FDA has not approved a new molecular entity so far in August, but that does not mean the agency has been quiet. The Divisions of Neurology and Anesthesia, Analgesia and Addiction Products stood out with particularly busy weeks for supplemental approvals.

Re-invention also emerged as a theme -- a discontinued eye drug re-emerged as the first drug for some rare neurological disorders, FDA accepted a new drug application that applies deuterium chemistry to improve the profile of a marketed drug product, and an abandoned antibiotic qualified for FDA incentives that could re-invigorate development.

Teaching An Old Drug New Tricks

When Taro Pharmaceutical Industries Ltd. launches its newly approved Keyevis as the first drug approved by FDA for a group of rare hereditary neurological disorders, it will also mean the return to market of a Merck & Co. Inc. glaucoma drug that hasn't been available since 2002. The oral carbonic anhydrase inhibitor dichlorphenamide, known as Daranide when it was used for reduction of elevated intra-ocular pressure, was approved under the new brand on Aug. 7 for treatment of primary hyperkalemic and primary hypokalemic periodic paralysis and related variants under a supplement to the Daranide NDA. As part of the approval, FDA also removed the ophthalmic indication from dichlorphenamide labeling.

The NDA is largely based on clinical work conducted by a National Institutes of Health-supported network of researchers led by University of Rochester neurologist Robert Griggs. Work on the five-year Phase III HYP-HOP study began in 2004, and by its completion in 2013 the study had enrolled 71 primary periodic paralysis patients who were switched between dichlorphenamide and another carbonic anhydrase inhibitor, acetazolamide, that has a more difficult side effect profile.

Meanwhile, Taro moved into position to produce the drug. In 2009, Taro submitted an sNDA to establish its Haifa, Israel facility as the manufacturing site for dichlorphenamide; an FDA action letter followed and the manufacturing change was finally approved in 2012. It submitted the sNDA for the new indication Nov. 10, 2014.

Taro expects to launch Keyevis in the third quarter of 2015 through the specialty pharmacy Diplomat Pharmacy, Inc. The accompanying "Keys2Care" program will offer "a suite of patient support services to ensure people diagnosed with periodic paralysis can receive treatment with Keyevis as soon as possible," Taro said.

(See the User Fee Goals chart on the FDA Performance Tracker for information on pending applications and FDA actions.)

Teva Moves Into Huntington Chorea Space With Deutetrabenazine NDA

Recent newsflow about Teva Pharmaceutical Industries Ltd. has centered on its bid for global generics dominance by acquiring Allergan Inc.'s generic business, but the company has also been building a branded portfolio in rare movement disorders – an effort that reached a new high-water mark with FDA’s acceptance of its NDA for SD-809 (deutetrabenazine) for treatment of chorea associated with Huntington disease, announced Aug. 12. Teva acquired the drug with its May 2015 acquisition of Auspex Pharmaceuticals Inc. ([A#14150330005]).

The NDA will be the first test of Auspex' strategy of applying deuterium chemistry to improve drug pharmacokinetic, dosing and tolerability profiles. SD-809 is a deuterated version of Lundbeck Inc./Valeant Pharmaceuticals International Inc.'s vesicular monamine 2 transporter (VMAT2) inhibitor Xenazine (tetrabenazine), the only FDA-approved drug for Huntington's chorea. Xenazine uptake has been limited by its side effect profile, especially the depression and suicidality risks that earned a black box warning. Deutetrabenazine studies have found "low rates of depression, somnolence, akathisia/restlessness, and anxiety," Teva said.

The deutetrabenazine NDA is based on two Phase III trials. The FIRST-HD trial is a placebo-controlled, randomized efficacy study that found reduced chorea in SD-809 patients. The ARC-HD trial, on the other hand, is an open-label trial that found patients could safely convert from Xenazine to the new drug "overnight with continued control of chorea."

Takeda/Lundbeck Think Cognitive Function Claim Could Make Brintellix Stand Out

Takeda Pharmaceutical Co. Ltd. and Lundbeck hope that March 28, 2016 will be an important landmark in the commercial growth of the antidepressant Brintellix (vortioxetine). That is the user fee goal for an sNDA that would add claims of improved cognitive function to the Brintellix label, giving the product a much-needed point of differentiation in the crowded, highly generic antidepressant market. Brintellix sales have been modest since its Sept. 30, 2013 FDA approval for major depressive disorder; Takeda reported $42m in US sales for the quarter ended July 30.

If FDA approves the sNDA, "Brintellix would be the first treatment for MDD to include clinical trial data showing an effect on certain aspects of cognitive function in the US label," the sponsors said Aug. 10. The application is based on the FOCUS and CONNECT trials, which used a common neuropsychological measure, the Digit Symbol Substitution Test (DSST), to assess executive function, processing speed and attention in adults with MDD over eight weeks.

BDSI's Onsolis Returns To A More Level Playing Field

BioDelivery Sciences International Inc.'s transmucosal opioid Onsolis will not return to the US market before 2016 while the company explores a partnership that provides "access to the target physician audience," the company said following FDA's Aug. 10 approval of a new formulation of the breakthrough cancer pain therapy. The company has "been engaged with a number of potential partners" and can now "proceed forward with those discussions in earnest," BDSI said, noting that commercializing the product on its own is also an option.

