Crohn’s Disease – Development Of Teduglutide As Treatment

NPS Pharmaceuticals, Inc. (Nasdaq: NPSP) announced today that the company plans to advance the clinical development of its experimental drug teduglutide based upon results achieved in a Phase 2a proof-of-concept study of 100 patients with moderate to severe Crohn’s disease.

The four-arm, eight-week clinical trial compared three doses of teduglutide delivered by daily subcutaneous injection to a placebo. The study was designed to evaluate the drug’s safety and potential efficacy in the treatment of Crohn’s disease. Overall, the study results showed a positive and consistent trend toward efficacy and a dose response favoring the highest dose group: 36.8% of patients receiving the highest dose of teduglutide reached clinical remission (Crohn’s disease activity index (CDAI) score of less than 150 points) at week two versus 16.7% of the placebo group, while 55.6% of patients in the highest dose group reached clinical remission by week eight compared to 33.3% of the placebo group. Teduglutide was well tolerated with no serious adverse events related to the drug. The most common treatment-related adverse event in the trial was redness at the injection site. Study investigators plan to submit the trial results for presentation at a future medical meeting.

Alan Buchman, M.D., a clinical investigator for the study and associate professor and director of the IBD Center at Northwestern University’s Feinberg School of Medicine, said, “The results from this preliminary study are encouraging and warrant further study of this novel agent alone or in combination with other drugs as a potential new class of therapy for the treatment of Crohn’s disease. Remission rates of this magnitude at two weeks and eight weeks are unusual in clinical trials and suggest that teduglutide may play an important role in the management of this difficult-to-treat disease.”

Although the study was not powered to demonstrate statistical significance and the primary end point (the percentage of patients who achieved remission or at least a 100-point reduction from their baseline CDAI score at week was not met due to the relatively small number of study subjects and a high placebo response, the company believes the high clinical remission rates seen in patients receiving the highest dose of teduglutide support further dose-ranging efficacy studies of teduglutide in patients with Crohn’s disease.

Hunter Jackson, Ph.D., NPS chairman and CEO, commented, “We are pleased with the results from this trial and the suggestion that some patients demonstrated remission as early as two weeks into the study. The high placebo response seen in this trial is not unusual in Crohn’s disease. We plan to conduct additional studies to confirm the efficacy response observed in this trial and look forward to advancing this novel compound into later-stage development this year as a promising treatment alternative in Crohn’s disease.”

Teduglutide is a proprietary analog of glucagon-like peptide 2 (GLP-2), a naturally occurring hormone that regulates the growth, proliferation and maintenance of cells lining the gastrointestinal tract. A previous Phase 2 clinical study in patients with Short Bowel Syndrome showed that daily subcutaneous injections of teduglutide resulted in significant growth of the intestinal lining and improved dietary absorption of nutrients and fluids. NPS is currently testing teduglutide in a pivotal Phase 3 study as a treatment for Short Bowel Syndrome.

About Crohn’s Disease

Crohn’s disease is a chronic inflammatory bowel disease characterized by inflammation of any part of the gastrointestinal tract and associated with chronic morbidity. Crohn’s disease affects nearly one million patients in the United States and Europe.

Conference Call and Webcast Information

NPS will conduct a conference call today at 5:00 p.m. EST with Daniel Present, M.D., clinical professor of medicine at Mt. Sinai School of Medicine, to discuss the teduglutide study. To participate in the call, dial 800-299-7098 and use passcode 59474346. International callers may dial 617-801-9715 and use the same passcode. In addition, live audio of the call will be webcast and may be accessed on the Investor Relations page, Calendar of Events section of the company’s website (http://www.npsp.com). The conference call replay may be accessed by dialing 888-286-8010 (with passcode 42742393). A replay for international callers can be accessed with the same passcode at 617-801-6888. Both the webcast and conference call will be archived until March 6, 2006.

About NPS Pharmaceuticals

NPS discovers, develops and commercializes small molecules and recombinant proteins as drugs, primarily for the treatment of metabolic, bone and mineral, and central nervous system disorders. The company has one FDA-approved product, one product candidate undergoing regulatory review for approval to market in the U.S. and Europe, as well as other drug candidates in various stages of clinical development backed by a strong discovery research effort. Additional information is available on the company’s website, http://www.npsp.com.

