Keeping Track: Approvals For Nuplazid, Cabometyx, Bevespi And More; Digital Aripiprazole Tablet Needs More Study

The latest drug development news and highlights from our FDA Performance Tracker.

FDA issued a host of approvals and actions in the past week representing new formulations, combinations and populations for approved molecules, but the week was free of novel agent news until the late-Friday announcement of the approval of Acadia Pharmaceuticals Inc.'s Nuplazid.

Indeed, the most commercially significant approval of the week was a generic – Watson Pharma Inc.'s generic version of AstraZeneca PLC's blockbuster cholesterol medication Crestor (rosuvastatin) (see related story, (Also see "Generic Crestor Marks The End Of An Era, Should Quickly Outperform PCSK9s" - Pink Sheet, 29 Apr, 2016.)).

In a flurry of activity earlier in the week, FDA's Center for Drug Evaluation and Research approved five new drug applications (NDAs) in two days, including a new breakthrough therapy-designated use for Exelixis Inc.'s kinase inhibitor cabozantinib.

The agency also declined to approve a first-of-its-kind digital medicine based on Otsuka Pharmaceutical Co. Ltd.'s venerable antipsychotic aripiprazole (Abilify).

Opko Health Inc. returned to the agency after a complete response letter for its oral formulation of vitamin D prohormone, Rayaldee. Johnson & Johnson submitted a new chewable formulation of its antihelmintic mebendazole, more than 40 years after the deworming drug's original approval.

Breakthrough designations were announced for new uses of Novartis AG's biologic Ilaris and Bristol-Myers Squibb Co.'s star oncologic Opdivo.

Acadia Nuplazid Label Includes Antipsychotic Class Box Warning

Acadia's Nuplazid (pimavanserin) is the first product to carry an indication for treatment of hallucinations and delusions associated with psychosis in patients with Parkinson's disease, but FDA decided to stick with an antipsychotic class-wide box warning in labeling.

FDA's advisory committee had debated the need for Nuplazid labeling to carry the standard box warning about the increased risk of death associated with use of antipsychotics in elderly patients with dementia-related psychosis. Some committee members thought categorizing Nuplazid as an antipsychotic was too broad, given the specificity of its indication and the product's novel mode of action (Also see "Nuplazid's Black Box: Warning May Depend On Antipsychotic Classification" - Pink Sheet, 4 Apr, 2016.). Unlike approved atypical antipsychotics, Nuplazid does not target dopamine receptors; dopaminergic drugs are not suitable for Parkinson's patients.

FDA's announcement of Nuplazid approval on April 29, however, groups Nuplazid with "other atypical antipsychotic drugs."

Nuplazid demonstrated efficacy in a 199-patient, six-week clinical trial that showed "superiority to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms of Parkinson's disease," FDA summarized.

FDA had struggled with the clinical meaningfulness of the primary endpoint in the Nuplazid trial, which was based on a new scale (Also see "FDA's Thinking On New Psychiatric Endpoints: What Does Brintellix CRL Portend For Nuplazid?" - Pink Sheet, 4 Apr, 2016.). But the unmet need in Parkinson's psychosis – and the breakthrough designation that Nuplazid had earned for it – appears to have pushed the agency toward approval.

Nuplazid is the eighth novel agent approved by CDER in 2016. (For a complete annual listing of new molecular entity and novel therapeutic biologic approvals, see the Novel CDER Approvals chart on the FDA Performance Tracker.)

Exelixis Cabometyx For RCC: The Story Of A New Name

Exelixis' cabozantinib received its second FDA approval on April 25, with a new tablet dosage form and a new tradename – Cabometyx – for treatment of patients with advanced renal cell carcinoma after anti-angiogenic therapy. Cabometyx labeling stipulates that the tablets are not interchangeable with cabozantinib capsules, which have been approved for medullary thyroid cancer as Cometriq since 2013.

Cabozantinib holds breakthrough therapy designation as second-line therapy for advanced RCC, and FDA's review followed the expedited timeline that often accompanies breakthrough designation – Cabometyx was approved almost three months before its July 22 user fee goal date.

