Keeping Track: US FDA Clears Kisqali For Breast Cancer And Keytruda In Lymphoma, But Turns Down AZ's ZS-9 Again

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

FDA's oncology drug review staff cleared two applications with breakthrough therapy designations last week, one for a solid tumor (Novartis AG's Kisqali) and one for hematologic cancer (a new indication for Merck & Co. Inc.'s blockbuster immuno-oncologic Keytruda).

FDA's Center for Drug Evaluation and Research (CDER) also turned down a new molecular entity, AstraZeneca PLC's hyperkalemia therapy ZS-9 (sodium zirconium cyclosilicate), with a second complete response letter for the new drug application (NDA).

Novartis' Kisqali (ribociclib) became the CDER's sixth novel approval in 2017 with its March 13 clearance as part of endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Kisqali is the first breakthrough-designated novel agent to receive approval in 2017.

Kisqali is also the second CDK 4/6 inihibitor to receive FDA approval in this patient population. Pfizer Inc.'s Ibrance (palbociclib), also designated a breakthrough therapy, was first with its 2016 approval.

Similarly, Merck's Keytruda (pembrolizumab) is the second IO antibody indicated for relapsed or refractory classical Hodgkin lymphoma, following Bristol-Myers Squibb Co.'s Opdivo (nivolumab).

Submission activity was centered around pediatrics, as GlaxoSmithKline PLC bid to extend use of its Fluarix Quad flu vaccine to even younger children and Sunovion Pharmaceuticals Inc. turned in an application to add pediatric use to the labeling of its adults-only anti-epileptic Aptiom.

And an FDA advisory committee announcement revealed that an NDA for Inspirion Delivery Sciences LLC's second opioid product candidate incorporating its SentryBond abuse deterrence technology is under review by FDA.

Kisqali Approved With Requirement To Study Dosing Changes For Improved CV Safety

FDA is requiring Novartis to study alternate dosing regimens of Kisqali that could improve the drug's cardiovascular safety profile.

Kisqali labeling approved March 13 warns about QT prolongation, hepatobiliary toxicity, neutropenia and embryo-fetal toxicity. Neutropenia and embryo-fetal toxicity are also highlighted in the warnings and precautions section of Ibrance labeling, which also cautions about pulmonary embolism. The overlaps in adverse event profile between the two CDK 4/6 inhibitors gives neither a notable safety advantage.

Kisqali, however, could lower its QT risk through the required post-marketing trial. FDA's approval letter outlines a PMR clinical trial "to address the efficacy and safety of an alternative dosing regimen for ribociclib" that could "mitigate the risks for QT prolongation without compromising efficacy." Novartis is to submit a final protocol for the trial by year-end 2018, after evaluating ECG, pharmacokinetic and efficacy data from two ongoing ribociclib trials, MONALEESA-3 and MONALEESA-7.

Novartis will introduce Kisqali with pricing that responds to the need for dose adjustments to manage side effects. Unlike Ibrance, the company said, Kisqali's dose can be reduced without treatment interruption. (Also see "Novartis Sets 'Flexible Pricing' For Kisqali To Compete Against Pfizer's Ibrance" - Scrip, 14 Mar, 2017.)

The Kisqali NDA rests on the Phase III MONALEESA-2 trial, which compared Kisqali plus letrozole with letrozole alone. The Kisqali regimen reduced risk of disease progression or death by 44% over letrozole alone, Novartis reported, and demonstrated tumor burden reduction with a 53% overall response rate. (Also see "Keeping Track: Novartis' Ribociclib, Tesaro's Niraparib Submitted; Catalyst Clears Path For Firdapse Resubmission" - Pink Sheet, 4 Nov, 2016.)

Keytruda Hodgkin Lymphoma Claim Allows Range Of Prior Treatments

Keytruda's new indication for refractory classical Hodgkin lymphoma includes adult and pediatric patients, including those who have relapsed after three or more prior lines of therapy. The indication is similar to one granted to Bristol's Opdivo a year ago, but Merck highlighted that Keytruda's indication is regardless of prior stem cell transplant or use of Seattle Genetics Inc.'s Adcetris (brentuximab vedotin). Opdivo's cHL indication specifies that use of the IO agent should follow treatment with autologous stem cell transplant and post-transplant Adcetris therapy. (Also see "Blood Cancer Sector More Competitive After Keytruda Approval" - Scrip, 15 Mar, 2017.)

Merck's supplemental biologics license application (sBLA) for Keytruda received accelerated approval that relied on data from 210 relapsed or refractory cHL patients in the open-label Phase II KEYNOTE-087 trial. (Also see "Keeping Track: Immuno-Oncologics And Abuse-Deterrent Opioids Take Center Stage (Again); Jardiance CV Claim Approved" - Pink Sheet, 3 Dec, 2016.) The study found an objective response rate of 69%, with a complete response rate of 22% and a partial response rate of 47%. The median duration of response in the 145 responding patients was 11.1 months.

Efficacy in pediatric patients was extrapolated from data in the adult cHL population, Merck said, supported by results from a study of 40 pediatric patients with advanced melanoma, PD-L1-positive solid tumors or lymphoma.