Safe Harbor Statement

Note: Statements made in this press release, which are not historical in nature, constitute forward-looking statements for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Such statements include those regarding our expectation that teduglutide may be a promising treatment alternative in Crohn’s disease, our intention to advance the clinical development of teduglutide into later-stage development this year, and our intent to commercialize small molecules and recombinant proteins as drugs. These statements are based on management’s current expectations and beliefs and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Such risks and uncertainties include: future clinicals may demonstrate that teduglutide is not safe and/or efficacious; we may not be able to enroll patients in our clinical trials in a timely manner; we may not be able to prepare and finalize clinical protocols in a timely manner to commence additional clinical trials with teduglutide for Crohn’s in a timely manner; we may not be able to collect, analyze and report data from our clinical trials in a timely manner; we may never develop additional products that generate revenues; our product candidates may not prove to be safe or efficacious; the FDA may delay approval or may not approve any of our product candidates; current collaborators or partners may not devote adequate resources to the development and commercialization of our licensed drug candidates which would prevent or delay introduction of drug candidates to the market. All information is as of February 27, 2006, and we undertake no duty to update this information. A more complete description of these risks can be found in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K/A for the year ended December 31, 2004 and our Quarterly Report on Form 10-Q for the quarter ended September 31, 2005.

NPS Pharmaceuticals, Inc. http://www.npsp.com

Cefazolin for Injection Recalled

Hanford Pharmaceuticals has issued a nationwide recall of approximately 380,000 vials of cefazolin for injection that may be contaminated with microorganisms.In a Feb. 24 press release that was circulated today by the Food and Drug Administration (FDA), Hanford, a New York-based contract manufacturer of sterile injectable products, stated that some lots of the active ingredient used to prepare the cefazolin product were contaminated with Bacillus pumilus, Staphylococcus hominis, Propionibacterium acnes, or Micrococcus luteus.

The recall affects 1-g/10-mL vials of Cefazolin for Injection, USP, lots C4650 and C4537, which were prepared for Sandoz Inc. and lots C4689 and C4665, prepared for Watson Pharmaceuticals. Hanford stated that the recalled cefazolin was targeted for use in hospitals.

Hanford has asked hospitals, clinics, and other recipients of the recalled cefazolin to immediately stop using it. The company stated that it has not received any reports of patients being harmed after receiving the contaminated cefazolin.

Fosamax cuts bone loss in men with prostate cancer

Testosterone-lowering therapy — one of the most effective and commonly used therapies for prostate cancer — often causes bone loss. However, once-weekly drug treatment combats the problem, according to a new study. Fosamax, used to treat osteoporosis in postmenopausal women, also helps prevent bone loss associated with so-called “androgen deprivation” treatment of prostate cancer, the researchers reported at the 2006 Prostate Cancer Symposium. “Patients on androgen deprivation therapy tend to lose bone mass early, within the first 6 to 12 months of treatment, and the bone loss continues for the duration of therapy,” noted Dr. Susan L. Greenspan from the University of Pittsburgh. “Currently,” Greenspan noted, “lifelong androgen deprivation therapy is common for advanced prostate cancer, but more recently it has been a common treatment for less aggressive disease.” Bone mass, she said, “should be evaluated in men who are starting therapy to lower testosterone because we are putting them in a situation similar to newly postmenopausal women with a relatively fast rate of bone loss.” In a 2-year study sponsored by the National Institutes of Health, Greenspan and colleagues are evaluating the effects of Fosamax on bone in a group of men with prostate cancer receiving androgen deprivation therapy. In the ongoing study — now in its second year — 112 men are receiving calcium and vitamin D supplementation and half of them are also taking weekly Fosamax. Greenspan presented 1-year data from a planned interim analysis. At the start of the study, “only about 10 percent of men had normal bone mass,” Greenspan said. “The average duration on androgen deprivation therapy was only about 22 months or roughly 2 years, but 90 percent of them did not have normal bone mass; in fact 39 percent had osteoporosis by WHO criteria.” After 1 year, bone mass increased by 4.9 percent in the spine and by 2.1 percent in the hip among men on Fosamax, compared with decreases of 1.3 percent in the spine and 0.7 percent in the hip among men on placebo. “Once weekly oral (Fosamax) should be considered to prevent this bone loss and prevent the occurrence of osteoporosis and fractures,” Greenspan concluded. The 2006 Prostate Cancer Symposium is co-sponsored by the American Society of Clinical Oncology, the American Society for Therapeutic Radiology and Oncology, the Prostate Cancer Foundation, and the Society of Urologic Oncology.

