Heidi Belden, PharmD

There has never been a drug used to treat phenylketonuria (PKU), a genetic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), until now. Last month, the Food & Drug Administration gave its approval to sapropterin dihydrochloride (Kuvan, BioMarin), a new molecular entity indicated to reduce blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4)-responsive PKU. The orphan drug will offer some hope to about 30,000 PKU patients in the United States and 50,000 worldwide.  

Sapropterin is a synthetic form of BH4, the cofactor for the enzyme PAH, which is normally responsible for hydroxylating Phe to form tyrosine. But in patients with PKU, PAH activity is absent or deficient. According to BioMarin, treatment with BH4 can activate residual PAH enzyme, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients. But not all PKU patients will respond to sapropterin. 

Once treatment is initiated, blood Phe should be monitored routinely. Sapropterin should be taken with food to increase its absorption and also should be dissolved in four to eight ounces of water or apple juice prior to administration. The mixture should then be consumed within 15 minutes. All patients receiving sapropterin should also be simultaneously maintained on a Phe-restricted diet. 

The most common adverse reactions during clinical trials included abdominal pain, diarrhea, headache, upper respiratory infection, vomiting, nausea, and pharyngolaryngeal pain. As part of several postmarketing commitments, the manufacturer will implement a PKU registry program along with several clinical trials, including one in children eight years of age and younger. 

According to BioMarin, sapropterin was co-developed with Merck Serono and will be available in nine specialty pharmacies immediately at a price of $29 per 100-mg tablet. The company expects 2008 sales of the drug to reach $35 to $70 million. Kuvan will be available through a specialty pharmacy limited distribution network, including Accredo, Aetna, Caremark, Curascript, Fairview, McKesson, Pharmacare, Precision Rx, and Tel-Drug. 

Articles

FDA approves a new molecular entity, Kuvan, to treat phenylketonuria.

Orphan drug gets FDA nod for phenylketonuria

Novel vaccines in three areas of research were the subject of the Ambulatory Care PRN Focus, held at the American College of Clinical Pharmacy's annual meeting in Denver in October. Mary S. Hayney, Pharm.D., MPH, presented vaccine candidates for the prevention or treatment of malaria, HIV, and nicotine addiction.  

"There is a complex genome and complex life cycle of this parasite" associated with malaria, Hayney told the audience. Hayney, an associate professor of pharmacy at the University of Wisconsin School of Pharmacy, explained that one obstacle is the various antigenic presentations of malaria in humans that make a vaccine difficult to develop. She added that affordability is another obstacle. "The areas of the world with the highest burden of malaria are also the poorest, with the fewest resources," she said. In addition, the ability to transport and administer this vaccine to remote areas will likely be other important issues that will need to be addressed. 

Despite the obstacles, there are several strategies for developing a malaria vaccine. "We do know that induction of CD8+ T cells is particularly important in the liver stage of the disease," said Hayney. Another approach is the prime-boost strategy where you "prime" with one recombinant vector and boost with a different one. "You use the same antigen, but you show it to the immune system in a different way such that your body magnifies the response to the antigen," she explained. 

HIV vaccines were the subject of the second part of Hayney's presentation. "Obstacles to HIV vaccine development include the genetic diversity of the virus and how easily it mutates. You can have many different types within one individual," she pointed out. "There have been millions of documented cases of HIV and yet no documented case of long-term immunity." 

One promising candidate in the pipeline is a joint effort between Sanofi-Pasteur and VaxGen. Currently in a Phase III trial in Thailand, the vaccine is a canarypox vector vaccine with rgp120 subunit boost. The strategy is to induce both cellular and humoral immunity. Preliminary study results are expected in 2009. 

A second product that is not quite as far along comes from the Vaccine Research Center at the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID). Phase II studies are currently underway for this vaccine that utilizes plasmid DNA inserted into a recombinant adenovirus. "It is hoped it will induce strong cellular immunity," said Hayney. Phase III studies are slated to begin in early 2008. 

