FDA modifies boxed warning for pulmonary arterial hypertension drug Letairis

The U.S. Food and Drug Administration today (March 4) announced that monthly liver enzyme tests are no longer required for those taking Letairis tablets (ambrisentan), used to treat high blood pressure in the vessels that carry blood to the lungs (pulmonary arterial hypertension, or PAH).

Citing data from clinical trials and postmarket reports, the FDA said that the drug poses only a low risk of liver injury. Information related to potential serious liver injury and the need to monitor for such serious injury is being removed from the drug’s boxed warning.

In patients with PAH, Letairis slows the worsening of symptoms and improves the ability to exercise. Approved in 2007, Letairis is in a class of medications called endothelin receptor antagonists, which stop the action of endothelin, a substance that narrows blood vessels and prevents normal blood flow in those with PAH.

“We have concluded that monthly liver enzyme testing for patients taking Letairis, as previously noted in the boxed warning, is not necessary,” said Mary Ross Southworth, Pharm.D., deputy director for safety in the Division of Cardiovascular and Renal Products at the FDA’s Center for Drug Evaluation and Research. “Health care professionals should still continue to order liver enzyme tests when they consider it clinically indicated.”

Letairis was approved with a Risk Minimization Action Plan (RiskMAP) to manage liver damage and fetal malformation. The RiskMAP called for liver enzyme testing prior to treatment and monthly during treatment for all patients. It also required monthly pregnancy testing for women of childbearing potential because Letairis causes birth defects in animals, like other drugs in this class. The Letairis RiskMAP was converted to a Risk Evaluation and Mitigation Strategy in 2009.

The boxed warning on the risk of serious birth defects and the contraindication for use during pregnancy will remain in the labeling. Letairis will continue to be available only through a restricted distribution program called the Letairis Education and Access Program (LEAP). For women who can become pregnant, monthly pregnancy tests will still be required before Letairis is shipped.

The liver warnings were based on experience with other drugs in Letairis’ drug class, as well as a few observed instances of increased liver enzymes in people treated with Letairis. The FDA’s further evaluation has shown that rates of liver problems in Letairis-treated patients are consistent with rates within the general PAH population. In the controlled clinical trials, the rates of liver problems in Letairis-treated patients are similar to the rates in people receiving an inactive pill (placebo).

For a discussion of the FDA’s rationale and regulatory decisions regarding Letairis, refer to the Drug Safety Communication issued today.

People who take Letairis should not stop taking it without talking to their health care professional. Health care professionals should order and review tests for liver function as necessary based on the patient’s condition and history. Adverse events involving Letairis should be reported to the FDA MedWatch program1.

Letairis is made by Gilead Sciences Inc., Foster City, Calif.

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UGA researchers identify key enzyme that regulates the early growth of breast cancer cells

New University of Georgia research, published this week in the early online edition of the journal Proceedings of the National Academy of Sciences, has found that blocking the action of an enzyme called GnT-V significantly delays the onset and spread of tumors in mice with cancer very similar to many cases of human breast cancer.

When the GnT-V enzyme activity in the cells was increased in mammary gland cells, they increased proliferation and began to take on many characteristics of cancer cells. Using a mouse model of human breast cancer, tumors appeared when the enzyme was deleted, but onset was delayed an average of 10 weeks in the mice.

“In human terms,” said Michael Pierce, director of the UGA Cancer Center and study co-author, “the corresponding delay would be many months and maybe years. You basically are slowing everything down and keeping the cancer from forming and progressing very early.” Slowing the pace of the cancer could eliminate its spread to other organs, keeping it localized where it could be treated successfully, Pierce explained.

The researchers, lead by Hua-Bei Guo, assistant research scientist in the department of biochemistry and molecular biology in the Franklin College of Arts and Sciences, stimulated breast cancer formation in mouse mammary glands by over-expressing a her-2 protein that is a growth receptor on the cell surface. The researchers note that over-expression of her-2 is associated with 25 to 30 percent of human breast cancers.

The GnT-V enzyme makes glycans, which are sugars on the cell surface that change in defined ways when the cell becomes cancerous. Glycans are released from the cell as glycoproteins, making them a promising early-detection marker in blood. The researchers studied a glycan made by GnT-V that appears when normal breast cells become cancerous. The GnT-V glycan product is found on her-2 and other receptors and acts to regulate the number of cancer stem cells in the tissue. The number of these cancer stem cells determines how rapidly the cancer will form and develop.