- Reuters Health

Diabetes Researchers Pioneer Islet Cell Xenotransplantation In Primate Studies

A team of researchers from the University of Alberta, the Yerkes National Primate Research Center of Emory University and the Emory Transplant Center has successfully transplanted insulin-producing neonatal porcine islet cells into monkeys, a procedure the researchers say represents a promising intermediate solution to the critical supply problem in clinical islet cell transplantation.
“Our work at the U of A and Emory, along with recent work at the University of Minnesota, is very exciting and shows that xenotransplantation in humans may soon be possible, thus solving the islet supply problem,” says one of the study authors Ray Rajotte, a professor of Surgery at the University of Alberta.

The paper appeared in an advanced on-line publication of Nature Medicine, February 26, entitled “Long-term survival of neonatal porcine islets in non-human primates by targeting co-stimulation pathways.” The work follows on the heels of similar work published last week by University of Minnesota researchers; those researchers used islets isolated from adult pig pancreases.

Neonatal islets were produced in Edmonton using a procedure Drs. Greg Korbutt and Rajotte developed in 1995. The pig islets were sent to the Yerkes Research Center for transplantation into diabetic rhesus macaques using an anti-rejection protocol developed by Drs. Christian Larsen and Kenneth Cardona of the Yerkes Research Center and the Emory Transplant Center. The isolation method developed by the U of A researchers is simple and reproducible with the neonatal pig islets having some growth potential post-transplant, considered a major advantage over adult pig islets.

The diabetic animals were treated with a CD28/CD154 co-stimulation blockade-based immunosuppressive regimen, and achieved sustained insulin independence (median survival >140 days with one animal now at 300 days) without evidence of porcine endogenous retrovirus (PERV) dissemination. “This represents a major step forward and proves neonatal porcine islets can correct diabetes long-term in primates,” said Drs. Korbutt and Rajotte.

“To meet the needs of the millions suffering from type 1 diabetes, we must find new donor sources to allow large-scale application of islet cell transplantation in humans,” said Dr. Larsen. “While there is much work to be done these studies suggest that the rejection response to porcine islets can be surmounted.”

“The next step is to prove that these neonatal porcine islet cells could become a source for human transplantation,” said Dr. Rajotte. “It’s hoped that within the next three to five years, we will be transplanting patients with pig islets once we prove that it is safe.”

Using a relatively simple and reproducible method of obtaining large numbers of islets from neonatal pig pancreata developed at the U of A, the researchers then transplanted islets comprised of endocrine and endocrine precursor cells into the monkeys. In vivo, these cells have been shown to proliferate, differentiate and reverse hyperglycemia in immunodeficient diabetic mice and allogeneic out-bred pigs.

However, humans and Old World primates have naturally occurring antibodies that are directed against antigens that can cause hyperacute or acute humoral rejection. To combat that, the researchers administered an anti-IL-2 receptor and anti-CD154 (H106) antibody, while maintaining immunosuppression using sirolimus and belatacept (a second-generation high affinity derivative of CTLA4-Ig)9-11 on diabetic rhesus macaques transplanted with neonatal porcine islets.

Other researchers involved in the work include: Zvonimir Milas1, James Lyon2, Jose Cano1, Wanhong Jiang1, Hameeda Bello-Laborn1, Brad Hacquoil2, Elizabeth Strobert3, Shivaprakash Gangappa1, Collin Weber1, and Thomas Pearson1. (1. Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta; 2. Surgical-Medical Research Institute, University of Alberta, Edmonton,; 3. Yerkes National Primate Research Center, Emory University, Atlanta.)

The research was supported by the Alberta Diabetes Foundation, Canadian Institutes of Health Research, Edmonton Civic Employees Charitable Assistance Fund, Canadian Diabetes Association, and University of Alberta Hospital Foundation MacLachlan Fund. Dr. Korbutt received a Career Development Award from the Juvenile Diabetes Research Foundation and a Senior Scholarship from the Alberta Heritage Foundation for Medical Research. The work at Emory was supported by National Institute of Health, the Juvenile Diabetes Research Foundation Center, Yerkes Research Center Base Grant P51-RR000165-45, the McKelvey Lung Transplant Center, and the Carlos and Marguerite Mason Trust.

The Islet Transplant Group at the University of Alberta is involved in all aspects of islet transplantation, from trying to develop an unlimited source of islets (this study) to developing transplant protocols that don’t need anti-rejection drugs or drugs that only need to be given for a short period of time (tolerance induction).

