Alzheimer’s disease (AD) affects more than 35 million people worldwide and is the sixth-leading cause of death in the US, where its care costs are predicted to rise from $200 billion in 2012 to $1.1 trillion by 2050. The disease is the only one of the top-ten leading causes of death in the US that cannot currently be treated, prevented or slowed, and while mortality from breast cancer, prostate cancer, heart disease, stroke and HIV declined by between 3 and 29% between 2000 and 2008, AD mortality increased by 66% (see Figure 1).
Figure 1: Alzheimer’s disease facts and figures
In 2012 we reviewed the state of the AD therapeutics field, and discussed the various disappointments, challenges and advances that drug development in this area has faced. This article will provide an update to the status of drugs reviewed at that time, and assess how the field has changed in the last year.
Of the six AD drugs in phase II or III trials in mid-2012, half have since been dropped from development (see Figure 2). Bristol-Myers Squibb’s gamma secretase inhibitor avagacestat and Baxter’s immunoglobulin Gammagard both failed to show significant levels of efficacy and were discontinued in November 2012 and May 2013, respectively. Abnormal liver biochemical results were seen in Eli Lilly’s phase III trial of its beta secretase inhibitor LY-2886721, resulting in termination of both the trial and the drug in June 2013.
Of the original six, the three drugs remaining in active development are the Abeta-targeting monoclonal antibodies (mAbs), crenezumab, gantenerumab and solanezumab. AD treatment trials initiated in 2011 for crenezumab and gantenerumab are ongoing, with data expected in 2014 and 2015, respectively. Since the previous review, a phase III trial of solanezumab for treating mild AD has been initiated. The 2100-patient EXPEDITION 3 trial began in July 2013 and is expected to complete in December 2016.
In addition to completed or ongoing trials for AD treatment, all three mAbs are also being assessed for their potential ability to prevent AD. Two of the investigator-led AD prevention trials that were in planning at the time of the 2012 review have since been initiated and one is to start early in 2014. The Dominantly Inherited Alzheimer Network (DIAN)-TU study is assessing the effects of solanezumab and gantenerumab on Abeta levels in asymptomatic subjects with AD-associated mutations in their presenilin 1, 2, or amyloid precursor protein genes. DIAN-TU is expected to complete in December 2016. Solanezumab has been picked for investigation by the anti-amyloid treatment in asymptomatic AD (A4) study, which will start enrolling elderly subjects with raised Abeta levels in early 2014. The Alzheimer’s Prevention Initiative (API) trial is underway and is looking at whether crenezumab can prevent AD onset in people at high risk, due to their family history, of developing early-onset AD. It is expected to complete in September 2020.
|Drug & Developer||Mechanism||Most Recent Data and Status, as of late 2012||Current Data and Status|
|Avagacestat, Bristol-Myers Squibb||Gamma secretase inhibitor||Potential for negative cognition effects and skin cancer risk. Phase II trials completed; future development uncertain||Discontinued in November 2012, as phase II data did not support advancement to phase III|
|Gammagard, Baxter International||Purified IgG – may bind Abeta||Improved cognition in phase II. Phase III underway; data expected from 2013||Discontinued in May 2013, due to lack of phase III effect on cognitive decline or functional ability compared with placebo|
|LY-2886721, Eli Lilly||Beta secretase inhibitor||Decreased CSF Abeta levels in phase I trials. Phase II underway; data expected from 2014. AD prevention trial planned||Discontinued in June 2013, following termination of the phase II trial due to abnormal liver biochemical tests|
|Crenezumab, AC Immune/Genentech/Roche||Abeta-targeting mAb, humanized||Plasma Abeta levels correlated with serum drug concentration in phase I trials; no vasogenic edema seen. Phase II underway; data expected from 2014. AD prevention trial planned||Phase II treatment trials BLAZE and ABBY for mild to moderate AD still ongoing; completion expected in 2014. The investigator-led API trial is underway and will assess the drug for AD prevention; completion is expected in September 2020|
|Gantenerumab, Roche||Abeta-targeting mAb, human||Reduced brain Abeta levels in phase I, but vasogenic edema seen. Phase III underway; data expected in 2015||Phase III treatment trial SCarlet RoAD for prodromal Alzheimer’s Disease still ongoing. The investigator-led, phase III, DIAN-TU trial for AD prevention is underway with completion expected in December 2016|
|Solanezumab, Eli Lilly||Abeta-targeting mAb, humanized||Phase III trials completed (failed endpoints, but improved cognition in patients with mild AD); approval likelihood low||Phase III treatment trial EXPEDITION 3 for mild AD began in 3Q13; data expected in December 2016. The investigator-led, phase III, DIAN-TU and A4 trials will assess the drug for AD prevention; DIAN-TU is underway with completion expected in December 2016, and A4 is to start in early 2014|
Figure 2: Current status of selected AD drugs that were in late-stage development in mid-2012
Since our last review of the field, Lundbeck and Otsuka have advanced their 5-HT 6 antagonist Lu-AE58054 into a four-trial phase III development program in 3000 subjects (see Figure 3). The first study, STARSHINE, is assessing the efficacy of Lu-AE58054 as an adjunct to donepezil in 930 patients with mild to moderate AD. It began in October 2013 and is expected to complete in September 2015. The STARBEAM trial, which began earlier this month, and the STARBRIGHT trial, which is to start imminently, have similar designs and are anticipated to complete in January 2016. In a phase II trial completed in 2012, Lu-AE58054 plus donepezil significantly improved cognitive function in 278 AD patients compared with donepezil alone. According to Consensus data from Cortellis Competitive Intelligence from Clarivate Analytics, the first sales of Lu-AE58054 are expected in 2017, with revenue of $132.9 million forecast for 2018.
