DID - Oct. 15, 2009 Issue

Vol. 8 No. 201

FDA Panel Recommends Approval of MS Drug to Improve Walking

Acorda Therapeutics’ Amaya should be approved by the FDA to improve walking in patients with multiple sclerosis (MS), despite the risk of seizures, an agency committee says.

The Peripheral and Central Nervous System Drugs Advisory Committee voted Wednesday to recommend Amaya, a sustained-release (SR) tablet form of fampridine, because the benefits of the drug to MS patients outweigh the risks. The panel decided the drug was efficacious in a 12–1 vote and recommended the treatment as safe in a 10–2 vote, with one abstention.

The drug improves conduction across segments of nerve fibers, or axons, where the myelin sheath protecting them has deteriorated, according to briefing materials provided by Hawthorne, N.Y.-based Acorda and posted on the FDA’s website before the meeting. Amaya is a member of a novel drug class targeting MS at the neuron level, the company says.

FDA staff briefing materials note that the agency has never granted approval for the indication sought for Amaya. Approved MS drugs are indicated to decrease relapse rates or prevent the worsening of disability.

Amaya emerged from university-based scientific investigation and entered a clinical development program sponsored by Elan, which was later transferred to Acorda. Fifty-six clinical studies have been conducted — 19 in healthy subjects, 24 in MS patients, 11 in patients with spinal cord injury and two in patients with Guillain-Barre syndrome. More than 1,900 subjects have been exposed to the drug, including more than 1,600 who were exposed to fampridine-SR tablets.

Acorda’s briefing materials provide details of two key Phase III efficacy trials, designated MS-F203 and MS-F204. In the first, results showed that treatment with fampridine-SR significantly increased the percentage of subjects who qualified as “timed walk responders” who showed consistent improvement in walking 25 feet compared with patients on placebo.

MS-F204 results were consistent with those from the other trial. The timed walk response rate in the fampridine-SR group was 42.9 percent.

The FDA staff review says that while both studies met their primary endpoints and the requirements of the special protocol assessments, secondary analyses “gave inconsistent results, and indicated a very limited effect on walking speed.” In addition, the agency cautioned that the drug’s efficacy “must be considered against a widely acknowledged safety signal for 4-aminopyridine and other pyridine compounds: seizures.”

The most frequently reported treatment-related adverse events in the studies were falls and urinary tract infections. — Martin Berman-Gorvine


Shire, Sandoz Settle Adderall XR Litigation

Shire has settled litigation over Sandoz’s generic versions of its extended-release (XR) Adderall, ending all litigation against ANDA applicants related to the attention deficit hyperactivity disorder drug.

The settlement allows Sandoz to market generic versions of Adderall XR (mixed amphetamine salts) in the U.S. after FDA approval, Shire says in a statement Wednesday. Sandoz would pay Shire a royalty from sales of the drug, the company adds.

However, Shire filed a citizen petition several years ago asking the FDA to require clinical trials proving the safety and efficacy of any generic version of the drug, company spokesman Matt Cabrey told DID. Specific blood level data were required for the drug’s approval, and a generic manufacturer should have to produce the same data and show its drug will have the same results, Cabrey said. He added Shire believes the FDA will take the petition into account.

Under the settlement, Sandoz agreed to a consent judgment confirming its proposed generic products infringe Shire’s ’819 and ’300 patents and that the two patents are valid and enforceable.

In January 2006, Shire reached a similar agreement with Impax Pharmaceuticals (DID, Jan. 23, 2006). Shire and Barr Laboratories settled their Adderall XR litigation in August 2006 (DID, Aug. 16, 2006).

Impax and Barr are the only authorized generic suppliers of Adderall XR, Shire says. The FDA and Sandoz did not respond to requests for comment on the citizen petition by press time. — April Hollis


Data Lead Ziopharm to Switch Cancer Drug to Phase III Trial

Ziopharm Oncology will stop enrolling new patients in its Phase II clinical trial of Zymafos for unresectable or metastatic soft-tissue sarcoma after the drug met its endpoint of progression-free survival.

The company decided to move on to a pivotal Phase III study of Zymafos (palifosfamide) as soon as the first half of 2010, the New York-based company says in a statement Wednesday. Ziopharm says it will report full interim results from the study at the annual meeting of the Connective Tissue Oncology Society Nov. 5.