Michael Robb
michael.robb@ualberta.ca
University of Alberta
www.ualberta.ca

FDA Approves First Drug Patch for Depression

The first skin patch to treat major depression in adults has won final approval to be sold in the United States, the U.S. Food and Drug Administration.

The once a day patch works by delivering selegiline, a monoamine oxidase inhibitor or MAOI, through the skin and into the bloodstream. At its lowest strength, Emsam can be used without the dietary restrictions that are needed for all oral MAO inhibitors that are approved for treating major depression.

Emsam provides a significant advance because at least in its lowest dose patients can use the drug without the usual dietary restrictions associated with these types of drugs known as MAO inhibitors,“ said Dr. Steven Galson, Director for the Center for Drug Evaluation and Research.

Major depressive disorder is a common psychiatric condition in the U.S. population. Symptoms of depression include general emotional dejection, withdrawal and restlessness that interfere with daily functioning, such as loss of interest in usual activities; significant change in weight and/or appetite; insomnia; increased fatigue; feelings of guilt or worthlessness; slowed thinking or impaired concentration; and a suicide attempt or suicidal ideation.

MAO inhibitors usually require specific dietary restrictions because when combined with certain foods they can cause a sudden, large increase in blood pressure, or “hypertensive crisis”. A hypertensive crisis can lead to a stroke and death. Symptoms of a hypertensive crisis include sudden onset of severe headache, nausea, stiff neck, a fast heartbeat or a change in the way your heart beats (palpitations), sweating, and confusion. Patients who have these symptoms should get medical care right away.

The lowest dose of the MAOI patch, which delivers 6 milligrams (mg) of the medication over a 24 hour period, can be used without such dietary restrictions.

Patients taking higher doses of the Emsam patch will have to follow strict dietary guidelines but those taking the lowest dose will be free to eat cheese, smoked meats and other foods usually restricted with certain antidepressants.

The Emsam patch will be made available in three sizes that deliver 6, 9, or 12 mg of selegiline per 24 hours. The patch is a matrix containing three layers consisting of a backing, and adhesive drug layer, and a release liner that is placed against the skin.

Emsam has been shown safe and effective for treatment of major depressive disorder in two 6-8 week studies and also in a longer-term study of patients. The data for EMSAM 6mg/24hr support the recommendation that a modified diet is not required at this dose. Patients are advised to change the patch once a day. The more limited data available for EMSAM 9mg/24hr and 12mg/24hr do not rule out food effects so that patients receiving these higher doses should follow dietary restrictions that advise them to avoid certain foods or beverages. This includes foods and beverages such as aged cheese and wine.

The only common side effect of Emsam detected in placebo-controlled trials was a mild skin reaction where the patch is placed. There may be mild redness at the site when a patch is removed. If the redness does not go away within several hours after removing the patch or if irritation or itching continues, patients are advised to contact their doctor.

Another side effect that was seen less commonly was light-headedness related to a drop in blood pressure.

The manufacturer and distributor of this new product have planned an educational campaign for patients and prescribers to ensure that advice on dietary modifications for the higher patch strengths is adhered to. They plan to conduct both patient and health care provider surveys to assess the effectiveness of the educational campaign. The manufacturer and distributor will also closely track reports of adverse events, and follow-up on those that might represent hypertensive crises, to further ensure the safe use of this product.

Although the effects of heat on the patch are not known, the drug labeling advises health care professionals and patients about the possible effects of direct heat applied to the Emsam patch. Direct heat may result in an increased amount of the drug absorbed from the patch. Patients should avoid exposing the patch to heating pads, electric blankets, heat lamps, saunas, hot tubs, or prolonged sunlight.

Like all approved antidepressants, this product carries a warning of increased suicidality in children and adolescents.

EMSAM was developed by Somerset Pharmaceuticals, Inc. In December 2004, Bristol-Myers Squibb and Somerset entered into an agreement that provides Bristol-Myers Squibb with distribution rights to market EMSAM after approval in the United States. Selegiline was initially approved in capsule form for use in Parkinson’s Disease.

The FDA conditionally approved the patch in 2004, provided the company supplied more data on post-marketing safety.

Some industry analysts and medical experts have low expectations for sales of the patch, saying a warning on some doses but not others could be confusing and patients’ sensitivity to the offending food compound varies widely.

Others said the patch offers a needed alternative for people who can’t take pills but the warnings could discourage some doctors from prescribing it.

 Source:

• Reuters Health
• FDA