mifepristone 300 mg Tablets: First and Only Approved Medication for Cushing’s Syndrome Patients

18.02.2012 19:21:00

MENLO PARK, Calif. - February 17, 2012

Corcept Therapeutics (NASDAQ:CORT announced today that the U.S. Food and Drug Administration (FDA has approved Korlym™ (mifepristone 300 mg Tablets as a once-daily oral medicine to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have diabetes mellitus type 2 or glucose intolerance and have failed surgery or are not candidates for surgery.

"We appreciate the FDA's diligent attention to our NDA and its grant of approval on the PDUFA date," said Joseph K. Belanoff, M.D., the company's Chief Executive Officer. "We plan to make Korlym available to patients by May 1 through a distribution system designed to support both patients and prescribers."

Corcept will be the sole marketer of Korlym. "A relatively small number of endocrinologists regularly treat patients with Cushing's syndrome," added Dr. Belanoff. "These doctors can be reached without a large sales and marketing infrastructure." The company has begun hiring Medical Science Liaisons to inform practitioners about the drug, which will be dispensed by the leading specialty pharmacy company CuraScript SP, a subsidiary of Express Scripts.

"Korlym is a significant advance in the treatment of patients suffering from the debilitating symptoms of Cushing's syndrome," said Robert L. Roe, M.D., Corcept's President. "For the first time, these patients have access to an approved therapy when surgery has failed or is not an option."

Korlym clinical trial investigator Amir Hamrahian, M.D., Department of Endocrinology, Diabetes and Metabolism at the Cleveland Clinic said, "There are not many effective treatment options for patients with Cushing's syndrome. Although surgery is standard first line treatment for the disease, it is not always successful and not all patients are candidates. As part of the clinical trial, I have used Korlym successfully and my patients continue to do well on the medicine. I'm excited to be able to continue using Korlym in these patients and others who need it. This medicine's approval gives me a much needed tool to better treat patients."

Dr. Hamrahian's comments were seconded by Maureen V., a patient in Corcept's Phase 3 clinical trial: "I had pituitary surgery to treat my Cushing's syndrome. Unfortunately, my surgery wasn't successful. I was lucky to get into the study and get Korlym treatment. I have been taking the medicine successfully for over a year, and I am extremely happy that it was approved by the FDA. Now I know I'll be able to keep taking it. It has made a big difference in my life."

Clinical Trial Results Supporting FDA Approval 
The clinical data supporting the FDA approval of Korlym resulted from an uncontrolled, open-label, multi-center, 24-week phase III study of 50 patients who had endogenous Cushing's syndrome and were either not eligible for or had relapsed from surgery and were either glucose intolerant (29 patients or had hypertension (21 patients . Within the glucose intolerant group, 60 percent of patients had a greater than 25 percent reduction from baseline in the area under the curve in the oral glucose tolerance test. In this group, mean hemoglobin A1C (HbA1C was reduced from 7.4 percent to 6.3 percent. All 14 patients with above-normal HbA1C levels at baseline experienced reductions. Eight of these 14 normalized their HbA1C. Antidiabetic medications were reduced in seven of the 15 patients with diabetes mellitus type 2 and remained constant in the others.

Patients who responded to therapy were allowed enrollment in an extension trial. Eighty-eight percent of the patients who completed the trial chose to do so.

A peer-reviewed analysis of the study results will soon be published in a leading journal.

Patients in the study started Korlym treatment on a dose of 300 mg administered once daily. Their dose was then titrated to maximum clinical effect. As indicated in the medicine's label, physicians prescribing Korlym may determine the appropriate dose for each patient by assessing tolerability and degree of improvement in Cushing's syndrome manifestations. In the first six weeks, these manifestations may include changes in glucose control, anti-diabetic medication requirements, insulin levels and psychiatric symptoms. After two months, assessment may also be based on improvements in cushingoid appearance, acne, hirsutism, striae, decreased body weight, along with further changes in glucose control.

About Korlym™ (mifepristone 300 mg Tablets
Korlym is a once-daily oral medication that blocks the glucocorticoid receptor type II (GR-II to which cortisol normally binds. By blocking this receptor, Korlym inhibits the effects of excess cortisol in Cushing's syndrome patients.

The FDA has designated Korlym as an Orphan Drug for treatment of the clinical manifestations of endogenous Cushing's syndrome. Orphan Drug designation is a special status designed to encourage the development of medicines for rare diseases and conditions. Because Korlym is an Orphan Drug, Corcept will have marketing exclusivity consistent with the FDA's designation until February 2019.

About Cushing's Syndrome 
Endogenous Cushing's syndrome is a rare and life-threatening endocrine disorder that results from long-term exposure to excess levels of the hormone cortisol. This excess is caused by tumors that usually occur in the pituitary or adrenal glands that over-produce, or prompt the over-production of, cortisol.

