Merck Halts Preladenant Development In Parkinson’s Following Phase III Failures
This article was originally published in The Pink Sheet Daily
Executive Summary
Company says it will not pursue regulatory filings for the adenosine-2a receptor antagonist because studies in moderate-to-severe and early-stage disease failed to show sufficient evidence of efficacy.
The failure of Merck & Co. Inc.’s preladenant to show efficacy in Parkinson’s disease leaves the big pharma with three neuroscience compounds in its late-stage pipeline as it awaits FDA regulatory action on two others.
Preladenant was Merck’s only neurology-focused compound in Phase III, but the company announced late May 23 that the oral adenosine-2a (A2a) receptor antagonist failed show sufficient evidence of efficacy over placebo in three pivotal trials.
“Based on these results, Merck is taking steps to discontinue the extension phases of these studies and no longer plans to pursue regulatory filings for preladenant,” the company said. “The decision to discontinue these studies is not based on any safety finding.”
The news came a day after Merck received what could arguably be viewed as a mixed verdict from FDA’s Peripheral and Central Nervous System Drugs Advisory Committee on another novel neuroscience compound in its pipeline, the potential first-in-class dual orexin receptor antagonist suvorexant for insomnia.
While the committee found the four doses proposed by Merck were effective for treating insomnia characterized by sleep onset or sleep maintenance, panelists were divided on the safety of the two highest doses and seemed to favor approval of a dose lower than has been proposed for marketing (Also see "Suvorexant’s “Twilight Zone”: Advisory Panel, FDA Favor Low Dose; Merck Does Not" - Pink Sheet, 22 May, 2013.).
Also pending at FDA is sugammadex, a neuromuscular blockade reversal agent that failed in its first bid for approval in 2008 over safety concerns. The Anesthetic and Analgesic Drug Products Advisory Committee will review sugammadex, including a new safety study conducted by Merck at the agency’s request, on July 18 (Also see "Merck Comes Prepared This Time As Sugammadex Faces Second Advisory Committee" - Pink Sheet, 10 May, 2013.).
Minimal Financial Impact
With the regulatory futures of suvorexant and sugammadex unclear and preladenant’s development discontinued, Merck still has three neuroscience late-stage compounds waiting in the wings, all of which are in Phase II, according to the company’s May 6 pipeline update.
These are: MK-8931, an oral inhibitor of beta-site amyloid precursor protein cleaving enzyme 1 that is being studied in Alzheimer’s disease, the dual orexin receptor antagonist MK-6096 for insomnia and MK-1602 for migraine.
ISI Group analyst Mark Schoenebaum said the financial hit from the preladenant failure would be small, estimating a $0.01-$0.02 impact on Merck’s earnings per share in 2016-2018. Consensus estimates for peak sales of preladenant were only about $200 million for 2018, he said.
“Today’s announcement of the unsuccessful preladenant Phase III trials comes at a time of recent, more positive news from Merck, including the announcement of a ~$5 Bn accelerated share repurchase, the recent scheduling of an analyst meeting at ASCO and the FDA AdCom recommendation for approval of suvorexant,” he said in a May 23 note.
Nevertheless, the preladenant story will only add to the woes of a company that has seen its share of late-stage failures and which recently brought in new R&D leadership (Also see "A Changing Of The Guard At Merck R&D As Perlmutter Succeeds Kim" - Pink Sheet, 7 Mar, 2013.).
Adjunctive And Monotherapy Studies
As with sugammadex, Merck gained preladenant through its 2009 acquisition of Schering-Plough Corp. (Also see "Shared Strengths: The Merck And Schering Pipelines" - Pink Sheet, 10 Mar, 2009.).
Preladenant was carried into Phase III, in part, on the strength of a Phase II study in which the 5 mg and 10 mg doses demonstrated a statistically significant and clinically relevant reduction in the primary endpoint of “off” time, which is the time during which patients treated with levodopa or dopamine agonists experience a return of symptoms (Also see "Schering’s Specialty Focus Includes Alzheimer’s, Oncology" - Pink Sheet, 8 Dec, 2008.).
Three Phase III studies of the potential first-in-class compound began in 2010. Two of the trials were conducted in patients with moderate-to-severe disease and studied preladenant as add-on therapy to levodopa, with the primary endpoint being change from baseline in the mean “off” time, according to ClinicalTrials.gov.
The third trial studied preladenant as monotherapy in early disease, and the primary endpoint was change from baseline in the sum of Unified Parkinson's Disease Rating Scale Parts 2 and 3 scores.
Collectively, the three trials were targeted to enroll more than 2,200 patients. Patients in the two studies in moderate-to-severe disease were eligible to enroll in a 40-week extension study.
Merck said results from the three trials will be presented at an upcoming scientific meeting and will be submitted for publication in a peer reviewed journal.
Such findings will be of interest to the handful of other companies that are developing A2a receptor antagonist drug candidates for symptom control in Parkinson’s (Also see "Parkinson’s Disease At A Crossroad: Deals And Emerging Therapeutics" - Pink Sheet, 13 Jun, 2011.).
Most advanced among these is Kyowa Hakko Kirin Co. Ltd.’s istradefylline, which was the subject of an FDA “not approvable” letter in February 2008. At that time, the agency questioned whether the efficacy findings supported clinical utility; it also requested a summary of nonclinical mineralization findings and clinical pharmacology follow-up information.
Nevertheless, Kyowa said istradefylline became the first A2a receptor antagonist approved for Parkinson’s when it gained clearance from Japanese regulators on March 25 under the brand name Nouriast.
Tozadenant, which is under development by Biotie Therapies Corp. and UCB Pharma SA, is entering Phase III. Other candidates from Heptares Therapeutics Ltd./Shire PLC and Domain Therapeutics SA are in early-stage development.