AstraZeneca's ZS-9 Tripped Up By Manufacturing – Again

FDA's second complete response letter (CRL) for AstraZeneca's ZS-9 (sodium zirconium cyclosilicate) followed FDA inspection of the hyperkalemia therapy's manufacturing facility, the company said March 17. The product's first CRL, issued in May 2016, also cited manufacturing issues.

AZ did not specify the facility that was inspected in its statement on the new CRL. The first CRL focused on manufacturing deficiencies found during a pre-approval inspection at a plant in Coppell, Texas. (Also see "AstraZeneca's ZS-9 Timeline Hit By FDA Complete Response Letter" - Pink Sheet, 27 May, 2016.)

ZS-9 formulated as a powder for oral suspension. The active ingredient is a "non-absorbed zirconium silicate that preferentially exchanges potassium for hydrogen and sodium," according to AZ. Hyperkalemia, or high potassium levels in blood serum, is a common complication of advanced chronic kidney disease and chronic heart failure. ZS-9, which AZ has touted a potential best-in-class option for hyperkalemia, was the lynchpin of AZ's acquisition of ZS Therapeutics in late 2015. (Also see "Buying ZS Pharma Could Give AstraZeneca Best-In-Class Blockbuster" - Pink Sheet, 6 Nov, 2015.)

New Pediatric Indications Submitted For Fluarix Quad, Aptiom

GSK hopes to expand use of its influenza flu vaccine Fluarix Quadrivalent to children aged six months to 35 months old with an sBLA submission announced March 15. The application is based on a Phase III study in the young patient population and two supportive studies, the company said. The pivotal data will be presented during the annual meeting of the European Society for Paediatric Infectious Diseases in Madrid on May 23-27.

Fluarix Quad has been approved for active immunization against influenza A and B in people three years of age and older. The sBLA would lower the age range without altering dosing, so the same Fluarix Quad dose would be used in all eligible patients from six months and older.

Sunovion's anti-epileptic Aptiom (eslicarbazepine) is only approved for adults, but the company has submitted an application for use as monotherapy or adjunctive therapy for partial onset seizures in children ages four and up. The sNDA is based on FDA guidance on extrapolation of data. Sunovion noted that Aptiom has been studied in five trials in adults. The new submission contains three trial in children that were conducted by Aptiom innovator BIAL, as well as PK analyses of adult and pediatric data to support the proposed pediatric dosing regimen.

Sunovion said it is planning a Phase III trial to study Aptiom in even younger patients, under four years of age.

Inspirion's Second Abuse-Deterrent Opioid Is Under Review

An FDA advisory committee announcement revealed that Inspirion has submitted its second abuse-deterrent opioid product using the company's SentryBond technology. The new candidate, an immediate-release oral tablet formulation of oxycodone, is intended for management of moderate to severe pain when use of an opioid analgesic is appropriate.

FDA's Anesthetic and Analgesic Drug Products Advisory Committee and its Drug Safety and Risk Management Advisory Committee will review the Inspirion oxycodone IR on April 5. Informa's BioMedTracker estimates that the user fee goal for the product is likely two to three months after the advisory committee meeting.

Inspirion's SentryBond technology is used in the company's approved extended-release morphine product MorphaBond. While MorphaBond has been approved since October 2015 with claims to deter abuse by intranasal and IV routes, but Inspirion held off on launching the drug. Daiichi Sankyo Co. Ltd. came on board as a strategic partner for US commercialization in October 2016, paving the way for an expected launch in early 2017. (Also see "Abuse-Deterrent Opioids: US FDA Follows The ‘Route Of Abuse’ To Exclusivity" - Pink Sheet, 27 Feb, 2017.)

The Daiichi agreement also covers a second Inspirion opioid using the SentryGuard technology, which presumably is the oxycodone IR under review. The SentryGuard platform "combines inactive excipients with active pharmaceutical ingredients," according to Inspirion materials. The technology creates tablets that deter abuse "via physical and chemical methods, without the use of antagonist or aversive agents," the company said.

Advisory Committees Air Concerns Over FDA Abuse-Deterrent Opioid Policy

The Anesthetic and Analgesic Drugs and Drug Safety and Risk Management Advisory Committees met March 13-14 to consider abuse risks with another opioid formulation, Endo Pharmaceuticals Inc.'s Opana ER (oxymorphone extended-release). During the meeting, panelists suggested that FDA should prioritize deterring intravenous use over the less risky intranasal abuse. (Also see "US FDA Strategy On Abuse-Deterrent Opioids Needs Rethinking, Panelists Say" - Pink Sheet, 15 Mar, 2017.)

Endo reformulated Opana ER with physiochemical properties that make it difficult to crush and submitted an sNDA with results from an intranasal abuse liability study and interim data from postmarketing epidemiology studies in 2016. The company subsequently withdrew the sNDA in anticipation of three-year data from the epidemiology studies becoming available in late 2016. Endo said is not currently seeking claims for abuse deterrence.

Data show that abuse patterns shifted following after the reformulation. While intranasal abuse decreased, intravenous abuse increased. The majority of panelists concluded that Opana ER’s benefits no longer outweighed its risks but were divided as to whether the drug should be withdrawn or remain on the market with revised labeling and a restrictive Risk Evaluation and Mitigation Strategy. (Also see "Opana ER Looking At REMS – Or Worse – After US FDA Panel Weighs Intravenous Abuse Risk" - Pink Sheet, 14 Mar, 2017.)