With 1.3 billion tobacco users in the world and nicotine as the major mediator for tobacco addiction, a successful anti-nicotine vaccine could be a true life-saver. One vaccine in development uses antibodies that bind to nicotine and prevent it from crossing the blood-brain-barrier. Because nicotine itself is not terribly immunogenic, it must be conjugated with something else, according to Hayney. "Scientists have conjugated nicotine to a protein which is recognized by the immune system and really does elicit an immune response," she said. That protein is recombinant Pseudomonas aeruginosa exprotein A.  

The product, NicVax from Nabi Biopharmaceuticals, is currently in Phase IIb trials and preliminary evidence suggests the height of antibody response correlates very strongly with smoking abstinence. "So, the higher you can boost your nicotine antibody with the vaccine, the more likely you are to not smoke," Hayney explained. But one potential question that has not yet been answered is whether or not the antibodies will become saturated – a situation where you could simply smoke more and saturate and overcome the antibody system. 

"It will require multiple doses – this will not be a one shot kind of thing," said Hayney of NicVax. "This is likely to be a vaccine that requires frequent boosters to maintain antibody response." The FDA has granted this vaccine fast-track status.  

Vaccines are not just for prevention, new ones are in development to treat diseases including malaria, HIV, and nicotine dependence.

Novel vaccines in works for three disease states

Currently available AMD therapies, such as ranibizumab (Lucentis, Genentech) or the off-label use of Genentech's bevacizumab (Avastin), require monthly intravitreal injections. Several companies are attempting to overcome the tedious process by developing AMD therapies that can be administered with the ease of eyedrops.

Also being investigated as an ophthalmic solution to treat AMD is ATG3 from CoMentis. This topical and noninvasive treatment inhibits endothelial nicotinic acetylcholine (nACh) receptors and has been shown to decrease angiogenesis and vascular permeability. Currently, ATG3 is in a phase II study designed to assess safety in patients with neovascular AMD. The company expects six-month data by the middle of 2008.  

Regeneron Pharmaceuticals and Bayer HealthCare initiated a phase III trial in August of this year to evaluate VEGF Trap-Eye, a fully human soluble vascular endothelial growth factor (VEGF) receptor fusion protein that binds to all forms of VEGF-A, along with placental growth factor, for the treatment of wet AMD. The anti-angiogenic agent will be stacked up against ranibizumab in a comparative trial involving approximately 1,200 patients. The study, VIEW1, will compare VEGF Trap-Eye at doses of 0.5 mg and 2 mg at four-and eight-week dosing intervals with 0.5 mg ranibizumab every four weeks.  

Results of an earlier phase II trial showed VEGF Trap-Eye met its primary endpoint of a statistically significant reduction in retinal thickness after 12 weeks of treatment. Regeneron received a $20 million milestone payment from partner Bayer HealthCare upon dosing of the first patient in the phase III study.

Because of the retina's susceptibility to oxidative damage, many believe that supplementation with antioxidants could have a major impact on progression of the disease. In fact, results of the age-related eye disease study (AREDS) showed that antioxidants are useful for the prevention and progression of AMD. Patients receiving vitamins C and E, zinc, and beta-carotene had a 28% reduction in the risk of progression to advanced AMD compared with placebo. AREDS-2 now seeks to assess the effects of lutein, zeaxanthin, and long-chain omega-3 fatty acids on the progression to advanced AMD. Enrollment in this study is expected to conclude by December 2007. 

GenVec Inc. seeks a novel solution to AMD. This company is in phase I with AdPEDF, a therapy that utilizes an adenovector DNA carrier to deliver the human pigment epithelium-derived factor (PEDF) gene. AdPEDF inhibits abnormal blood vessel growth and protects the photoreceptors which can be damaged by leaky blood vessels.

New drugs in development for age-related macular degeneration (AMD).

In the pipeline: Keeping an eye on the AMD market

Additional data from trials of COX-2 inhibitors have reinforced the link between the CV events and the drugs. In addition, several reports have identified an increased risk of CV events even with the nonselective NSAIDs. Thirdly, other countries have introduced similar warning statements and advisories to both healthcare professionals and the lay public about the use of NSAIDs. 

