The Ongoing Battle to Crack the Alzheimer’s Treatment Dilemma

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David H. Crean highlights R&D efforts and ongoing investments in Alzheimer’s disease treatments as we enter the month of June, brain awareness month.

 

Alzheimer’s disease is a complex chronic disease characterized biologically by the accumulation of extracellular protein plaques, neurofibrillary protein tangles, a loss of functional synaptic connections, and eventually complete loss of neurons. It is a type of brain disease, just as coronary artery disease is a type of heart disease. It is also a degenerative disease, meaning that it becomes worse with time. Alzheimer’s disease is thought to begin 20 years or more before symptoms arise, with small changes in the brain that are unnoticeable to the person affected. The loss of neuronal activity often begins in regions of the medial temporal lobe, an area deep inside the brain where long-term memory is consolidated. Clinically, it is a type of dementia characterized by progressive deterioration in cognition and memory, and impairment in the ability to carry out activities of daily living. Most cases of Alzheimer’s are diagnosed later in life (over the age of 65); however, Alzheimer’s can appear as early as 40 years of age. Because of this observation, the disease can be referred to as early-onset and late-onset Alzheimer’s. A detailed categorization of the disease progression includes a pre-symptomatic phase, a “prodromal stage” characterized by mild cognitive impairment (MCI), followed by mild, moderate, and severe stages of dementia.

 

Facts & Figures

The 2019 Alzheimer’s Disease Facts and Figures report from the Alzheimer’s Association highlights that Alzheimer’s disease comprises up to 80% of all diagnosed dementia, which affects 5.8 million people in the U.S. alone and costs the U.S. healthcare system $277 billion annually, with Medicare and Medicaid shouldering $186 billion (67%) of the total. While prevalence refers to existing cases of a disease in a population at a given time, incidence refers to new cases of a disease that develop in a given period of time in a defined population — in this case, the U.S. population age 65 or older. Incidence provides a measure of risk for developing a disease. According to one study using data from the Established Populations for Epidemiologic Study of the Elderly (EPESE), approximately 487,000 people age 65 or older will develop Alzheimer’s dementia in the United States in 2019. The growing Alzheimer’s disease epidemic is expected to affect more than 13.8 million people in the U.S. by 2050 and cost well over $1 trillion annually. Global estimates for dementia by 2050 suggest close to 152 million people with a cost at over $2 trillion annually.

As the population of the United States ages, Alzheimer’s is becoming a more common cause of death. Alzheimer’s disease is ranked as the sixth leading cause of death in the USA. Although deaths from other major causes have decreased significantly or remained approximately the same, official records indicate that deaths from Alzheimer’s disease have increased significantly. Between 2000 and 2017, the number of deaths from Alzheimer’s disease as recorded on death certificates has more than doubled, increasing 145 percent, while the number of deaths from the number one cause of death (heart disease) decreased 9 percent (2019 Alzheimer’s Disease Facts and Figures report). The long duration of illness before death contributes significantly to the public health impact of Alzheimer’s disease because much of that time is spent in a state of disability and dependence. Taken together, these statistics indicate that not only is Alzheimer’s disease responsible for the deaths of more and more Americans, but also that the disease is contributing to more and more cases of poor health and disability in the United States.

Total annual payments for health care, long-term care and hospice care for people with Alzheimer’s or other dementias are projected to increase from $290 billion in 2019 to more than $1.1 trillion in 2050 (in 2019 dollars). This dramatic rise includes four-fold increases both in government spending under Medicare and Medicaid and in out-of-pocket spending. While there are currently no treatments that prevent or cure Alzheimer’s disease, several groups of researchers have estimated the cost savings of future interventions that either slow the onset of dementia or reduce the symptoms. Researchers estimate that a treatment introduced in 2025 that delays the onset of Alzheimer’s by 5 years would reduce total health care payments 33 percent and out-of-pocket payments 44 percent in 2050. Overall, projections by several groups suggest that a treatment that prevents, cures or slows the progression of the disease could result in substantial savings to the U.S. health care system. Without changes to the structure of the U.S. health care system, however, access to new treatments for Alzheimer’s may be severely restricted by capacity constraints (source: Alzheimer’s Association).

 

Pathophysiology

The pathophysiology of Alzheimer’s appears to be achieving greater clarity and unravelling each day as researchers learn more, despite treatment options remaining elusive. Alzheimer’s is characterized by the presence of amyloid plaques (amyloid β) and neurofibrillary (tau) tangles, leading to the progressive loss of neurons and synapses in the cerebral cortex and certain subcortical regions.

