Keeping Track: Xiidra, New Repatha Regimen Approved; Abuse-Deterrent Opioid Gets Negative, But Timely, Response
Executive Summary
The latest drug development news and highlights from our FDA Performance Tracker.
Shire PLC's Xiidra became the FDA Center for Drug Evaluation and Research's 15th novel approval in 2016 when it cleared FDA on July 11.
Getting Xiidra to approval took two review cycles, but Shire emerged with the first product to receive an indication for both the signs and symptoms of dry eye disease.
A complete response letter for Elite Pharmaceuticals Inc. abuse-deterrent opioid candidate announced July 15 is the latest sign of FDA's discomfort with the state of the new drug applications (NDAs) it has received to address the risk of opioid addiction.
FDA's growing comfort with new clinical trial approaches was signaled by a breakthrough therapy designation awarded to Loxo Oncology Inc. for TRK fusion cancers – one of the first BTDs granted for a cancer indication defined by genetic signature instead of a tumor's tissue of origin.
Approvals of a new once-monthly single-injection regimen of Amgen Inc.'s cholesterol medication Repatha and the first Rx to over-the-counter switch for a retinoid anti-acne product rounded out the week.
Elite's Abuse-Deterrent Opioid SequestOx Falls Short Of Approval
Elite Pharmaceuticals announced an FDA complete response letter for SequestOx (oxycodone and naltrexone) on July 15, the day after the user fee goal for the abuse-deterrent opioid. The timeliness makes the action stand out: the agency has missed multiple user fee goals for abuse-deterrent opioid formulations, including Teva Pharmaceutical Industries Ltd.'s Vantrela ER, Purdue Pharma LP's Avridi and Pfizer Inc.'s Troxyca ER.
The public health imperative for abuse-deterrent formulations of mainstay opioid therapies has not translated into a smooth review and approval process at FDA. The agency has been convening advisory committee reviews of the backlog and issuing CRLs, most recently for KemPharm Inc.'s Apadaz (benzhydrocodone and acetaminophen), which uses prodrug technology to deter abuse. (Also see "Keeping Track: More Bumps On The Abuse-Deterrent Opioid Road" - Pink Sheet, 20 Jun, 2016.)
SequestOx is a multi-particulate capsule formulation of the opioid agonist oxycodone and opioid antagonist naltrexone. The naltrexone is only released if the beads are crushed or dissolved.
(For more information on FDA non-approval actions, see the FDA Performance Tracker's Complete Response Letters chart.)
Delay In Xiidra Approval Helped Cement Broad Label For Dry Eye
Shire's Xiidra (lifitegrast) overcame mixed results in its pivotal trials and an FDA complete response letter to achieve labeling with both signs and symptoms claims. The broad indication gives Xiidra a compelling commercial advantage over the only other drug for dry eye, Allergan PLC's Restasis (cyclosporine ophthalmic emulsion), which has yielded blockbuster sales despite marginal efficacy and a label that only cites its ability to increase tear production in patients with chronic dry eye.
The Xiidra NDA was submitted with two Phase III trials. One showed a statistically significant improvement in symptoms and the other was statistically significant for improving the signs of dry eye disease. But neither trial met the endpoints for both measures with statistical significance. The company went ahead with an NDA based on the two Phase III studies, OPUS-1 and OPUS-2, but also proceeded with another Phase III trial, OPUS-3, well before FDA issued a complete response letter (CRL) on Oct. 16, 2015.
Shire was able to re-file the NDA roughly three months later. The submission included OPUS-3 data as well as Phase II data backing the improvement of signs of dry eye disease claim. The "totality of the data" across all five studies submitted – the Phase II included – helped demonstrate "reproducible effects on both the signs and symptoms of this disease," Shire Head of R&D Philip Vickers told the Pink Sheet in an interview. (Also see "Shire's Xiidra Gets Advantageous Label Covering Signs, Symptoms Of Dry Eye Disease" - Pink Sheet, 12 Jul, 2016.)
"Nobody has previously come forward with data demonstrating signs and symptoms of dry eye disease – you obviously want to hit both of those and we felt the Phase II data added information that would be important to the FDA, when they've never had this type of data to look at before," he said.
(For more information on new molecular entity and novel biologic approvals, see the CDER Novel Approvals chart.)