"The new scientific advisory is important, as it reemphasizes the step-wise approach for pain management that has been around for decades-although, in this case, it has been tailored for CV patients or patients at risk for CV disease," said Tien M. H. Ng, Pharm.D., BCPS, assistant professor of clinical pharmacy at the University of Southern California School of Pharmacy. Specifically, the new guide recommends that physicians start with nonpharmacologic treatments such as exercise, physical therapy, weight loss, and heat or cold therapy. If there is no relief of pain, physicians should consider acetaminophen, aspirin, and even short-term use of narcotic analgesics as a first step, taking the patient's medical history into account. If more pain relief is needed, non-COX-2 NSAIDs should be considered first, with a move toward the least selective COX-2 inhibitors, and eventually more selective COX-2 inhibitors, only if necessary. In each case, the lowest dose possible should be used to control symptoms and for the shortest duration.  

Naproxen appears to be the preferred choice, although clinical trials to date have had limitations. Next, in increasing degrees of selectivity for COX-2, and increased cardiovascular risk, are ibuprofen, diclofenac, celecoxib (Celebrex, Pfizer), valdecoxib (Bextra, Searle), rofecoxib (Vioxx, Merck-no longer marketed), and etoricoxib (Arcoxia, Merck-not yet Food & Drug Administration-approved). Once a decision is made to prescribe an NSAID, additional concerns come into play.  

For instance, patients should be monitored for increased blood pressure, edema, worsening renal function, and gastrointestinal bleeding. The new statement also suggests adding a proton pump inhibitor to patients who require low-dose aspirin, to diminish the risk of bleeding.   

"The data clearly indicate that non-COX-2 NSAIDs and selective COX-2 inhibitors are associated with an increased risk of CV events," said Ng. "The risk appears to be accentuated in patients with underlying CV risk factors or documented CAD [coronary artery disease], although the exact magnitude of increased risk is poorly defined." Ng explained that there are numerous potential mechanisms that have been postulated to cause the increased risk, but the most commonly cited include inhibition of endothelial prostacyclin, which increased prothrombotic potential and raised blood pressure. "The risk also appears to be dose-dependent," Ng explained. 

One other issue highlighted in the new statement involves whether patients using aspirin for cardioprotection can also use NSAIDs or selective COX-2 inhibitors for pain relief. According to the authors, evidence indicates that ibuprofen, but not rofecoxib, acetaminophen, or diclofenac, interferes with aspirin's ability to irreversibly acetylate the platelet COX-1 enzyme, and could, although it has never been proven, reduce the protective effect of aspirin on thrombosis. The FDA has also said that patients taking low-dose aspirin and ibuprofen 400 mg should take the ibuprofen at least 30 minutes after aspirin ingestion, or at least eight hours before aspirin ingestion to avoid any potential interaction.  

"It is important for both healthcare practitioners and the lay public to recognize that the concomitant use of aspirin with ibuprofen is not recommended for patients with CV disease. In many instances, acetaminophen can be substituted for ibuprofen or other NSAIDs," Ng said. 

The new guide recommends that physicians start with nonpharmacologic treatments such as exercise, physical therapy, weight loss, and heat or cold therapy. If there is no relief of pain, physicians should consider acetaminophen, aspirin, and even short-term use of narcotic analgesics as a first step, taking the patient&apos;s medical history into account.

American Heart Association revision stresses stepped care for pain

"The drug is designed to have a reduced abuse potential," said Marcia L. Buck, Pharm.D., FCCP, clinical pharmacy specialist at University of Virginia's Children's Hospital and associate professor of pediatrics in the schools of medicine and nursing. Since it requires oral ingestion to be converted to the active drug, the capsule contents are unlikely to be sought out for inhalation or injection, she explained. "Lisdexamfetamine is converted to dextroamphetamine and L-lysine in the GI tract. Although the exact mechanism is not well understood, the conversion is believed to be the result of first-pass metabolism in the gut lining and/or the liver." 

"While it appears that this drug will be very similar to products already on the market, at this time there are no published studies comparing lisdexamfetamine to either dextroamphetamine or methylphenidate," explained Buck. But, she added, there may be situations in which it would be advantageous for a patient to have a medication supply that is not easily tampered with or has very little street value. In fact, in clinical studies, lisdexamfetamine produced a lower preference on the scale of "Drug Liking Effects" [DLE] among known substance abusers. 

