As I detailed in a previous article, the insidious effects of Alzheimer’s disease (AD) are not only restrained to the patients who struggle with it on a daily basis; the effects have placed a malignant burden on the global healthcare system as well. In recent years, drug-development failures have coincided with limited success.
“I have not failed. I’ve just found 10,000 ways that won’t work.” – Thomas A. Edison
Failure is part of success. Clinical research in the past has become akin to this notion and has continuously validated it. As you will see in this article, Alzheimer’s drug-development failures are being used as bricks to build an edifice of treatment for this enigmatic disease. And once regulatory and financial obstacles are overcome, researchers will be able hasten construction.
The incentive for non-risk-averse pharmaceutical companies to develop a treatment or cure for Alzheimer’s is clear, winning FDA approval in this realm is like receiving a golden lottery ticket. According to AstraZeneca, an effective FDA approved Alzheimer’s therapy could bring upwards of $5 billion with the cost of drug development totaling around 1% of that.
The current AD drug-development market is characterized by:
- Increasing awareness and prevalence of neurodegenerative diseases
- Increasing government and private sector investments
- Increasing prevalence of M&As and collaborations
- Lack of longitudinal studies
- Lack of unequivocal mechanism knowledge
- Lack of concrete efficacy guidelines
- Dissuading regulations (hopefully this will soon change)
- Expensive clinical trials that carry high risk (creating an entry barrier)
Presently, there are five FDA approved drugs for AD patients, encompassing two types of medications, which include: cholinesterase inhibitors and NMDA receptor antagonists. Both of these regulate neurotransmitter release important to memory function. These therapies provide minimal symptom relief for a short period of time (typically 6 months) and are only effective in roughly half of people who take them. Moreover, there is no evidence that they treat the underlying disease or slow down its progression. From an economic perspective these drugs only increase the financial burden on society, so it’s pivotal that disease-modifying drugs are discovered.
Prior to the setback announced by Roche last week, there have been prodigious advances in drug-development. Currently the majority of candidate drug trials target specific mechanisms of AD progression, including: Aβ accumulation, tau peptide collapse, inflammation, and insulin resistance. There are hundreds of ongoing trials, but for the purpose of this article I will only highlight the most promising investment-rich candidate drug trials, along with their sponsoring company.
Eli Lilly has remained optimistic in the face of adversity, and rightly so. The tempest that the company has endured over the years, has poised them for their latest endeavors in pursuit of an elusive AD treatment. Eli is accustomed to failures: in 2010 its drug semagacestat, a gamma-secretase therapy, was scrubbed after it harmed patients who took it. In 2012, solanezumab, an anti-Aβ drug was reluctantly deemed a failure after showing no benefit (then failed a second time). And finally last year its BACE inhibitor drug, LY2886721, was scrapped due to adverse effects on patient’s liver.
Despite suffering these morale-crushing blows, Eli has learned from its mistakes. Post-hoc analysis on the solanezumab trial failure reviled the lack of functional benefit on patients (that resulted in its termination), overshadowed its benefit on cognition in a subgroup of patients with only mid-Alzheimer’s related dementia (prodromal). These results add to the idea that treatment for AD needs to begin in the prodromal stage, and suggests the need to find a widely accepted way to measure cognitive efficacy. This drug is a monoclonal antibody that is bioengineered to bind to soluble Aβ and get rid of it before it starts to clump into insoluble plaques. The next chapter in the solanezumab saga is set to begin within a few months in a Phase III study titled, The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (“A4” for short), and treatment outcomes will be measured by cognition changes rather than functional changes.
Another sign of Eli Lilly’s vigor is reflected in its risky campaign involving the previously scuttled BACE inhibitor drug, LY3314814 or AZD3293. BACE (aka: beta-secretase 1 or beta-site amyloid precursor protein cleaving enzyme 1) is an enzyme that catalyzes the cleavage of amyloid precursor protein (APP), resulting in Aβ accumulation (see figure 1). So inhibiting BACE is expected to impede plaque formation by blocking Aβ accumulation in the first place. Hope for this drug was renewed in September when AstraZeneca partnered with Eli Lilly to co-develop the drug, citing phase I studies that “Significantly and dose-dependently reduced levels of Aβ of (prodromal) patients,” according to a press release. The drug is in a phase II/III trial called AMARANTH; it enrolled its first patient on December 1st of this year.