The approved labeling for Cabometyx gives Exelixis a solid footing as it prepares to launch into the competitive RCC space in two weeks. The label's description of the pivotal METEOR trial comparing Cabometyx with Novartis' Afinitor reports not only the benefit seen on the primary endpoint of progression-free survival, but also the advantage seen on the secondary endpoint of overall survival (Also see "Exelixis’ Cabozantinib Cleared For Kidney Cancer, With Competitive Labeling" - Pink Sheet, 26 Apr, 2016.).

AstraZeneca Builds Respiratory Franchise With Bevespi Approval

The dual bronchodilator Bevespi for chronic obstructive pulmonary disease (COPD) will be AstraZeneca's first launch using Co-Suspension technology to enable delivery of drug combinations in a single pressurized metered dose inhaler (MDI). Bevespi combines two off-patent drugs in a pMDI – glycopyrrolate, a long-acting muscarinic antagonist (LAMA) that was first approved by FDA for respiratory use in October 2015 in Novartis' Utibron and Seebri Neohaler, and the mainstay long-acting beta-2 agonist (LABA) formoterol fumarate.

Bevespi is the fourth LAMA/LABA combination approved by FDA, but AstraZeneca emphasizes that it is the first to use a single pMDI to deliver multiple medicines; the others, like Novartis' Utibron (glycopyrrolate and indacaterol), use dry powder inhalers. AZ US President Paul Hudson recently opined that "for these COPD patients that are using a lot of albuterol or LAMAs, there is something comforting and appropriate about a metered dose inhaler. We feel we are well differentiated" (Also see "AstraZeneca's Hudson Optimistic On Return To Growth In 2017" - Pink Sheet, 25 Jan, 2016.).

Bevespi, previously known as PT003, was a keystone of AstraZeneca's purchase of Pearl Therapeutics Inc. and its Co-Suspension porous low-density phospholipid particle technology in 2013 (Also see "AZ Centers Pearl As The Jewel Of Its Respiratory Franchise" - Pink Sheet, 10 Jun, 2013.). AZ has continued to invest in respiratory products to complement its aging blockbuster Symbicort, acquiring Almirall SA's respiratory operations in 2014 and Takeda Pharmaceutical Co. Ltd.'s respiratory business in late 2015.

(See the User Fee Goal Dates chart on the FDA Performance Tracker for information about submissions and approvals.)

AbbVie Builds Viekira Label With Genotype 1b Cirrhotics Approval

AbbVie Inc. announced April 25 that FDA approved its supplemental New Drug Application (sNDA) to include genotype 1b chronic hepatitis C-infected patients with compensated cirrhosis in the labeling for Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets, dasabuvir tablets). The new labeling also adds that co-administration of ribavirin is not necessary for these patients.

Viekira initially was approved by FDA to treat genotype 1 HCV, including patients with compensated cirrhosis. Depending on the subgroup, the product's label recommends co-administration of ribavirin.

The Chicago-area pharma has been working to add patient subgroups to the Viekira label since that initial approval. This latest addition was backed by data from the open-label, single-arm Phase IIIb TURQUOISE-III study, in which 100% of patients (60/60) receiving Viekira for 12 weeks achieved sustained virologic response 12 weeks after the conclusion of treatment (SVR12).

Compensated cirrhosis, also known as Child-Pugh A disease, is a less severe type of cirrhosis than decompensated cirrhosis. Viekira is not indicated for treatment of patients with decompensated cirrhosis, also known as Child-Pugh B disease. In October, FDA revised Viekira's label to clarify that the fixed-dose combo therapy is contraindicated for Child-Pugh B disease; previously it was not indicated for such patients (Also see "AbbVie Downplays Impact Of Viekira Pak Safety Issues" - Pink Sheet, 30 Oct, 2015.). The labeling also contraindicates treatment of patients with Child-Pugh C disease.

On Feb. 26, AbbVie announced that the same regimen – under the brand names Viekirax and Exviera – got a positive opinion from the EU's Committee for Medicinal Products for Human Use (CHMP) for genotype 1b patients with compensated cirrhosis and is now cleared in Europe for treatment of that subpopulation. –Contributed by Joe Haas ([email protected])

New Forms Of Triferic, Orfadin, Aftanate

The oral solution formulation of Swedish Orphan Biovitrum AB's Orfadin (nitisinone) approved April 22 will facilitate pediatric administration of the drug, which treats the orphan disease hereditary tyrosinaemia type-1 (HT-1). Orfadin was previously approved in capsule form. "As more countries introduce newborn screening for HT-1, infants are diagnosed earlier in life," Sobi commented.

