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Acelrx hit with surprise CRL for Zalviso pain management product

By Marie Powers, Staff Writer

Sitting on a Sunday PDUFA date for Zalviso, Acelrx Pharmaceuticals Inc. had to fend off rumors of the drug-device combo’s approval by the FDA on Friday as shares (NASDAQ:ACRX) inched higher. But in a surprise move, the agency issued a complete response letter (CRL) for the pain management product seeking more information to ensure proper device use.

The agency asked for:

* bench data demonstrating a reduction in the incidence of optical system errors which require premature drug cartridge change;

* changes to the device use instructions; and

* additional data to support the shelf life of the product.

The company said some of the issues were addressed in amendments to the new drug application (NDA) submitted prior to receipt of the CRL though the agency acknowledged that they were not reviewed. Acelrx president and CEO, Richard King, said in a statement that the company can “satisfy all of FDA's requests in the CRL and resubmit the NDA by the end of 2014, although we will have more clarity on the process and timing after our conversation with FDA. We are confident in the Zalviso development program and will work closely with the FDA to address the Agency's concerns as outlined in the CRL to ensure that health care professionals and patient communities will have access to Zalviso."

In what would be the first approved product for the Redwood City, Calif.-based firm, Zalviso comprises opioid agonist sufentanil in a sublingual tablet delivered non-invasively through a pre-programmed, hand-held, patient-controlled device. The development program was referred to as Sufentanil Nanotab PCA (patient-controlled analgesia) System, or ARX-01.

Zalviso is designed to improve the management of moderate-to-severe acute pain in adult hospital patients. The device evolved from work by Palo Alto, Calif.-based Ideo Inc., which also helped make Apple’s user-friendly products.

With pricing and launch strategies yet to come, a tipoff to its pricing rationale came last month. The company presented data at the Annual International Society for Pharmacoeconomics and Outcomes Research in Montreal suggesting that intravenous (I.V.) PCA can typically cost a health system more than $200 in drug and equipment, combined, over a typical post-op patient’s two-day inpatient stay, excluding “the additional health care burden of programming errors and other health risks attributable to I.V. PCA therapy.”

Acelrx successfully completed three phase III trials for Zalviso, reporting positive top-line data from the first of these in November 2012. The combination drug/device met its primary endpoint of noninferiority (p < 0.001) in patient global assessment (PGA) of pain control method compared to I.V. PCA with morphine (1 mg/dose). Additional analyses showed statistically significant superiority of the Nanotab system over I.V. morphine in the PGA measurement. Patients were treated for post-op pain following major abdominal or orthopedic surgery for 48 hours to 72 hours. (See BioWorld Today, Nov. 16, 2012.)

A second double-blind, placebo-controlled phase III registration trial mirrored these efficacy results. In both studies, adverse events considered possibly or probably related to treatment were mild-to-moderate in nature and similar to placebo, with the exception of itching, which was significantly greater (p < 0.05) in the Zalviso-treated group.

In the third phase III – an open-label, active-comparator trial comparing the Acelrx candidate to I.V. PCA with morphine – Zalviso showed non-inferiority based on the primary endpoint of PGA measurement over 48 hours. Secondary endpoints of summed pain intensity, summed pain relief and dropouts due to inadequate analgesia over the 48-hour study period were similar between treatment groups.

The company submitted its new drug application in September 2013. In December, Aachen, Germany-based Grunenthal GmbH paid $30 million up front and potentially $220 million more in development and regulatory milestones for marketing rights to Zalviso in Europe and Australia in what Acelrx president and CEO Richard King described as a competitive process with “a lot of very large-scale players interested.” (See BioWorld Today, Dec. 17, 2013.)

The arrangement calls for Grunenthal to make tiered royalty, supply and trademark fee payments in the mid-teens to mid-20 percent range on net Zalviso sales in the Grunenthal territory. The German firm assumed commercial activities for Zalviso, including regulatory approval for the drug, while Acelrx is overseeing regulatory activity for the device in Europe. The companies submitted their marketing authorization application to the EMA earlier this month.

Although investor interest spiked in the run-up to Zalviso’s PDUFA, with analysts generally predicting approval, the stock still was down 10 percent year-to-date before the market opened Friday.

On Friday, prior to market close, Acelrx shares (NASDAQ:ACRX) rose as much as 11 percent early before settling back later in the day to close at $10.83 for a gain of 61 cents. Volume was nearly 4 million shares, or about six times the daily average. In after-hours trading, the stock gained 2.49 percent to $11.10.