Hoffmann-La Roche Ltd.
When news broke that Roche and its partner on the trial, MorphoSys, were discontinuing their phase III study on the anti-Aβ medicine gantenerumab, an inverse relationship emerged between stock prices and skeptics of companies pursuing anti-Aβ candidate drugs. Since this was the first study to investigate an anti-Aβ medicine on prodromal AD patients, doubt has been raised about similar therapeutic approaches; however, that logic isn’t completely justified.
Gantenerumab is a monoclonal antibody that binds to the N-terminus of fibrillar Aβ, which is similar to the Pfizer’s scrubbed anti-amyloid drug, bapineuzumab. This is actually the silver lining to the failure; it targets the insoluble plaques, whereas other drugs, like solanezumab, target the soluble oligomeric Aβ deposits, which are seen in pre-symptomatic patients.
Even though Roche also recently terminated its BACE inhibitor candidate drug (for safety concerns), the company met its newest demise with optimism; citing it’s two other candidate drugs for AD that are both in phase II development. One of them is another monoclonal antibody for Aβ, called crenezumab, but it is different from gantenerumab in that it targets soluble deposits. Results from one study of cenezumab, released in July, showed little benefit for late-stage AD patients but significant cognition benefits for a subgroup of high-dose prodromal AD patients; analogous to those of the initial solanezumab study. These results prompted a 5-year NIH-backed $100 million trial on the drug, which began in 2013.
Their other candidate is called RG1577, which is a monomine oxidase-B (MAOB) inhibitor. MAOB is a mitochondrial enzyme that inactivates dopamine release and generates hydrogen peroxide and thereby produces ROS radicals, which lead to oxidative stress. This trial is set to complete next year.
Earlier this month Cambridge, MA based firm, Biogen
Idec, announced that the trial for its candidate drug, aducanumab (aka BIIB037), is being promoted to phase III. BIIB037 is a monoclonal anti-Aβ drug that showed both reduced amyloid levels in the brain and positive effects on cognition compared with a placebo in a dose and time dependent manner, after a 54-week phase I trial. These results are very surprising considering other phase III anti-Aβ drugs have failed to show both of these effects, especially since this phase I study was primarily concerned with accessing safety. This effect may be explained by the fact that this drug targets yet another form of the protein, insoluble fibrillar Aβ, but not a specific terminus (unlike Roche’s gantenerumab failure). How significantly the drug actually helped, what stage of the disease the patients were in, and whether or not its safe won’t be known until the company releases the trial data. It should also be noted that phase I studies are small-scale studies, so this ‘good’ news should be approached with cautious optimism as the phase III trial get underway and is set to complete by 2016. In addition, Biogen partnered with Eisai Co. Ltd. in March of this year to study another anti-Aβ antibody called, BAN2401, which targets soluble Aβ and is currently in phase II trials.
Biogen & Eisai are also currently co-developing two other candidates for AD: a BACE-inhibitor (E2609) and an anti-tau monoclonal anti-body. Although Biogen’s multi-target approach coincides with a significant R&D investment, this spending, combined with a diversified pipeline is a harbinger of a prudent drug development strategy and a boon for investors.
Other Therapeutic Approaches
As knowledge about the pathophysiologic process behind AD grows, treatment strategies have also targeted various processes involved in the development of AD. Here are some highlights:
- Though still in the very early stages, drugs aimed at “fixing” protein-folding defects at the cellular level could provide a novel target. The biotech startup at the forefront of this movement is called Yumanity Therapeutics, which was founded two weeks ago.
- A recent in vitro study published in the Journal of Alzheimer’s Disease, found that low levels of THC (contained in marijuana) reduced the production of soluble Aβ and prevented abnormal accumulation of the protein. This study corroborates the results of previous studies on THC and AD.
