Drug Industry Daily - March 9, 2011 Issue

Vol. 10 No. 48

Advisory Committee Recommends Lower Dose of Novartis’ Indacaterol

An FDA advisory committee agreed to recommend approval of a lower dose of Novartis’ chronic obstructive pulmonary disease (COPD) drug indacaterol after finding that a high dosage version didn’t provide any additional benefit.

Ultimately, members of the FDA’s Pulmonary-Allergy Drugs Advisory Committee Tuesday were not satisfied with the drug’s long-term safety and clinical benefits at the 150 mcg dose and rejected approval for that strength.

However, the panel voted 13-4 to approve the 75 mcg dose and 12-5 to reject the 150 mcg dose.

“I saw no evidence that there was significant difference between the 75 and 150-level doses,” in regards to efficacy, committee chairman Peter Terry, a professor of pulmonary and critical care medicine at Johns Hopkins University, said.

While indacaterol has demonstrated clinical benefit, the drug has also shown to increase the number of adverse respiratory events in asthma patients, a common comorbidity in COPD. Therefore, the drug, which some industry insiders are calling a potential blockbuster, had its safety record scrutinized by FDA reviewers in background documents (DID, March 7).

Because Novartis initially sought and studied indacaterol at higher doses, less data existed for 75 mcg and lower levels. Members called for more data and longer studies under the 75-mcg level.

Indacaterol, which has a proposed trade name of Arcapta Neohaler, is classified as a long-acting beta-agonist, a drug class that includes Merck’s Foradil (formaterol fumarate) and GlaxoSmithKline’s Serevent (salmeterol xinafoate).

Some industry analysts predicted the panel’s voting, saying members would express concern with the risk-benefit assessment of the dosing levels.

The FDA already rebuffed Novartis’ efforts to approve the drug in October 2009 (DID, Feb. 11). However, the EU approved indacaterol in November 2009 under the name Onbrez Breezhaler, and the drug is approved in more than 50 countries to date, Novartis says. — David Pittman


FDA Accepts NDA for Novel Type 2 Diabetes Treatment Dapagliflozin

The FDA has agreed to review Bristol-Myers Squibb’s (BMS) and AstraZeneca’s NDA for dapagliflozin, a potentially first-in-class compound for the treatment of adult type 2 diabetes.

A separate marketing authorization application has been accepted for review by the European Medicines Agency, the companies announced Tuesday. The NDA has a user fee action goal date of Oct. 28.

If approved, dapagliflozin could be the first in a novel class of agents that control blood sugar independently of insulin pathways. The compound works by inhibiting sodium-glucose cotransporter-2 (SGLT2), which is located in the kidneys, causing the body to excrete excess glucose and associated calories in the urine.

The submissions are based on data from roughly 6,000 patients in 40 clinical trials. In one of those, a 24-week randomized, double-blind Phase III study of 597 adult patients with inadequate glycemic control, dapagliflozin plus glimepiride, a sulfonylurea, led to significant reductions in glycosated hemoglobin levels (HbA1c) and greater weight loss compared with patients who received glimepiride only, the companies said.

In another randomized, double-blind Phase III study of patients inadequately controlled on metformin therapy, dapagliflozin was shown to be non-inferior to glipizide, also a sulfonylurea, in improving HbA1c. Dapagliflozin plus metformin also resulted in significant reductions in key secondary endpoints, such as weight gain, and a decline in the number of patients reporting one or more hypoglycemic events, the companies said.

The NDA also includes data on dapagliflozin’s effects on cardiovascular health.

BMS and AstraZeneca developed the product jointly under a 2007 collaborative agreement (DID, Jan. 12, 2007). — Meg Bryant


Tufts: New Indications for Existing Drugs on the Rise

A new report says additional indications for existing drugs have steadily increased in the U.S. over the past decade as drug companies look for new ways to maintain profitability.

The Tufts Center for the Study of Drug Development (CSDD) study, released Tuesday, shows drug developers have been seeking new revenue streams through regulatory approvals for new or modified indications of existing drugs.

New or modified indication approvals in the U.S. increased by 17 percent from 1998 to 2009, and 65 percent of U.S. approvals for new or modified indications during that timeframe were granted for sNDAs. Only 9 percent were for original NDAs.

During that period, anti-infective and central nervous system (CNS) drugs accounted for 41 percent of all sNDA approvals. Although only 12 percent of NDA approvals were for CNS drugs, they captured 20 percent of additional indication approvals.

Meanwhile, immunologic, gastrointestinal and respiratory drugs were categories with the fewest additional indication approvals.

While new indication approvals can translate into revenue growth, it can vary widely depending on indication and the number of competitor products. The number of new or modified indications per drug ranged from one to 20 from 1998 to 2009, CSDD says.

Therefore, many drug companies are working to find the right balance between investing limited R&D resources in finding new indications for existing drugs and developing novel compounds, the study says. But as review periods get shorter, companies are seeing quicker returns on their investments.

Results show that from 1998 to 2009 the mean time from NDA approval to approval of a supplemental indication averaged about nine years.

But approval times varied based on therapeutic class, ranging from 8.7 months for antineoplastic drugs to 13.6 months for CNS drugs.