The company conducted an interim analysis of trial data from 58 of the 62 patients treated as of the end of September. The data monitoring committee, sarcoma experts and the company’s medical advisory board found that Zymafos, or ZIO-201, combined with doxorubicin is more effective in helping patients achieve progression-free survival compared with doxorubicin alone.

The interim safety data also indicate that Zymafos does not add to the toxicity of doxorubicin. The most frequently reported side effects in both arms of the study include neutropenia and fatigue, hypokalemia, nausea, anemia, leucopenia and hair loss. Palifosfamide is usually administered as an outpatient treatment.

While Ziopharm is seeking the FDA's approval of Zymafos for sarcoma as a good first approval pathway, it also is interested in developing the drug for indications such as breast cancer, CEO Jonathan Lewis told DID Wednesday. He added that the drug has both an intravenous and an oral form, but the oral form has not yet undergone testing in human subjects in the interest of saving time on the NDA filing.

Palifosfamide includes a novel composition of the functional active metabolite of ifosfamide, a standard-of-care drug for treating sarcoma, lymphoma, testicular and other cancers, Ziopharm says.

The investigational drug “delivers only the cancer-fighting component of ifosfamide” and may overcome the drug resistance seen with ifosfamide and cyclophosphamide, another chemotherapy compound, the company adds. The drug also lacks the toxic metabolites of ifosfamide that cause debilitating mental side effects, encephalopathy and severe bladder inflammation. — Martin Berman-Gorvine


Mylan Plans to Sell Generic Vfend in 2011 Under Pfizer Agreement

Mylan expects to be the first company to sell a generic version of Pfizer’s antifungal drug Vfend after reaching a settlement and licensing agreement with the company.

The agreement will give Mylan the right to market 50- and 200-mg tablets of generic Vfend (voriconazole) in the first quarter of 2011, the generic-drug maker says in a statement Wednesday. The company also is likely to have 180 days of marketing exclusivity for the drug because its subsidiary Matrix Laboratories was the first to submit a substantially complete ANDA containing a Paragraph IV certification to the FDA, Mylan says.

Matrix filed its application April 14, 2008, and Pfizer failed to file suit within the 45-day time period provided by the Hatch-Waxman Act (DID, Oct. 31, 2008).

Further details of the agreement were not disclosed by the companies.

Vfend had U.S. sales of $164 million for the 12 months ended June 30 and was one of Mylan’s 35 pending ANDAs representing potential first-to-file opportunities, the company says. — David Belian


J&J, Abbott Look to Collaborations to Boost Pipelines

Abbott Laboratories and Johnson & Johnson (J&J) are largely turning to collaborations to advance their pipelines.

Both companies reported third-quarter financial results this week. Abbott has three hepatitis C virus compounds in human trials, with additional preclinical compounds in development, the company says in a statement Wednesday. Abbott’s hepatitis C program includes a partnership with Enanta Pharmaceuticals to develop protease inhibitors, as well as its internal polymerase inhibitor program.

Development of two Abbott-discovered oncology compounds is progressing in a collaboration with Genentech, Abbott says. The compounds include ABT-263, a Bcl-2 family protein antagonist, and ABT-869, a multitargeted kinase inhibitor (DID, June 27, 2007). Abbott’s oncology research also includes a drug in Phase II testing to prevent DNA repair in cancer cells to enhance the effectiveness of cancer treatments.

Abbott is awaiting FDA approval for cholesterol drug Certriad, a fixed-dose combination of Trilipix (fenofibric acid) and Crestor (rosuvastatin calcium) (DID, June 5). Abbott submitted an NDA in the second quarter for the drug, which it is developing with AstraZeneca.

The company also has developed compounds to regulate mood, memory and other neurological functions to address conditions such as attention deficit hyperactivity disorder, Alzheimer’s disease and schizophrenia, and it is pursuing compounds to provide pain relief. It has ongoing studies for ABT-874, an anti-interleukin 12/23 biologic, in Crohn’s disease and plans a regulatory submission next year for psoriasis (DID, July 16).

Abbott also is exploring additional indications for rheumatoid arthritis drug Humira (adalimumab).