Onsolis (fentanyl buccal soluble film) has had a rocky ride on the commercial side since FDA approval in 2009. When the product was launched by BDSI's then-marketing partner Meda AB, it carried a "highly restrictive" Risk Evaluation and Mitigation Strategy that was not matched for competing transmucosal opioids for breakthrough cancer pain like Teva's Fentora and Actiq, the company said. Onsolis sales were negligible in this "unfavorable environment" until FDA approved a shared REMS for all transmucosal immediate release fentanyl products on Dec. 29, 2011 Also see "Shared REMS For Transmucosal Fentanyls Could Expand Market For Meda’s Onsolis As It Exits More Restrictive Program" - Pink Sheet, 29 December, 2011..

BDSI and Meda planned to re-launch Onsolis in the US when FDA implemented the shared REMS in March 2012, but a manufacturing inspection of North American manufacturer Aveva Drug Delivery Systems identified "appearance-related issues" involving formation of microscopic crystals and fading of the color in the mucoadhesive layer of the Onsolis film, which the agency thought could "confuse patients," BDSI explained.

BDSI reformulated Onsolis without the source of both the crystals and the fading (an excipient that had been used as a buffer in the original formulation) and collected 12 months of stability data with the new formulation. An sNDA was submitted in the first quarter of 2015.

While Onsolis was off the market, Meda had been shifting its focus to respiratory products. BDSI announced that it had re-acquired the NDA and North American marketing rights to Onsolis from Meda on Jan. 27.

FDA Request Results In New OxyContin Pediatric Claim

The pediatric indication for Purdue Pharma LP's severe pain therapy OxyContin, approved Aug. 13, is a result of an FDA request under the procedures established by the Best Pharmaceuticals for Children Act of 2002, the agency explained in a Q&A about the expanded use of the extended-release oxycodone product. OxyContin remains a lightning rod for opioid abuse concerns despite FDA-cleared claims that the current formulation discourages nasal and I.V. abuse. The agency noted that Duragesic (fentanyl) is the only other extended-release opioid approved for pediatric use.

FDA asked Purdue to study the pharmacokinetics of its extended-release oxycodone product in pediatric patients in situations where they could be expected to require pain management with an opioid for many weeks, for example after extensive trauma or major surgery, the agency said. That data became the basis of the OxyContin sNDA submitted by Purdue on Dec. 8, 2014 for treatment of patients ages 11 to 16 years old with pain severe enough to require long-term around-the-clock use of an opioid. FDA stressed that OxyContin's pediatric approval, unlike the adult indication, is limited to patients already shown to be opioid-tolerant.

Orexo's Opioid Dependence Treatment Zubsolv Gains Induction Claim

Orexo AB's Zubsolv (buprenorphine/naloxone) extended its indication for treatment of opioid dependence to include initial, or induction, treatment with FDA approval of an sNDA on Aug. 10, 2015. The new claim gives physicians the flexibility to use Zubsolv "from induction through stabilization, maintenance and tapering phases" of addiction treatment, Orexo said.

Opdivo Review Extension Could Have Silver Lining

FDA's goal date for a decision on a first-line melanoma indication for Bristol-Myers Squibb Co.'s PD-1 inhibitor Opdivo (nivolumab) will move ahead three months, from Aug. 27 to Nov. 27, 2015, but the delay could result in improved competitive positioning for the immuno-oncology agent against regimens using BRAF inhibitors inhibitors like Novartis AG's Tafinlar and Roche's Zelboraf. "The company has taken the opportunity to submit additional data from the Opdivo clinical trial program to ensure the broadest data set, irrespective of BRAF status, was available for review," Bristol said Aug. 12, suggesting the company may be looking for approval in both BRAF wild-type and mutant patients ([A#14150812004]). Bristol's supplemental BLA filing was based primarily on the CheckMate-066 trial in treatment-naïve BRAF wild-type advanced melanoma patients.

Will QIDP Status Help Revive Ceftobiprole?

Basilea Pharmaceutica Ltd. can sweeten its ongoing search for a partner for ceftobiprole in the US with the incentives that accompany the antibiotic's new Qualified Infectious Disease Product status, including extended exclusivity and priority review. The company announced FDA's award of QIDP status to ceftobiprole for two indications, community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), on Aug. 12.

Basilea pulled the plug on its efforts to get US approval of the cephalosporin antibiotic in 2014 after a seven-year odyssey that included an NDA for complicated skin and skin structure infections (cSSSI) plagued with data integrity problems, three FDA "complete response" letters, and a failed collaboration with Johnson & Johnson's Cilag GMBH International division that ended up in court – all while FDA overhauled its standards for antibiotic approval ([A#14140625003]). Quintiles Inc. commercializes the I.V. antibiotic for Basilea in the 13 European countries where it is approved for CABP and hospital-acquired pneumonia (but not ventilator-associated pneumonia). Ceftobiprole also received approval for cSSSI in Switzerland and Canada but Basilea discontinued marketing for that use in 2010.

FDA has consistently told Basilea that it wants to see prospective data from new pivotal clinical trials that conform to current agency guidance – not post hoc analyses of older studies – if it is to consider approving ceftobiprole. Basilea has consistently said it will not start new US Phase III trials on its own, but the company's Aug. 12 announcement reported that Basilea was "in discussions with potential collaborators for the clinical development of ceftobiprole in the US."

(See the Qualified Infectious Disease Product Designations chart on the FDA Performance Tracker for more information.)

Keeping Track: Neurology And Pain Products Keep FDA Occupied

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