Repatha Monthly Dose Approved With Novel On-Body Infusor System
The once-monthly single-injection dose regimen of Amgen's PCSK9 inhibitor Repatha (evolocumab) could give the product a convenience advantage over Sanofi/Regeneron Pharmaceuticals Inc.'s PCSK9 drug Praluent (alirocumab). A new higher 420mg dose is administered through the Pushtronex system, an on-body infusor with a prefilled cartridge that delivers the drug subcutaneously over the course of nine minutes. FDA approved Amgen's supplemental biologics license application (sBLA) on July 8.
The original 140mg dose of Repatha and 75mg starting dose of Praluent are both administered every two weeks by subcutaneous injection. The drugs were approved in summer 2015 for the treatment of high cholesterol for certain patients who aren’t able to lower their cholesterol on statins alone.
It’s not clear how much of a commercial edge the new monthly dose has versus an injection every two weeks, but it does provide a new option for patients. (Also see "Repatha Monthly Dose Approved With On-Body Pushtronex System" - Scrip, 11 Jul, 2016.) The true test for the PCSK9 inhibitors will come early next year when cardiovascular outcomes trials of the new class start producing data.
The Pushtronex system, developed in collaboration with packaging and delivery systems developer West Pharmaceutical Services Inc., is a hands-free device that adheres to the body so patients can use their hands during administration and perform moderate physical activities, such as walking or reaching. The system was designed to use the smallest possible needle (29 gauge) to deliver 420mg of medication in 3.5mL of solution subcutaneously at a steady state. West said the approval marks the first product to incorporate its SmartDose technology in the US.
(See the User Fee Goal Dates chart on the FDA Performance Tracker to follow the progress of applications submitted to FDA.)
Galderma Differin Is First Product To Follow NDA Path To OTC Acne Market
CDER's approval of Galderma Laboratories Inc.'s topical anti-acne product Differin (adapalene) for over-the-counter use on July 8 marked the first time an OTC acne treatment proposed in an NDA will compete in a consumer market that has included only monograph-ingredient products containing benzoyl peroxide, salicylic acid or sulfur.
FDA approved the 0.1% gel formulation of Differin for once-daily topical treatment of acne by consumers 12 years of age and older. Galderma, owned by Swiss firm Nestle SA, has marketed Rx adapalene oral and topical formulations since 1994 in Europe and since 1996 in the US.
An FDA statement explained that Differin Gel’s safety and efficacy for Rx were initially established in five clinical trials with subjects with mild to moderate acne. For the OTC switch, Galderma submitted data accrued from 1996-2016 on post-marketing safety; from a label comprehension and self-selection studies and an actual use trial; and from a maximal use trial. (Also see "Galderma Pioneers NDA Path Into OTC Acne Treatment Market" - Pink Sheet, 10 Jul, 2016.)
The agency said the results from the label comprehension and self-selection studies and actual use trial showed consumers can understand information on the OTC label, and appropriately select and use the product. The maximal use trial, a study of absorption of the drug through acne-affected skin when applied daily over a large surface area, demonstrated that absorption is limited.
Differin Gel's approval could prompt other OTC switch applications for acne ingredients, with Valeant Pharmaceuticals International Inc.’s Retin-A/Renova (tretinoin) line a likely candidate.
Loxo's Lead Targeted Oncologic Gets Breakthrough Status For Tissue-Agnostic Claim
Loxo Oncology Inc. is focused on cancers that are "uniquely dependent on single gene abnormalities," an approach that received a vote of confidence from FDA in the form of a breakthrough therapy designation for the company's LOXO-101 announced July 13.
The drug, a selective tropomysin receptor kinase (TRK) inhibitor, received the breakthrough designation for "treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments," Loxo Oncology reported.
LOXO-101 is one of the first products to receive a breakthrough designation for a tissue-agnostic indication for genetically-defined cancers.
Loxo's BTD application included data from an ongoing Phase 2 basket trial of the drug for solid tumors that harbor TRK fusions, as well as ongoing Phase I studies in adults with advanced solid tumors and pediatric patients with advanced solid tumors or primary CNS tumors.
(See the FDA Performance Tracker's Breakthrough Therapy Designations chart for more information.)