Merck & Co’s beta secretase inhibitor MK-8931 has also recently entered phase III development, with the phase II/III EPOCH trial for mild to moderate AD beginning in November 2012, and the phase III APECS study for prodromal AD starting in November 2013. Data from EPOCH and APECS are expected at the end of 2017 and in 2018, respectively. Consensus data from Cortellis forecast MK-8931 sales of $100 million in 2018 and $200 million in 2019.
|Drug & Developer||Mechanism||Current Data and Status|
|Lu-AE58054, Lundbeck/Otsuka Pharmaceutical||5-HT 6 antagonist||Improved cognition in phase I trials. Phase III data for mild to moderate AD are expected from the STARSHINE trial in September 2015, and from the STARBEAM and STARBRIGHT trials in January 2016|
|MK-8931, Merck & Co||Beta secretase inhibitor||Phase II/III data from EPOCH trial for mild to moderate AD expected in 2017; phase III data from APECS trial for prodromal AD expected in 2018|
Figure 3: Selected AD Drugs Newly Entering Late-Stage Development
Alzheimer’s disease diagnostic agents
Less has changed in the diagnostic field than in AD therapeutics and preventatives, since our last review. In October 2013, the FDA approved the University of Pittsburgh and Uppsala Imanet’s Abeta-binding AD diagnostic agent, flutemetamol (18F), which incorporates fluorine-18 to enable visualization of Abeta deposition. The agent is expected to be launched in 2014, where it will join Avid Radiopharmaceuticals and Eli Lilly’s AD diagnostic agent Amyvid (florbetapir (18F)), which in June 2012 was the first 18F-based Abeta imaging agent onto the market. Flutemetamol (18F) is currently being reviewed for approval in Europe. In the same class of agents, Piramal Healthcare’s Neuraceq (florbetaben (18F)) is awaiting approval decisions in the US and Europe having been filed by March 2013, and Navidea Biopharmaceuticals’ NAV-4694 entered phase III development in June 2013 (see Figure 4).
|Drug & Developer||Current Data and Status|
|Florbetapir (18F) (Amyvid), Avid Radiopharmaceuticals/Eli Lilly||First 18F-based Abeta imaging agent onto the market, in June 2012|
|Flutemetamol (18F), University of Pittsburgh/Uppsala Imanet||Approved in the US in October 2013; launch expected 2014. An EU approval decision is awaited|
|Florbetaben (18F), Piramal Healthcare||Awaiting US and EU approval decisions|
|NAV-4694, Navidea Biopharmaceuticals||Phase II data were positive; phase III development began in June 2013, with trial completion expected in late 2016|
Figure 4: Selected Abeta-Binding/18F-Based AD Diagnostic Agents
Alzheimer’s disease and its links to insulin pathways
Data demonstrating links between AD, insulin and inflammation has recently suggested that AD may be at root a metabolic disease linked to insulin resistance in the brain, with the Abeta plaques being symptoms of the condition rather than the cause. (See Figure 5.)
|Drug & Developer||Mechanism||Current Data and Status|
University of Washington/ Veterans Affairs Puget Sound Health Care System
|All insulin pathways||Promising data obtained in phase II; data from the phase II/III SNIFF trial in mild AD expected in 2014|
|Pioglitazone, Takeda Pharmaceutical/Eli Lilly||Insulin-sensitizing PPAR gamma agonist||Failed to show efficacy in phase II trial in mild to moderate AD; the phase III TOMMORROW trial for AD prevention in cognitively normal subjects at high risk of AD was initiated in August 2013 with data expected in 2019|
|MSDC-0160, Metabolic Solutions Development||Insulin-sensitizing, but only low PPAR gamma affinity||Phase II data showed the drug maintained glucose metabolism in brain regions associated with cognitive decline in mild AD. Further trials likely|
|Liraglutide, Novo Nordisk||GLP -1 analog||Lancaster University reported positive data from preclinical AD models. Imperial College London is to assess the drug in the phase IIb ELAD trial for mild AD, starting shortly and expected to complete in 2016. If successful, Novo Nordisk will consider phase III studies|
Figure 5: Insulin-Related Approaches to AD Treatment and Prevention
The changes in the Alzheimer’s disease field
In the last year, there have been a number of changes in the AD field, although there remains neither prevention, treatment nor delaying tactic for the disease. Setbacks came in the form of the three drugs (avagacestat, Gammagard and LY-2886721) that had reached late-stage trials being dropped from further development due to efficacy or safety issues. However, trials of three other agents (crenezumab, gantenerumab and solanezumab) are ongoing, and two further agents (Lu-AE58054 and MK-8931) have recently entered phase III development. Also promising is the initiation of the DIAN-TU, API, A4 and TOMMORROW trials that are looking for ways to prevent AD and will begin to provide data from 2016. For the diagnosis of AD, a second 18F-based Abeta imaging agent (flutemetamol (18F)) has been approved in the US, and a third (Neuraceq) is undergoing regulatory review. Furthermore, potential links between AD and insulin pathways continue to be explored, with a number of phase II or III trials in progress and preparation. Crucially though, AD remains a disease desperately in need of a cure.
Read more from the author Charlotte Jago on the latest developments in Alzheimer’s disease research.