J&J Collaborations

J&J also is benefiting from partnerships and acquisitions. The company entered into a licensing and collaboration agreement with Gilead Sciences in July for a once-daily, fixed-dose antiretroviral product, which will include J&J’s investigational compound TMC278 and Gilead’s Truvada (emtricitabine/tenofovir disoproxil fumarate), Chief Financial Officer Dominic Caruso said on an earnings call this week (DID, July 20).

The company also agreed to collaborate with Crucell early in the fourth quarter to focus on the discovery, development and commercialization of monoclonal antibodies and vaccines for influenza and other diseases (DID, Sept. 29).

In the past quarter, J&J also acquired substantially all of the rights and assets to Elan’s Alzheimer’s disease immunotherapy program and an equity interest in Elan, Caruso said, noting J&J will continue development activities for bapineuzumab, a potential first-in-class drug designed to slow the progression of Alzheimer’s that is in Phase III clinical trials (DID, July 6).

Also in the past quarter, J&J acquired Cougar Biotechnology, gaining rights to CB7630 (abiraterone acetate), a late-stage first-in-class prostate cancer treatment (DID, May 26). — April Hollis


P&G Gets Warning Letter for Nyquil, Dayquil Labeling

Labeling for Procter & Gamble’s (P&G) Vicks Nyquil Plus Vitamin C and Vicks DayQuil Plus Vitamin C fails to list the vitamin as an active ingredient, the FDA says in a warning letter.

Each product is also described in the labeling as effective for “Cold and Flu Multi-Symptom Relief.” The agency took issue with P&G’s marketing of the products as drug-dietary supplements, saying the intended uses of the drugs’ active ingredients render the entire product a drug in both cases, according to the letter dated Oct. 14 that the FDA says was posted inadvertently.

Several active ingredients, including acetaminophen and dextromethorphan hydrobromide, also are mislabeled under a supplemental facts panel where they are listed as “other ingredients,” according to the letter. The term “other ingredients” is not applicable or allowable for components of a drug product, the letter says.

In addition, the products suggest that the vitamin C is intended for temporary relief of cold and flu symptoms listed in the uses section of the drug facts panel in labeling. That violates the FDA’s final monograph for OTC Cold-Cough Drug Products, which doesn’t include the use of vitamin C because there isn’t enough evidence to classify vitamin C as safe and effective for treatment or prevention of the common cold, the letter says.

P&G disputed the FDA’s claims in a statement, saying the company made an adequate distinction between the drug and dietary supplement uses of the products.

The company “has clearly differentiated the benefits provided by the Nyquil or Dayquil active ingredients versus the dietary supplement Vitamin C in Nyquil or Dayquil plus Vitamin C marketing elements,” P&G says in a statement Wednesday. “We believe we are marketing within the FDA regulations and will work with the FDA to resolve the concern together.”

“The Agency has no further comment at this time,” according to an emailed statement from the FDA Wednesday. The warning letter is available at www.fdanews.com/ext/files/Procter-Gamble-Warning-Letter.pdf. — David Belin


Drugmakers Can Monitor TGA Applications for OTC Drugs Online

Drugmakers seeking approval for OTC products in Australia can now monitor the progress of their applications online.

The new process allows OTC medicine applicants to use the agency’s eBusiness Services to monitor their application throughout the TGA’s nine-step approval process, the Therapeutic Goods Administration (TGA) says in a statement this week.

Applicants using the system to submit an application will receive a notification that their payment has been processed and their application is under review. The TGA will perform an administrative check of the submission, which verifies that all documentation outlined in the Australian Regulatory Guidelines for OTC Medicines has been provided and all relevant fees have been paid.

A TGA officer will screen the submission to ensure that the required supporting information also has been submitted and will then contact the drugmaker in writing about the status of their application.

The application is placed into an evaluation queue where it is assigned to a TGA evaluator. The evaluator may contact an applicant with requests for further information and may seek independent expert advice from the Medicines Evaluation Committee.

After the evaluation phase is complete, the reviewer may ask the applicant to verify any changes made to the information originally submitted, and then applicants will receive a message indicating that a decision is pending on their application.

When an application is approved, a copy of the notification letter will be posted online and an administrative team from the TGA will contact the applicant to finalize paperwork associated with the submission. The online system will reflect that the process has been completed, and an entry in the Australian Register of Therapeutic Goods will be created. — David Belian

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