The new formulation will simplify use in infants and improve dose accuracy. "Dosing is adjusted by weight and as babies grow month by month, their dose is adjusted continuously," the company said.

Rockwell Medical Inc. is touting the convenience advantage for dialysis centers offered by a new powder packet package of Triferic (ferric pyrophosphate citrate)approved April 25. Triferic, an iron replacement product to maintain hemoglobin in adults with hemodialysis-dependent chronic kidney disease, is added to patients' dialysate on-site.

The powder packet "is much smaller and lighter than the current Triferic liquid ampule and it enables us to place three-times greater the number of units in an even smaller carton," Rockwell said. "This presentation is much more convenient for customers as it reduces storage space and requires fewer reorders to maintain inventory."

Aqua Pharmaceuticals LLC added a new 75 mg capsule strength to its tetracycline antibiotic Acticlate (doxycycline) franchise on April 26. Acticlate was previously available in 75 mg and 150 mg tablets.

Official Stamp Of Approval For Xtampza ER

Collegium Pharmaceutical Inc. plans to launch its abuse-deterrent extended-release oxycodone Xtampza ER in mid-2016 after receiving final approval from FDA on April 26. Xtampza ER was tentatively approved Nov. 6, 2015 but full approval was precluded by patent litigation filed by Oxycontin manufacturer Purdue Pharma LP (Also see "Keeping Track: Approvals For Genentech And AstraZeneca, CR Letter For Neos, And Breakthrough For Teva" - Pink Sheet, 16 Nov, 2015.).

A US district court issued a final judgment on Feb. 11, 2016, in favor of Collegium in the litigation.

Xtampza ER's approval comes as FDA is reviewing the shared Risk Evaluation and Mitigation Strategy (REMS) for long-acting and extended-release opioids, including Xtampza ER; advisory committee review of the REMS is scheduled for May 3-4 to address questions including how to assess the effectiveness of risk management programs (Also see "Opioid REMS: FDA Sees No Clear Verdict On Risk Management Program's Impact" - Pink Sheet, 27 Apr, 2016.).

Human Factors Trip Up Proteus/Otsuka Digital Aripiprazole Tablet

Proteus Digital Health Inc. and Otsuka are navigating new territory with their NDA for a "digital medicine" drug/device system that tracks medication adherence in patients taking the antipsychotic aripiprazole (Otsuka's Abilify, available generically), and FDA appears to want to make sure the path is well-lit for eventual users. The agency's complete response letter, announced April 26, requests "data regarding the performance of the product under the conditions in which it is likely to be used," Proteus and Otsuka said.

The CRL requests further human factors testing "to evaluate use-related risks and confirm that users can use the device safely and effectively," the sponsors continued.

Proteus' Ingestible Sensor and the Proteus Patch wearable monitor have already cleared the Center for Devices and Radiologic Health, but the real test of the technology requires approval of a specific drug embedded with the sensor (Also see "Proteus Seeks Pharma Partnerships For Ingestible Sensor" - Medtech Insight, 15 Jul, 2015.). Proteus and Otsuka submitted the NDA for the sensor embedded in aripiprazole tablets in June 2015; the sensor sends a signal to the patch, which is relays information to a Bluetooth-enabled device (Also see "Digital Age: Otsuka Sets Sights On Abilify Combo Tablet With Sensor" - Pink Sheet, 10 Sep, 2015.).

(For more information on FDA action letters, see the Complete Response Letters chart.)

Opko's Rayaldee Returns To FDA

Opko resubmitted its NDA for Rayaldee (calcifediol extended-release capsules) on April 22, less than a month after receiving a complete response letter citing deficiencies observed at a facility inspection at third-party manufacturer Catalent (Also see "FDA Hold-Up: Opko Scrambles To Fix Problems At Manufacturing Site" - Pink Sheet, 30 Mar, 2016.).