Drugs used in other conditions
- An increasing body of evidence suggests that insulin resistance contributes to AD. ‘Repurposed’ diabetes drugs have proven to be effective in slowing the rate of structural damage to the brain.
- Anticancer drugs that stabilize microtubules (Ex: epotholine D) may help to reduce tau-protein induced damage.
- Sildenafil (Viagra) and Tadalafil (Cialis) act as phosphodiesterase type 5 (PDE5) inhibitors, which showed reversal of hippocampal Aβ induced synaptic function damage in a 2013 AD animal-model study.
- Gemfibrozil, a drug for the treatment of hyperlipidemia, is currently being studied for its ability to increase miR-107 that down-regulates BACE1, thus preventing the cleavage of APP.
- Exercise & diet
- This past summer, the results of a randomized controlled Finnish study (FINGER study) revealed evidence that maintaining a healthy diet and exercising prevents structural and functional brain changes associated with cognitive decline. Exercising produces ketone bodies, as a byproduct of breaking down fat and glucose. A 2013 NIA-funded animal study showed that a ketone-rich diet improved learning and memory ability as well as reducing levels of Aβ and tau.
- New research from the National Runners and Walkers’ Health Study indicated that running over 15.3 miles per week lowers AD risk by 40% compared with someone who runs less than 4.6 miles per week.
- In addition to exercise a recent UCLA study showed that increasing omega 3 fatty acid levels by increasing sleep and vitamin D levels, regulating insulin level through diet, and reducing stress all significantly reversed AD symptoms in patients.
- Curcumin (a compound found in turmeric plants)
- There has been inconsistent results about its benefit for AD patients, but this past month the FDA granted a patent to Arjuna Natural Extracts Ltd. for their turmeric extract combination, which proved to be beneficial in preventing cognitive decline and reducing Aβ plaques in a series of human clinical trials.
- Red wine
- Preclinical studies have shown that resveratrol, an antioxidant compound found in red wine and chocolate, may protect the health of neurons by directly activating enzymes known as sirtuins.
- Drinking 3-5 cups of coffee per day may help protect against AD. According to a report by the Institute for Scientific Information on Coffee, caffeine and polyphenols are the agents in coffee responsible for preventing Aβ and NFT accumulation and reducing inflammation in the brain.
- Exercise & diet
“Change is the law in life. And those who look only to the past or present are certain to miss the future.” – John F. Kennedy
The turbulent past of AD drug-development shouldn’t be taken as a reflection on its future. Transcending the current regulatory, financial, and scientific hurdles will streamline AD drug-development. Given the rapid pace of AD innovation in the past two years, it is not absurd to believe that they will be overcome.
Relation to other diseases
Insights and influence can be gleaned from the chronicles of treatment paradigms in other enigmatic diseases. A few examples are cardiovascular disease, Cancer, Rheumatoid Arthritis (RA), and stroke. In all of these conditions secondary prevention and early treatment are the most effective ways to mitigate risk. For example, prodromal treatment to prevent amyloid plaques (and thus AD) can be juxtaposed to using statins to lower cholesterol levels to prevent a heart attack; it makes no sense to begin lowering cholesterol after you have a heart attack. Another example comes from RA treatment, where focus has shifted from managing symptoms to aiming for disease remission. The value of early intervention in RA treatment was recognized in 2012 by the American College of Rheumatology, which specifically recommended more “aggressive earlier treatments.”
In all these conditions, the significant progress made stems from the culmination of modest developments; in other words, the true value of a therapy often is not apparent in the initial clinical trial data submitted for FDA approval. This reinforces the notion that the FDA needs to hasten proposed regulation changes for AD treatment approval. For example in Cancer drug-development, the FDA has approved drugs based off of initial surrogate endpoints showing treatment response on the cellular level, but no overt functional benefits. Citing approval based on lack of effective treatments outweighing the remaining ambiguity of the drug’s overall clinical significance. As time progressed and long-term data became available, the full value of these drugs became apparent; survivorship in those treated with the experimental drug increased dramatically. The logic used to approve these drugs seems to align with the imminent need for effective AD drugs; however, an apt test for AD drug efficacy still needs to be developed. Currently, commonly used endpoint markers include: ADAS-cog, ADL, and CGIC. Novel brain imaging techniques that target tau protein tangles may prove to be an adequate test.