The report is based on information from the FDA and the CSDD Approved Drug Database and included 1,538 approvals and a subset of new or modified indication approvals of 889 approvals. — Molly Cohen


FDA Warns Abbott’s Kaletra May Cause Health Problems in Babies

The FDA is ordering a label change for Abbott’s HIV drug Kaletra (lopinavir/ritonavir) to warn of serious health problems reported in premature babies after receiving the oral solution preparation of the medicine.

Kaletra oral solution contains alcohol and propylene glycol. Premature babies may be at increased risk for health problems because they have a decreased ability to eliminate propylene glycol, a solvent, which could lead to adverse events include serious heart, kidney, or breathing problems, the FDA says.

The FDA Tuesday said the drug’s label is being revised to include a new warning, saying the use of Kaletra oral solution should be avoided in premature babies until 14 days after their due date, or in full-term babies younger than 14 days of age unless a healthcare professional believes that the benefit of using the HIV infection treatment immediately after birth outweighs the potential risks. If that is the case, the FDA strongly recommends monitoring for increases in serum osmolality, serum creatinine and other signs of toxicity.

Toxicities include hyperosmolality with or without lactic acidosis, renal toxicity, CNS depression, seizures, hypotonia, cardiac arrhythmias, ECG changes and hemolysis. The appropriate dose of Kaletra for each child should be based on body weight or body surface area to avoid overdosing or exceeding the recommended adult dose.

A safe and effective dose for babies less than 14 days of age (whether born premature or full term) has not been established, the agency added.

The agency advises that patients call their physician immediately if their baby appears too sleepy or breathing has changed while taking Kaletra.

The warning is based on a review of the Adverse Events Reporting System that shows 10 postmarket cases of life-threatening events reported in neonates who received Kaletra liquid between September 2000 and September 2010.

Life-threatening events included cardiac toxicity, lactic acidosis, acute renal failure, central nervous system depression and respiratory complications. There was also a case of death due to cardiogenic shock related to a large overdose of Kaletra (DID, Aug. 15, 2007). — Molly Cohen


Salix Gets Complete Response on Xifaxan, Asks for Immediate Meeting

Salix Pharmaceuticals has received a complete response letter for its sNDA for its antibiotic Xifaxan and has requested an immediate meeting with the FDA to discuss the agency’s concerns.

The company was hoping to gain approval for the drug as a treatment for non-constipation irritable bowel syndrome (IBS) and IBS-related bloating, though it noted last month it expected to receive the letter (DID, Feb. 28).

The FDA informed the company that its application for a new indication of Xifaxan (rifaximin) 550-mg tablets could not be approved, primarily due to a need for retreatment information, Salix said Tuesday.

Xifaxan was first approved by the FDA in 2004 as a treatment for traveler’s diarrhea caused by certain bacteria, and gained an additional indication last year to reduce the risk of recurrence of overt hepatic encephalopathy — a worsening of brain function — in patients with liver failure (DID, March 26, 2010).

Salix says it has requested a Type A meeting with the FDA to discuss the complete response letter, which the agency describes as a meeting that is “immediately necessary for an otherwise stalled drug development program to proceed.”

If the FDA accepts the request, the meeting should occur within 30 days, the company says.

While the company is declining to comment on how it will proceed with Xifaxan until after the meeting, Wall Street analysts have said they expect Salix to abandon its plans for the IBS indication.

“We think the trial may be very onerous to run and could delay IBS approval by at least 3 years,” Irina Rivkind, an analyst with Duncan-Williams, said in a note last month. “We also lack conviction that results will be positive since the FDA may want the design to be based on its new composite responder analysis (per IBS Guidance), or require demonstration of a bacterial infection.” — David Belian   


Phase II Trial to Resume for Amicus Pompe Drug After FDA Lifts Hold

Amicus Therapeutics, which specializes in small-molecule drugs to treat genetic diseases, will resume a Phase II study for a rare genetic disorder after the FDA lifted a clinical hold for a rare disease treatment.

The FDA halted Amicus’ trial for AT2220 (1-deoxynojirimycin HCl), a treatment for Pompe disease, two years ago after safety concerns arose. But the announced Tuesday the FDA has removed the hold and will start the study in the first half of the year with preliminary results expected in the second half.

“Amicus completed a thorough investigation of the events, including the completion of additional preclinical and Phase I studies,” the company said. “As a result the company decided to continue development of AT2220 co-administered with (enzyme-replacement therapy) but not as a monotherapy.”

After promising preclinical and Phase I studies, two patients in the Phase II study of AT2220, which has orphan drug status, experienced serious adverse events believed to be linked to the drug. As a result, the FDA placed a clinical hold on the trial (DID, March 2, 2009).

Patients with Pompe disease carry a mutation in the gene that produces an essential enzyme, alpha-glucosidase, which breaks down glycogen. With flawed production of the enzyme, excessive amounts of the stored form of sugar accumulate in the heart and liver, causing muscular, skeletal and respiratory problems. Pompe disease inflicts roughly one in every 40,000, according to the NIH’s National Institute of Neurological Disorders and Stroke. — David Pittman

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Reporters: David Belian, Virgil Dickson, Wilson Peden, Molly Cohen, David Pittman

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