FDA has assigned Rayaldee a new user fee goal date of Oct. 22, 2016, for prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. According to Opko, Rayaldee, a vitamin D prohormone, is more tolerable than vitamin D analogs currently used for SHPT (Also see "Keeping Track: Submissions By Insys, Elusys, Opko and Bio Products; Immuno-Oncology User Fee Goals; A Genzyme 'Breakthrough'" - Pink Sheet, 8 Jun, 2015.).

Opko expects to launch Rayaldee in the fourth quarter of the year.

J&J Files Child-Friendly Formulation Of Deworming Agent

J&J's Janssen Pharmaceuticals Inc. announced submission of an NDA for a new chewable, orally disintegrating tablet formulation of mebendazole for soil-transmitted helminthiasis (STH) on April 27. FDA approved mebendazole as Vermox solid tablets in 1974 for treating the intestinal worm infestations, a condition that FDA and WHO consider a neglected tropical disease; that prior approval, however, appears to make the new submission ineligible for a priority review voucher.

If approved, the 500 mg chewable tablet will replace the Vermox 500 mg solid tablet in J&J's donation program to treat intestinal worms in high-burden countries. The company noted that the World Health Organization "recommends only chewable deworming tablets be given to children under five years, and that chewable tablets be mixed with water in children under three years."

The new mebendazole formulation can be chewed without need for potable water, J&J pointed out. When mixed with water, the tablet forms a soft mass that can be given to children as young as one year of age who cannot take a solid tablet dosage form.

Novartis Nabs Ilaris Breakthrough Designations For Rare Periodic Fever Syndromes

FDA review of Novartis' supplemental biologics license applications (sBLAs) extending use of Ilaris (canakinumab) to a group of three rare autoinflammatory diseases known as Periodic Fever Syndromes is likely to be expedited now that FDA has awarded breakthrough therapy designations to the anti-interleukin-1 beta monoclonal antibody for tumor necrosis factor-receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), and familial Mediterranean fever (FMF) not adequately controlled with colchicine.

Novartis submitted the three separate sBLAs during the first quarter of 2016. The Phase III CLUSTER trial, which provided the data supporting the breakthrough designations, is the pivotal trial for the sBLAs. Ilaris is approved for other rare autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS) and for a rare autoinflammatory form of juvenile idiopathic arthritis.

Head & Neck Cancer Gives Bristol's Opdivo Its Fifth Breakthrough Designation

Bristol announced the fifth breakthrough therapy designation awarded to its immuno-oncology agent Opdivo (nivolumab) on April 25, for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) after platinum therapy.

The designation is based on results of the Phase III Checkmate-141 trial, which compared Opdivo with investigator's choice of therapy in SCCHN patients with tumor progression within six months of platinum therapy in the adjuvant, primary, recurrent, or metastatic setting. The trial was stopped early in January 2016 because it met its primary endpoint of overall survival.

(For more information on breakthrough products, see the Breakthrough Therapy Designations page on the FDA Performance Tracker.)

The Path Of Breakthrough Therapies Is Not Always Smooth

Breakthrough therapy status is associated with faster FDA review and approval, but the designation is no guarantee of a smooth pathway to the market, as two recent events show.

Novartis' bimagrumab (BYM338) failed to meet the primary endpoint in a Phase IIb/III study in sporadic inclusion body myositis, the company disclosed April 21. FDA granted the monoclonal antibody breakthrough status for sIBM in 2013 on the basis of data from a Phase II proof-of-concept study.

And Catalyst Pharmaceuticals Inc. will need to submit "positive results from an additional adequate and well-controlled study" in patients with Lambert-Eaton myasthenic syndrome (LEMS) to support resubmission of its Firdapse (amifampridine phosphate) NDA, the company announced April 26 after meeting with FDA. Firdapse received a breakthrough designation for LEMS in 2013, but FDA refused to file its NDA in February 2016 (Also see "Catalyst Stumbles With Filing Of Controversial 'Breakthrough Therapy' Firdapse" - Pink Sheet, 17 Feb, 2016.). The NDA included claims for both LEMS and another rare neuromuscular disorder, congenital myasthenic syndromes (CMS).

FDA said that the Phase III LMS-002 trial submitted in the application will not be sufficient for acceptance of the NDA. The agency is "open to discuss" a design for the new LEMS study that "could efficiently accomplish the requirement with a small, short-term study," Catalyst said. FDA also is asking for "several more short-term toxicology studies."