Combination therapy is another treatment method that needs to be further explored in AD. Again, various deleterious diseases have shown combination therapy efficacy. Certain types of cancers respond significantly better to use of a drug combined with chemotherapy or another drug. This strategy is important because it can allow for patients to tolerate highly toxic drugs by managing dose-limiting adverse side effects and utilizing multiple mechanisms of action. Employing this strategy with BACE-inhibitors could help prevent the liver toxicity that was seen in Eli Lilly’s halted trial. Using a cocktail of drugs to combat multiple mechanisms of AD, such as Aβ accumulation and tau protein collapse could also result in significant clinical benefit. It will be interesting to see if companies, like Biogen, explore this type of therapy using the three drugs in their AD pipeline.
Lastly, it is imperative that AD drug-development isn’t stymied by industry abandonment. The aforementioned trials and tribulations of candidate anti-Aβ drugs have allowed researchers to hone in on defining the precise deleterious Aβ species and picking out its corresponding anti-body. If the current phase III failure rate keeps up it will surely result in reduced investments, thus hindering progress. To ensure this doesn’t happen, policies need to be adjusted and trial designs need to be fixed. The recent curtailing of stroke therapies in the pharmaceutical industry can serve as an illustration of how to limit failures for AD drug-development. A review on stroke therapies by Victoria O’Collins and colleagues notes that the high attrition rate (99%) is due to lack of alignment of preclinical studies and human clinical trails design. Luckily for AD, there is uniformity in regards to its pathology (or lack-thereof) which allows preclinical studies to better predict clinical success. If pharmaceutical companies adhere to this alignment when designing preclinical studies, the rate of negative trials could be reduced.
Similar to the aim of combination therapies, drugs that use an all-encompassing symptom approach, might provide the key to unlock therapy and prevention for AD. One example of this type of treatment is using a synthetic form of the hormone Erythropoietin (EPO) (I previously explored its potential clinical significance here). The major issue with these are the high risk for off-target effects, but utilizing different methods to administer them could reduce these effects.
In the past two decades, the dramatic increase in survivorship in various diseases due to innovation should provide hope for those suffering from AD and those at risk. With continued and uninterrupted progress, AD surely seems to be headed down a similar path.
*If you would like to help change the course of Alzheimer’s by participating in a clinical trial or donate to AD research, click here.
Part 4 of this series can be viewed here: The numbers behind the facts
Alzheimer’s Association, “Factsheet,” (March 2012) Retrieved from http://www.alz.org/documents_custom/2012_facts_figures_
Alzheimer’s Association (2014) Research Advances from 2014 Alzheimer’s Association International Conference (press release). Retrieved from http://www.alz.org/aaic/releases_2014/mon-730pm-finger.asp
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National Institutes of Health, National Institute on Aging, Alzheimer’s Disease Education and Referral Center (2011) Alzheimer’s Disease: Unraveling the Mystery: The Search for New Treatments. Retrieved from http://www.nia.nih.gov/alzheimers/publication/part-3-ad-research-better-questions-new-answers/search-new-treatments
O’Collins VE et al. (2006) 1,026 Experimental Treatments in Acute Stoke. Annals of Neurology 59(3): 467-77. doi: 10.1002/ana.20741
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Phrma (2012) Researching Alzheimer’s Medicines: Setbacks and Stepping Stones. Phrma.org: Profiles and Reports. Retrieved from http://www.phrma.org/sites/default/files/pdf/alzheimersetbacksreportfinal912.pdf
Williams PT (2014) Lower Risk of Alzheimer’s Disease Mortality with excercise, Statin, and Fruit Intake. J Alzheimer’s Disease. doi:10.3233/JAD-141929