Lisdexamfetamine will be classified as a Schedule II controlled substance and is expected to launch during the second quarter of 2007. According to Buck, the recommended starting dose is 30 mg taken orally once daily in the morning. The dose may then be increased by up to 20 mg per day at weekly intervals, up to a maximum daily dose of 70 mg. "The capsules are available in 30-, 50-, and 70-mg strengths," she said. 

Because Shire's leading ADHD product, Adderall XR, will lose its patent protection in two years, the company is hoping to transition patients currently taking Adderall XR over to lisdexamfetamine, which will maintain its patent until 2024.  

For the 4.4 million American children who have attention deficit hyperactivity disorder (ADHD), there will soon be another option for treatment. The Food & Drug Administration recently approved the first prodrug to treat the condition: lisdexamfetamine dimesylate (Vyvanse).

Less abuse potential for new ADHD drug

A major change in the treatment of advanced or metastatic colon cancer has been made in a new update from the National Comprehensive Cancer Network (NCCN). The network's "Clinical Practice Guidelines in Oncology: Colon Cancer," published in January, were revised to reflect new scientific data and expert judgment. 								

For one, the update has added the regimen CapeOx, a combination of capecitabine (Xeloda, Roche) and oxaliplatin (Eloxatin, Sanofi-Aventis), as an alternative to FOLFOX for the treatment of advanced or metastatic colon cancer. The FOLFOX regimen includes oxaliplatin, leucovorin, and 5-fluorouracil (5-FU). 

"I think many physicians were already gaining experience with this regimen [CapeOx] and are comfortable giving it," said Mark Kirstein, Pharm.D., assistant professor of experimental and clinical pharmacology at the University of Minnesota's Cancer Center and College of Pharmacy. He pointed out that the European head-to-head trial of CapeOx and FOLFOX will likely provide some of the data clinicians have been lacking. 

NCCN also recommends discontinuation of oxaliplatin from FOLFOX or CapeOx after three months of therapy-or sooner if significant neurotoxicity develops (>grade 3)-with other drugs maintained until the time of tumor progression. Oxaliplatin may then be reintroduced if it was discontinued previously for neurotoxicity rather than for disease progression.  

"There is acute and chronic," said Kirstein of oxaliplatin-associated neurotoxicity. "The chronic is the one that requires a dosage adjustment or stopping the regimen." With FOLFOX, Kirstein explained, some physicians will give oxaliplatin for six cycles and then stop, but continue with the 5-FU. 

Following disease progression on a bevacizumab (Avastin, Genentech)-containing regimen, the new guide has now added two new options for treatment: FOLFIRI plus cetuximab (Erbitux, BMS/ImClone), or irinotecan (Camptosar, Pfizer) plus cetuximab. The FOLFIRI regimen includes treatment with 5-FU, leucovorin, and irinotecan. Cetuximab may also be used as a single-agent therapy for patients who cannot tolerate irinotecan. According to NCCN, there are no data to support continued use of bevacizumab with a second-line regimen after first progression on a bevacizumab-containing regimen and, therefore, it is not routinely recommended. Practitioners should keep in mind that there is an increased risk of stroke and other arterial events, especially in the over-65 population. The use of bevacizumab may also interfere with wound healing. 

The NCCN colon cancer panel also added panitumumab (Vectibix, Amgen) as an alternate option to cetuximab after first or second progression on previous therapy. Panitumumab has been Food & Drug Administration-approved for the treatment of patients with EGFR (epidermal growth factor receptor)-expressing metastatic colorectal carcinoma with disease progression on or following regimens containing fluoropyrimidine, oxaliplatin, or irinotecan. The NCCN panel stated that patients should not be excluded from this therapy, however, on the basis of EGFR results. 

Kirstein believes that pharmacists can manage the supportive care surrounding a regimen, such as emetogenicity and neurotoxicity. "Another issue is the transition of many of our antitumor regimens toward more orally administered agents, like capecitabine. This requires us to counsel our patients, since they will be receiving more of their treatments away from the clinic." 

The NCCN "Clinical Practice Guidelines in Oncology: Colon Cancer" can be accessed on-line at 

A major change in the treatment of advanced or metastatic colon cancer has been made in a new update from the National Comprehensive Cancer Network (NCCN). The network's "Clinical Practice Guidelines in Oncology: Colon Cancer," published in January, were revised to reflect new scientific data and expert judgment.