Scrip 100: Has novelty in the depression pipeline hit a wall?
This article was originally published in Scrip
The health of the depression pipeline was brought into question in early 2014 when Shire's Vyvanse (lisdexamfetamine dimesylate) failed in Phase III, becoming just another product to fall at the final development hurdles for major depressive disorder (MDD).
According to BioMedTracker, an affiliate of Scrip, only seven novel drugs have been granted approval for the indication of MDD since 2007, and what's more, all of them have had SSRI/SNRI (selective serotonin reuptake inhibitors/ serotonin and norepinephrine reuptake inhibitors) or atypical antipsychotic mechanisms of action. The successes include Forest Laboratories' Viibryd (vilazodone; approved in US in 2011) and Fetzima (levomilnacipran; approved in US in July 2013), and Takeda's Brintellix (vortioxetine; approved in US in September 2013).Reinforcing the impression that novelty is not paying off in depression research, the three new molecular entities currently still in Phase III development are all atypical antipsychotics: Otsuka's OPC-34712 (brexpiprazole); Forest/ Gedeon Richter's cariprazine; and Dainippon Sumitomo Pharma's Latuda (lurasidone hydrochloride).
*excludes drugs that are not new molecular entities, but includes drugs for which MDD is a new indication
But these successes for tried-and-tested mechanisms have been accompanied by notable disappointments with more novel strategies, with late-stage failures in this indication including Lilly's highly selective norepinephrine reuptake inhibitor edivoxetine (LY-2216684) in December 2013 as well as the more recent failure of Shire's ADHD amphetamine-based drug, Vyvanse (scripintelligence.com, 7 February 2014).
Adding to the casualty lists at the Phase II stage are Johnson & Johnson and partner Addex Therapeutics, who announced that their drug JNJ-40411813 (ADX71149), a first–in-class metabotropic glutamate receptor allosteric modulator, had failed in Phase II MDD studies. The companies said that though efficacy signals were evident, they were not enough to support further development. Plus AstraZeneca has announced in 2014 that it has dropped its ketamine-like NMDA targeting drug, AZD 6765, which it had hoped that this product would go into Phase III in 2013/14.
Looking at the same time period, from January 2007 until now, 59 drug candidates in development for the treatment for MDD were placed on hold or suspended (see full table below). 2014 alone saw one product, Iron Pharmaceuticals' IW-2143, placed on a program hold and three other pipeline MDD drugs suspended: Sumitomo Dainippon Pharma's 5-HT1receptor DSP-1053; Corcept Therapeutics' progesterone receptor Korlym; and Mitsubishi Tanabe Pharma's MKC-231.
These unsuccessful candidates are varied and many used unproven mechanisms of action. What were seen as promising novel classes such as neuropeptide modulators (corticotropin releasing factor [CRF], neurokinin [NK], and vasopressin) have not managed to produce any approved therapies in the last seven years. Nor has the class of triple reuptake inhibitors (serotonin/norepinephrine/dopamine [SNDRI]) or other reuptake inhibitors that did not target serotonin.
Late-stage MDD drugs that use alternative mechanisms that have been dropped by big pharma companies include:
Sanofi's nelivaptan (SSR149415), a vasopressin V1b receptor antagonist, dropped in July 2008, after Phase II studies, and its NK receptor saredutant in April 2009.
While, Roche ended clinical trials for its antidepressant RG7351, a trace amine associated receptor 1 (TAAR1) in July 2010.
As for MDD therapies that were in development using CRF mechanisms, GlaxoSmithKline, Sanofi, Bristol-Myers Squibb, Ono Pharmaceuticals and Neurocrine Biosciences have all called time on their CRF MDD products at some point in the last seven years.
But despite the lack of success for novel therapies, Datamonitor Healthcare analyst Daniel Chancellor told Scrip he believes there is still hope that new classes will emerge onto the market.
Pharma companies have "sunk a lot of money into failed mechanisms over the last decade without producing many success stories," but opioid-based drugs are one class to keep an eye on, he said, highlighting Alkermes' opioid-based medicine ALKS 5461. "The drug has just entered Phase III after generating some very encouraging Phase II data," he said.
The Phase III pivotal trial program for ALKS 5461 will include three studies in a total of 1,500 patients. Phase II data showed that the oral, once-daily medicine significantly reduced symptoms in patients. Harvard Medical School psychiatry professor Maurizio Fava, a clinical investigator on the study, said at the time that results from the trial were the "most robust I have seen in a Phase II study for depression in the past two decades," (scripintelligence.com, 18 April 2013).
Despite the failure of AstraZeneca's offering, Mr Chancellor still believes that there good data "to support ketamine-like NMDA targeting drugs as fast-onset antidepressants in patients that don't respond to traditional therapy."
Mr Chancellor said AstraZeneca's decision may not have been owing to a lack of efficacy. "The majority of depression discontinuations are for efficacy reasons, but the proof-of-concept is good with ketamine." Mr Chancellor pointed to neuropharmaceutical company Naurex, which has recently showed encouraging data for its ketamine-based drug GLYX-13 in treatment-resistant depression.
But even as new mechanisms emerge for the treatment of MDD, in the immediate future at least, public attention will remain on the old stalwart methods.
In March Otsuka/Lundbeck presented data for brexpiprazole at European Congress of Psychiatry in Munich, Germany. Brexpiprazole again uses an atypical antipsychotic mechanism. "Given brexpiprazole relation to aripiprazole (Abilify), positive data was expected," Mr Chancellor said.
Otsuka has submitted new drug applications for brexpiprazole with the US FDA for two indications, MDD and schizophrenia. BioMedTracker has set the drugs likelihood of approval at 88% for its MDD application, 7% above the average for a product at the same stage of development.
The NDA was based on data from more than 6,500 patients, including 5,300 who received brexpiprazole, the companies said. Some data for the product in MDD were presented earlier this year and showed efficacy and good tolerability as an adjunct treatment to patients with an inadequate response to antidepressant therapy. Three additional studies in both indications were due to conclude in the first half of 2014, suggesting that the companies are confident in their results to support the broad application at this time (scripintelligence.com, 14 July 2014).