Human and financial costs of Alzheimer’s disease are growing rapidly as the population ages, but future treatments to slow or halt the disease have been disappointing as trial outcomes in the past five years have been not so encouraging. Pharmacoeconomic data supporting the use of expensive disease-modifying therapies will be an additive burden on the companies while going for reimbursement for their agents. Consequently, major pharma companies are slowing down the search for new treatments after series of failures of high expectation drugs.
Major failures cover Elan’s AN1792, Axonyx’ phenserine, Myriad Genetics’ Flurizan, and Eli Lilly’s semagacestat. The questions that are raised after having additions every year to the failed list: Is it the need of the hour to have sufficient supporting data in hand before going in for Phase III trials? Or we collectively need significant improvements at all stages be it pathological, clinical or sensitive diagnostics? There is a basic challenge that lies with the current diagnostics that they are not susceptible to early stage detection of the disease.
Drugmakers had put their money on Beta amyloid hypothesis but looking at recent Phase III blowups namely bapineuzumab and solanezumab (with the data that we have on date), the Beta amyloid story is in deep question. Amyloid beta is the main component of deposits found in the brains of patients with Alzheimer’s disease. The Amyloid hypothesis is that there is a fault with the over production of beta amyloid or with the mechanism that usually clears it from the brain, or possibly both. Despite the buzz around the Amyloid hypothesis, it remains disappointing and today experts have challenged the whole idea of targeting the amyloid cascade.
The number of Phase III emerging therapies is limited at present; some of the expected entries into Phase III include Elan/Transition Therapeutics’ Aβ-aggregation inhibitor ELND-005, and GlaxoSmithKline’s serotonin receptor antagonist SB-742457. There are at least a dozen different approaches, but drug developers are focusing upon beta-amyloid plaque inhibitors and amyloid synthesis inhibitors. Cholinesterase inhibitors offer some help in treating cognitive and global functioning, the N-methyl-d-aspartate (NMDA) antagonist is similarly effective alone or in combination with cholinesterase inhibitors in moderate to severe stages of the disease. Recent insights into the pathophysiology of AD have led to promising investigational therapies, including the development of γ- and β-secretase inhibitors, tau therapies as well as active and passive immunization against the amyloid β-protein. Moving forward companies are targeting some novel MOAs for e.g. Lipoprotein-associated phopholipase A2 (Lp-PLA2) inhibitor, Cathepsin S inhibitor etc.
Pharmaceutical manufacturers worldwide have been cutting back in the recession, but neuroscience has been affected strongly, with AstraZeneca, Pfizer, Merck, Sanofi, Novartis and GlaxoSmithKline all downsizing their European departments. AstraZeneca had a very large neuroscience group with some 300 scientists. It is reducing that to a team of 40, who will act as a virtual team – not doing their own research but monitoring developments and forging links with other companies. Elan had announced plan to Spin-Off Discovery Science and Neotope Biosciences to shareholders within a week of discontinuation of Phase 3 Development of Bapineuzumab Intravenous (IV) in Alzheimer’s disease. With drug trials costing up to $1 billion and no guarantee of success, companies – including Pfizer and AstraZeneca – are increasingly opting for simpler projects with more chance of yielding a marketable drug.
The area of AD requires thinking in terms of funding and how to enable an atmosphere to continue developing drugs:
- Perhaps the answer lies somewhere in sharing “Benefit and Risk (Cost)” among different companies so as to continue developing drugs for AD with multiple stakeholders
- Incentives can be offered in Patent coverage
- FDA, EMEA can collaborate more closely with drug developing companies
Recently FDA has shown inclination to loosen the rules for approving new treatments for Alzheimer’s disease. FDA has said drugs can be considered for approval if they show to better at very early stage of disease on their performance in memory or reasoning tests, even before they developed any obvious impairments. Companies would now aim to target at a very early stage of the disease, which could be studied with cognitive tests. Those with mild symptoms could be evaluated by combined test of function and cognition. Later this year, Lilly will start a new test of solanezumab (which failed in mixed group of patients) in subjects with mild symptoms. Researchers found that if they looked only at memory tests and only at patients with mild disease, it seemed to benefit them. Genentech is also planning a study of Gantenerumab in people who have no symptoms, but have a gene mutation that virtually guarantees they will get Alzheimer’s eventually. F.D.A. would also expect that companies to study the drugs after they are on the market to show they actually benefited patients. There is significantly large unmet medical need for Alzheimer’s treatments and millions are looking forward to actions of different stakeholders. Aricept sales are around $4 billion even when it’s acting only on symptoms. Needless to say a disease modifying therapy will be an attractive opportunity and a large market.