The cause for most Alzheimer’s cases is still mostly unknown except for 1-5% of cases where genetic factors have been identified. APOE4 is the major genetic risk factor for Alzheimer’s. Various competing theories based on amyloid, tau, and neurovascular involvement have been postulated to explain the fundamental cause of the disease.

 

The Realities of Where Researchers are in the Hunt

Despite a colossal investment by biopharma industry in research and an expanding pipeline, no new Alzheimer’s drug has been approved in more than a decade. The year 2018 and early 2019 witnessed many high-profile clinical trial failures of late-stage candidates despite promising early-stage results. A recent 2019 report by BIO (Biotechnology Innovation Organization) highlights the enormous R&D efforts that are being made within the healthcare and life sciences industry toward diagnosis and treatment. Despite the many disheartening failures in the past few years that have been reported by a large number of biopharma companies looking to find a disease-modifying approach to tackle this complex disease, the pursuit to continue to progress our knowledge and find answers in tackling this disease lives on.

The R&D challenges with this disease are enormous and the level of investment and innovation is not where we need it to be to adequately address this growing public health crisis

Over the last decade, there has been significant progress in advancing our understanding of the biological mechanisms underlying Alzheimer’s disease. Despite this progress, there are only four active drugs on the market that treat symptoms of Alzheimer’s disease, such as mental alertness and depression. However, as of this writing, there are no disease-modifying therapeutics FDA approved for Alzheimer’s disease. Clinical development success for disease-modifying drug programs for Alzheimer’s has been difficult in late-stage trials, with no disease-modifying drugs moving beyond Phase III to FDA filing. Since the start of 2008, a total of 87 clinical-stage disease-modifying programs have been suspended and the probability of success in developing therapies for Alzheimer’s are lower than industry standard versus other therapeutic area indications. There are 74 clinical-stage programs with disease-modifying potential in Alzheimer’s disease. The drug candidates in these programs are attempting to stop, prevent, or slow the progression of Alzheimer’s disease using numerous strategies involving 30 distinct molecular targets.

IQVIA assembled the data demonstrating the slew of trial failures recorded over the years. Except for one good piece of news in 2014 — for a dementia drug, Namzaric — there’s nothing by way of an FDA approval going back to 2002, 17 years of failure and disaster, with Eli Lilly, Pfizer, J&J and others going over the amyloid beta cliff. Although there are many novel, innovative and disease modifying molecules that are being investigated for Alzheimer’s, around 200 candidates have been either abandoned in development or have failed in late-stage clinical trials. Many candidates that were under development are now deemed inactive because no further developments have been reported for the past 3 years. That’s made the big players leery of this field, but the prospect of being the only significant therapy on the market for millions of patients continues to fuel the drive toward something to throw against the disease. It’s the high-risk, high- reward equation that fuels activity.

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High Failure Rates

The development of Alzheimer’s drugs has been marred by a high failure rate. A study revealed that Alzheimer’s clinical trials fail at a rate of 99.6% compared to a failure rate of 81% for cancer drugs. Disease-modifying drugs aim to block progression of the disease by interfering with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and of intracellular neurofibrillary tangles, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. The approved drugs for symptomatic management are not so effective. The current Alzheimer’s clinical research stalemate has encouraged more physicians to recommend lifestyle modification as non-pharmacological alternatives for the disease management.

With the repeated failures in the past years in the class of anti-β-amyloid monoclonal antibodies and γ-secretase inhibitors, focus shifted towards alternate pathways such as β secretase/β-site amyloid precursor protein cleaving enzyme 1 (BACE-1). However, 2018 saw high-profile failures in clinical trials with BACE-1 inhibitors even in prodromal patients. Eight of the drugs, mostly disease-modifying therapies, on which hopes have been pinned based on promising early-stage results, failed in phase III trials in 2018 and early 2019. These products failed either due to interim futility analysis confirming no favorable risk/benefit ratio or drug/placebo difference, or due to unacceptable toxicity. Bottom line, developing Alzheimer’s drugs is a daunting task even for the top pharma companies and it is more impactful if the failure is so late at phase III.

 

Why Do the Alzheimer’s Trials Keep Failing?