Although cortisol at normal levels is essential to health, in excess it causes a variety of problems, including hyperglycemia, upper body obesity, a rounded face, stretch marks on the skin, an accumulation of fat on the back, thin and easily bruised skin, muscle weakness, bone weakness, persistent infections, high blood pressure, fatigue, irritability, anxiety, psychosis and depression. Women may have menstrual irregularities and facial hair growth, while men may have decreased fertility or erectile dysfunction. More than 70 percent of Cushing's syndrome patients suffer from glucose intolerance or diabetes.

The treatment of an endogenous Cushing's syndrome patient depends on the cause. The first-line approach is surgery to remove the tumor.  If surgery is not successful or is not an option, radiation may be used, but that therapy can take up to ten years to achieve full effect.  Surgery and radiation are successful in only approximately one-half of all cases.

If left untreated, Cushing's syndrome has a five-year mortality rate of 50 percent.

An orphan disease, Cushing's syndrome occurs in about 20,000 people in the United States, mostly women between the ages of 20 and 50.

Conference Call Information 
Corcept will hold a conference call on Tuesday, February 21, 2012 at 9:00 a.m. Eastern Time (6:00 a.m. Pacific Time to discuss this announcement. To participate in the live call please dial 1-800-264-7882 from the United States or +1-847-413-3708 internationally. The pass code is 31838602. Please dial in approximately 10 minutes before the start of the call.

A replay of the conference call will be available through March 6, 2012 at 1-888-843-7419 from the United States and +1-630-652-3042 internationally. The pass code is 31838602.

IMPORTANT SAFETY INFORMATION

WARNING: TERMINATION OF PREGNANCY

See full prescribing information for complete boxed warning.

has potent antiprogestational effects and will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym, or if treatment is interrupted for more than 14 days in females of reproductive potential.

Contraindications

• Pregnancy
  
• Use of simvastatin or lovastatin and CYP 3A substrates with narrow therapeutic range
  
• Concurrent long-term corticosteroid use
  
• Women with history of unexplained vaginal bleeding
  
• Women with endometrial hyperplasia with atypia or endometrial carcinoma
  

Warnings and Precautions

• 
  Adrenal insufficiency
  : Patients should be closely monitored for signs and symptoms of adrenal insufficiency.
  
• 
  Hypokalemia
  : Hypokalemia should be corrected prior to treatment and monitored for during treatment.
  
• 
  Vaginal bleeding and endometrial changes
  : Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if patient also has a hemorrhagic disorder or is on anti-coagulant therapy.
  
• 
  QT interval prolongation
  : Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.
  
• 
  Use of Strong CYP3A Inhibitors
  : Concomitant use can increase plasma levels significantly. Use only when necessary and limit dose to 300 mg.
  

Adverse Reactions

Most common adverse reactions in Cushing's syndrome (≥ 20% : nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

To report suspected adverse reactions, contact Corcept Therapeutics at 1-855-844-3270 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch.

Drug Interactions

• Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym
  
• CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Limit mifepristone dose to 300 mg per day when used with strong CYP3A inhibitors.
  
• CYP3A inducers: Do not use Korlym with CYP3A inducers.
  
• Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym.
  
• Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz.
  
• Hormonal contraceptives: Do not use with Korlym.
  

Use in Specific Populations

• Nursing mothers: Discontinue drug or discontinue nursing.
  

Please see the accompanying full Prescribing Information including boxed warning at
www.corcept.com/prescribinginfo.pdf

Please see the accompanying Medication Guide at 
www.corcept.com/medicationguide.pdf

About Corcept Therapeutics Incorporated
Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders. Korlym, a first generation GR-II antagonist, is the company's first FDA-approved medication. The company has a portfolio of new selective GR-II antagonists that block the effects of cortisol but not progesterone. Corcept also owns an extensive intellectual property portfolio covering the use of GR-II antagonists, including mifepristone, in the treatment of a wide variety of psychiatric and metabolic disorders. The company also holds composition of matter patents for its selective GR-II antagonists.

Statements made in this news release, other than statements of historical fact, are forward-looking statements. Forward-looking statements are subject to a number of known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances that clinical results will be predictive of real-world use, or regarding the pace of Korlym's acceptance by physicians and patients, the reimbursement decisions of government or private insurance payers, the effects of rapid technological change and competition, the protections afforded by Korlym's Orphan Drug Designation or by Corcept's other intellectual property rights, and the cost, pace and success of Corcept's other product development efforts. These and other risks are set forth in the Company's SEC filings, all of which are available from our website (www.corcept.com or from the SEC's website (
www.sec.gov . We disclaim any intention or duty to update any forward-looking statement made in this news release.

CONTACTS:

Invvestor Contact
Charles Robb
Chief Financial Officer 
Corcept Therapeutics
650-688-8783 

Media Contact
Alissa Maupin
Communications Strategies, Inc.
973-635-6669

From 
http://www.corcept.com/news_events/pr_1329524335

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