“Glycans often are ignored by scientists, because they’re very complicated and present unusual problems to identify and understand,” said Pierce. “This study is an example of how particular glycans that are present on various cell receptors can actually modulate the onset of tumor formation. That may give us new drug targets and new ways to kill the cancer cells specifically.”

The finding of Guo and the research team at UGA’s Complex Carbohydrate Research Center that the elimination of a glycan-synthesizing enzyme significantly reduced the population of breast cancer stem cells is unprecedented, they note.

“That population of cells appears to drive breast tumor formation in many cases,” said Pierce, who also is UGA’s Mudter Professor in Cancer Research, “and our research suggests that glycans may be potential targets to kill them selectively.”

Pierce likened the cancerous stem cells to the queen of an ant colony. “You can try to get rid of the anthill, but it will just come back if you don’t kill the queen,” Pierce said. “If we can target those cancer stem cells for elimination, that would be the most effective treatment.”

The research was supported by the National Institutes of Health. For more information on the UGA Cancer Center, see www.uga.edu/cancercenter/.

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New Survey by Enzymedica Links Autism & Digestion, Suggests Successful Strategies

(BUSINESS WIRE)--Autism is the fastest growing developmental disorder in the world. With 1 child in 91 facing the disorder, the diagnosis is more common than pediatric cancer, diabetes, and AIDS combined.

“A product containing a full spectrum blend of all enzymes is considered an ideal digestive aid.”

Autism and Digestion: The Surprising Link

A new survey by Enzymedica and the Enzyme Research Group (ERG), links autism and digestive problems, and suggests diet modification and dietary supplements as successful tools for families facing the diagnosis.

While autism is generally considered a neurological disorder, the new survey reminds us that autistic children face additional health challenges, including 80% who report digestive difficulty, sensitivity, or intestinal inflammation.

Survey Participants Tout Special Diets for Autism

Food sensitivities and cravings are widespread in the autism community. The ERG survey found that 35% of children craved sugary treats, 30% dairy, 25% wheat and 32% junk foods; and cravings were not mutually exclusive.

Interestingly, the craved foods also caused the greatest digestive reaction. Lactose, gluten, casein, and phenol were the top reactive contenders in children on the spectrum.

* 70% currently follow, or have tried, a restrictive diet
* 52% gluten-free
* 55% casein-free
* 44% eliminate artificial flavors and additives
* 70% use digestive enzymes or probiotics

Since even healthy foods can cause problems, supplementation can be used to prevent nutritional deficiency. 80% of parents said they offer dietary supplements in some form, typically in combination with a special diet, to soothe and support healthy digestion, and reduce dietary sensitivities.

Healthy Digestion Requires Digestive Enzymes

Our body uses enzymes to enhance digestion and turn the food we eat into energy. Produced throughout the digestive tract, and available from raw foods and supplements, these enzymes include amylase for carbohydrates, lipase for fats, protease for proteins, and cellulase for fiber.

“Many of our children are enzyme deficient,” writes Elizabeth Lipski, Ph.D., C.C.N., a board-certified clinical nutritionist in her book, Digestive Wellness for Children. “These deficiencies can play a pivotal role in the development of childhood disease.” Lipski has over 20 years experience working in the field of holistic and complementary medicine and views enzymes as the body’s workhorses.

“In children, enzyme supplements have been used successfully to treat food allergies, gastroenteritis, asthma, and other illnesses, and research on enzymes for children is promising,” she continues.

Like healthy bones and muscle tissue, our enzyme producing organs rely on good nutrition to fuel production. Physical stressors and inflammation are also implicated as a component in compromised enzyme capacity, and these conditions are common with autism.

The ERG researchers found a statistically significant 80% of autistic children experience digestive disturbances related to certain types of food, with dairy topping the list. 57% said dairy is the culprit, and wheat was second in line with 43%.

Autism Breeds Picky Eaters

“Many children on the spectrum are unwilling to eat a sufficient quantity of raw, unprocessed foods,” declares Kristin Selby Gonzalez, Director of Autism Education for Enzymedica, herself the mother of a son with autism. “It’s unfortunate because these healthy foods naturally contain the enzymes and micronutrients needed to support a healthy intestine and aid digestion.”

