This article is a Clarivate Analytics Market Insight report, an ongoing series featuring expert reviews of hot topics in the pharma/biotech field, with analysis and discussion on the factors currently affecting the industry. Data leveraged for this analysis was gathered from Clarivate Analytics Cortellis.
The unmet need
The new year has seen major setbacks for the already challenging field of Alzheimer’s disease (AD), with confirmation of three significant drug development failures plus a major pharma company exiting the area entirely. AD is the sixth leading cause of death in the U.S., and the only one of the top 10 that cannot be prevented or treated. Effective drug treatment is desperately needed, but remains elusive. The failure rate for potential AD drugs, including ones that have reached the final stages of development, is notoriously high: No new drugs have entered the market since Namenda in 2004, and the failure rate in clinical trials is almost 100%. Driven by the failures of agents assessed in the later stages of the disease course, drug developers are looking to earlier and earlier intervention in the hope that early treatment or even prevention is the best, or only, chance of success. With the decade-long course of disease progression, data readout from ongoing trials of the most anticipated potential AD drugs remains some years away.
Alzheimer’s disease is the sixth leading cause of death in the U.S., and the only one of the top 10 that cannot be prevented or treated.
Pfizer quits neuroscience research
In early January 2018, Pfizer announced that it was to close its neuroscience division and exit AD and Parkinson’s disease research, terminating a neuroscience pipeline which included four phase I AD drugs. Pfizer’s last major success in the AD field was the market entry of the acetylcholinesterase inhibitor Aricept in 1997. Over the following 20 years, despite significant investment and many tens of trials, it has had no further market entrants and has suffered the late-stage losses of the drugs Dimebon and bapineuzumab.
Pfizer’s statement on the closure reflected the stark truth of AD research: “after our internal programs faced continual setbacks, we had to come to terms with the fact that our research efforts were simply not making the progress necessary to translate into truly transformational therapies for patients.” Although Pfizer plans to create a venture fund to invest in neuroscience biotechs, and its statement affirmed the belief that meaningful therapies for AD will be discovered in the long-term, its analysis of the commercial potential of this field is a sobering one.
Two 5HT-6 antagonists fail in late-stage trials
Within days of Pfizer’s announcement, the AD field was hit with the confirmation of two further late-stage drug failures. The 5HT-6 antagonists intepirdine and idalopirdine had been in phase III trials with Axovant/GlaxoSmithKline and Eli Lilly/Lundbeck, respectively. Previously, sales of intepirdine had been forecast to reach almost $1 billion by 2024 (source Thomson Reuters I/B/E/S).
Axovant reported in September 2017 that intepirdine had failed to meet its co-primary endpoints of improved cognition and activities of daily living in the phase III MINDSET trial in mild to moderate AD. At that time, trials were ongoing for dementia with Lewy bodies (the phase IIb HEADWAY study) and for improving gait and balance in dementia patients. However, in January 2018, both trials also failed their endpoints, and development of the drug was halted. Development of idalopirdine had been discontinued in February 2017 based on negative topline trial data, but it was in January 2018, the day after the intepirdine news was announced, that full data from the trials were published. The phase III STARSHINE, STARBRIGHT and STARBEAM trials had assessed the drug in patients with mild to moderate AD, and all three failed to show improvements in cognition over 24 weeks. Secondary endpoints were also considered non-significant.
Trial failure for the insulin hypothesis
Postulated links between insulin resistance and AD have prompted a number of investigations into the repurposing of diabetes drugs, among them Takeda’s PPAR-gamma agonist and insulin sensitizer, pioglitazone. In 2013, Takeda and partner Zinfandel began the phase III TOMMORROW trial of pioglitazone. Its aim was to delay the onset of AD-associated mild cognitive impairment in cognitively normal individuals assessed as high risk due to their APOE and TOMM40 genotypes. However, in late January 2018 it was announced that an interim futility analysis had shown an inadequate treatment effect; the 3,500-patient trial was terminated. The investigator-led phase II ELAD trial of Novo Nordisk’s GLP-1 analog liraglutide is ongoing, with completion expected in March 2019. It remains to be seen whether that diabetes drug will be more successful.
Despite these failures, there are still promising drugs in late-stage studies for AD. (See Table 1, Table 2 and Figure 1.) These include the anti-amyloid antibodies solanezumab (Eli Lilly), crenezumab and gantenerumab (Roche/Chugai) and aducanumab (Biogen/Eisai), and the beta secretase (BACE) inhibitors JNJ-54861911 (Johnson & Johnson), AMG-520 (Novartis/Amgen), verubecestat (Merck & Co) and lanabecestat (AstraZeneca/Eli Lilly). They are being assessed as interventions from the mild stage of the disease (the BAYBREAK and Marguerite ROAD studies), to the earlier prodromal phase and/or mild disease (CREAD1 and 2, ENGAGE, EMERGE and AMARANTH), to prodromal (APECS), and even as potential preventatives (A4, DIAN-TU, ADAD, EARLY and Generation S1 and S2). However, for many of these studies, data are not expected for several years (see Figure 1).
AD drug development has shown high rates of attrition over the years, and looks set to remain an extremely challenging field. The failure of drugs at late stages of development, and the cost of those losses, has contributed to reducing the attractiveness of this field to drug developers. However, the unmet need remains vast, both in terms of healthcare costs and patient need, and despite the setbacks, hope remains that the ongoing trials that are expected to complete within the next few years will address the course of this devastating disease.
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