Many explanations have been proposed and reviewed by IQVIA that try to explain failures of trials of disease-modifying drugs for Alzheimer’s. These include:

  • Alzheimer’s pathology is still a mystery and often the treatment too late
  • Amyloid hypothesis is under attack and in question
  • Are researcher’s using the appropriate clinical trial design?
  • Outdated standards in measuring endpoints

In an effort to make necessary changes in the way experimental drugs are testing for the disease, US regulators recognized the urgent need for new medical treatments for Alzheimer’s and proposed changes in requirements of dual-endpoint of cognition and function in its draft guidelines, removing an unnecessary barrier to testing Alzheimer’s drugs (March 2018). For trials testing stage 2 Alzheimer’s patients having biomarker evidence of the disease and subtle cognitive impairment, but no problems with function, the agency proposed to test only cognition as an endpoint. For trials evaluating stage 1 Alzheimer’s patients having no clinical symptoms of the disease, but having biomarker evidence of it, the agency proposed that improvements in relevant biomarkers could serve as a basis for accelerated drug approval.

 

Trends in Venture Investment and Clinical Trial Initiation in Alzheimer’s Disease

 

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As can be seen in the Figure above from the recent BIO Report, venture investment into U.S. companies with lead Alzheimer’s disease programs from 2008 to 2017 totaled $741 million. This report shows the venture investment trend is positive, but still significantly lower than other therapeutic areas such as cancer. Lead stage programs in Alzheimer’s disease are 16 times below oncology funding ($1.0 billion vs. $16.5 billion over the last decade). Nine companies with lead Alzheimer’s disease drugs were financed each year, on average. By comparison, there were 79 oncology companies financed each year, on average, suggesting that early-stage investors currently prioritize other disease areas, such as oncology, over Alzheimer’s disease. Using the broader Neurology disease area excluding pain, only $3.4 billion for Neurological diseases has been invested versus $12.2 billion for cancer.

 

Final Thoughts

Although clinical trials of many agents over a wide array of mechanisms of action are being conducted, more than a decade has passed since any of these drugs received approval from the US FDA for Alzheimer’s. The biopharma industry is exploring drugs acting on numerous targets and various mechanism of action. Diagnostic tools to detect the disease before it is too late to intervene are in development in parallel to therapeutic options. Although no drug has entered the market in the last 15 years and the trials are fraught with setbacks, every unsuccessful trial is a learning opportunity and takes us closer to the next truly transformational and successful disease-modifying Alzheimer’s drug that might be approved for the treatment of this incurable disease. Let’s continue to support the efforts of the research so that one day, we can witness the first patient to survive the disease.

 

Other Key Findings from BIO Report

Lack of Approved Drugs: There are currently no FDA-approved disease-modifying drugs for Alzheimer’s disease.

Poor R&D Success Rates: Clinical development success for disease-modifying drug programs for Alzheimer’s has been difficult in late-stage trials, with no disease-modifying drugs moving beyond Phase III to FDA filing. Since 2008, a total of 87 clinical-stage disease-modifying programs have been suspended.

Inconsistent Clinical Trial Initiations: Clinical trial starts for disease-modifying Alzheimer’s drugs have ranged from 11-21 trial starts per year since 2008, with no detectable trend. Phase III trial starts have been the least consistent, ranging from 0-5 per year.

Growing & Diverse R&D Pipeline: There are 74 clinical-stage programs with disease-modifying potential in Alzheimer’s disease. The drug candidates in these programs are attempting to stop, prevent, or slow the progression of Alzheimer’s disease using 10 different strategies involving 30 distinct molecular targets. Small biotech companies account for more than three-fourths of these clinical programs.

 

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Disclosure

Objective Capital Partners is a leading investment banking advisory firm whose Principals have collectively engaged in more than 500 successful transactions serving the transaction needs of investment banking, private equity, and business ownership experience that enables Objective Capital Partners to provide large enterprise caliber investment banking services to companies with annual revenues up to $500MM. Services include sale transactions, equity and debt capital raises and comprehensive advisory services. The firm’s industry expertise includes healthcare, life sciences, business services, technology, and consumer products. Additional information on Objective Capital Partners is available at www.objectivecp.com.

This article is provided for informational purposes only and does not constitute an offer, invitation or recommendation to buy, sell, subscribe for or issue any securities. Securities and investment banking services are offered through BA Securities, LLC Member FINRA, SIPC. David H. Crean is a Registered Representative for BA Securities. Objective Capital Partners and BA Securities are separate and unaffiliated entities. While the information provided herein is believed to be accurate and reliable, Objective Capital Partners and BA Securities, LLC makes no representations or warranties, expressed or implied, as to the accuracy or completeness of such information. All information contained herein is preliminary, limited and subject to completion, correction or amendment. It should not be construed as investment, legal, or tax advice and may not be reproduced or distributed to any person.

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