Taking a daily enzyme supplement can create the foundation of a healthy digestive process,” says Ellen Cutler, D.C., whose Mill Valley, California practice caters to patients with allergies and digestive distress. “A product containing a full spectrum blend of all enzymes is considered an ideal digestive aid.”*

While typical parents may experience difficulty getting growing children to eat their fruits and veggies, consider the behavioral challenges present in some autism diagnoses. Families with autistic children often find mealtime a battleground.

The junk foods and processed snacks craved by many children on the spectrum contain common allergens which cause food sensitivities. These types of foods are hard to digest and are a frequent and familiar source of the constipation and diarrhea autistic children experience.

Science Investigates the Autism / Digestion Link

A 2009 study in Pediatics, described a gene called MET, involved in both brain development and the process of gastrointestinal system repair. The study indicated a genetic variation may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.

More than 58% of parents, aunts and uncles, 45% of grandparents, and 20% of siblings reported problems in the ERG survey. While still considered controversial, the new survey indicates the familial autism/digestion link may indeed be viable.

Diet and Enzymes Provide Hope

“Given the option, my son would survive on processed snacks and treats like cookies, crackers, chicken nuggets and French fries,” declares Gonzalez. “I’ve learned by keeping them out of his diet and adding enzymes Jaxson behaves better, his attention is more focused, and many of his digestive reactions evaporate.”*

To read the results of the entire survey, please visit www.Enzymedica.com. To learn more about Enzymedica’s commitment to the autism community, visit www.hopeineverybottle.com.

About the Survey:

Enzymedica sponsored the recent survey in association with The Enzyme Research Group. The survey evaluated 143 parents with children on the autism spectrum, surveying their experience with digestive health issues. The survey was conducted online and in anonymous interview and ran from May – June, 2010.

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FDA Approves New Treatment for Late-Onset Pompe Disease

The U.S. Food and Drug Administration approved Lumizyme (alglucosidase alfa) for patients ages 8 years and older with late-onset (non-infantile) Pompe disease, a rare genetic disorder.

Pompe disease occurs in an estimated 1 in every 40,000 to 300,000 births. Its primary symptom is heart and skeletal muscle weakness, progressing to respiratory weakness and death from respiratory failure.

In Pompe disease, a gene mutation prevents the body from making an enzyme, or making enough of the enzyme called acid alpha-glucosidase (GAA), necessary for proper muscle functioning. GAA is used by the heart and muscle cells to convert a form of sugar called glycogen into energy. Without the enzyme action, glycogen builds up in the cells and, ultimately, weakens the heart and muscles.

Lumizyme is believed to work by replacing the deficient GAA, thereby reducing the accumulated glycogen in heart and skeletal muscle cells.

“Pompe disease is a devastating condition without the appropriate treatment,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “The approval of Lumizyme will provide an important treatment for patients diagnosed later in life with Pompe disease.”

Lumizyme is being approved with a risk evaluation and mitigation strategy (REMS). It will only be available through a restricted distribution system called the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program to ensure that it is used by the correct patient group.

Lumizyme will carry a Boxed Warning because of the risk of anaphylaxis, severe allergic reactions, and immune-mediated reactions.

Currently, the only other treatment for Pompe disease available in the United States is Myozyme, which is also manufactured by Genzyme at its manufacturing facilities in Framingham and Allston Landing, Mass. Myozyme has been in short supply due to limited manufacturing capacity. The manufacturer reserved Myozyme to treat infants and children with Pompe disease because younger patients generally have a much more aggressive form of the disease.

Some adult patients in the U.S. received Lumizyme under a temporary access program. The approval of Lumizyme will ensure that treatment is available for all U.S. adult Pompe patients in need of treatment. Lumizyme is manufactured at Genzyme facilities in Ireland and Belgium.

Lumizyme’s safety and effectiveness have not been evaluated in patients with infantile-onset Pompe disease or in patients ages 8 years and younger with late-onset disease. These patients should be treated with Myozyme, not Lumizyme.

The safety and efficacy of Lumizyme are based on a clinical study in 90 patients, ages 10 years to 70 years, with late-onset Pompe disease. The most commonly reported side effects for Lumizyme were infusion-related reactions and included severe allergic reactions, hives, diarrhea, vomiting, shortness of breath, itchy skin, skin rash, neck pain, partial hearing loss, flushing, pain in extremities, and chest discomfort.

Myozyme and Lumizyme are marketed by Cambridge, Mass.-based Genzyme.

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