Stopping Alzheimer’s with a Preventative Vaccine?

AS BABY BOOMERS age, the number of people with Alzheimer’s disease (AD) will skyrocket. According to the Alzheimer’s Association, AD is the sixth-leading cause of death in the United States. Currently, 5.8 million Americans are living with AD, and that number is projected to rise to nearly 14 million by 2050.¹ And, because the rate of AD doubles every five years beyond age 65, the National Institute on Aging (NIA) says the number of people who will develop AD will exponentially increase.² These alarming statistics have prompted researchers to refocus their research on AD from drugs to vaccines with the hope to prevent, cure or slow it.

AD is a neurodegenerative brain disorder characterized by memory loss, cognitive impairment and functional decline. It is a very complex, multifaceted disease with no known singular cause. But, researchers have identified many potential causes of AD, including genetic, biological, lifestyle, environmental and comorbid conditions. Although AD symptoms typically present in people aged 65 years and older, it is suspected to be present up to 20 years prior to the onset of symptoms. After symptoms appear, AD can last anywhere from three or four years up to 10 years, depending on the time of diagnosis. AD is always fatal.

It was first described by Alois Alzheimer, MD, in 1906, but no progress was made on AD until 1974, when NIA was founded. NIA leads the nation in AD research by funding extramural research at universities and medical centers in the U.S. and around the world. Since NIA was formed, the AD field has progressed from the assumption the disease is a natural form of aging to a full-blown war on preventing and treating AD.³

Based on current vaccine research, two camps have emerged with opposing theories regarding the causes and symptoms of AD: amyloidists and tauists. Amyloidists believe plaques and tangles are the causes of AD; tauists believe plaques and tangles are the symptoms of AD.

According to Canaccord Genuity, a global, full-service investment banking and financial services company, there are currently 70 products in the AD clinical development pipeline of which 42 (60 percent) are small molecules and 28 (40 percent) are biologics. Biologics dominate the amyloid-beta (11 of 16; 69 percent) and anti-tau (9 of 13; 69 percent) approaches. Of these products, 16 rely on the amyloid-beta hypothesis and 13 rely on the anti-tau hypothesis. The amyloid beta-based products are farther along in the pipeline than the anti-tau products since the latter are relatively young. However, the amyloid-beta hypothesis is hanging by a thread after some recent drug failures, but it remains the single largest category in terms of the number of products still using that approach. But, now, there are signs this may change going forward.⁴

Following are some of the most promising AD biologic vaccine research projects:

AADvac-1

Axon Neuroscience has developed AADvac-1, an active immunotherapy vaccine that stimulates the patient’s immune system to generate specific antibodies against diseased forms of the tau protein and, thus, protects the brain from neurodegeneration. AADvac-1 is intended to be a disease-modifying treatment for AD and aims to halt its progress.⁵

A first-in-man Phase I clinical trial was conducted with the vaccine from May 2013 to March 2015 on 30 patients with mild to moderate AD. The trial found the vaccine increased antibody titers with repeat injections, and mean Alzheimer’s Disease Assessment Scale cognitive (ADAS-cog) scores remained stable over a six-month period. In addition, it had a favorable safety profile and excellent immunogenicity.⁶

In March 2016, a 24-month Phase II safety trial to evaluate the vaccine began to enroll 185 patients with mild to moderate AD. This trial is not trying to ascertain the presence of amyloid or tau pathology at study entry. Rather, it is comparing eight subcutaneous injections of 40 micrograms of the vaccine with the adjuvant aluminum hydroxide to placebo. The primary outcome is safety; secondary outcomes include cognitive and clinical batteries, as well as a measure of immunogenicity. It was slated to run until February 2019, but no results have yet been published.⁶

In June 2017, Axon Neuroscience started a two-year, open-label Phase I pilot trial of two doses of AADvac-1 in 30 people with nonfluent/agrammatic variant primary progressive aphasia between the ages of 18 years and 85 years. Participants are receiving either 40 or 160 micrograms of AADvac-1 in a series of six subcutaneous injections spaced six weeks apart, followed by five booster shots spaced 13 weeks apart. The trial will continue to run at three sites in Germany until July 2020.⁶

ABvac40

Araclon Biotech is developing an investigational, active immunotherapy vaccine called ABvac40. This vaccine is currently being evaluated in a Phase II multicenter, randomized, doubleblind, placebo-controlled, 24-month study to investigate the safety, tolerability and immune response of repeated subcutaneous injections in patients with amnestic mild cognitive impairment or very mild AD. The trial, which started recruiting in December 2017, is also evaluating responses at both the cognitive and molecular levels, providing the first data regarding a possible clinical impact. Previous to this trial, the safety and tolerability of ABvac40 was evaluated in a Phase I trial in which the vaccine demonstrated a good safety and tolerability profile. While this Phase I blinded study did not evaluate the vaccine’s efficacy, it produced an immune response in more than 87 percent of patients who received it.⁷

According to Jose Terencio, CEO of Araclon Biotech, “The innovative feature of this vaccine is the use of the C-terminus of the amyloid-β (Aβ) 40 peptide as an immunogen, a differentiated approach compared with other products in clinical development that are focused on Aβ 42 peptide. Aβ 40 peptide has been associated with plaque initiation and vascular amyloid deposition.”

ACI-24 and ACI-35

AC Immune is currently developing two promising vaccine candidates: ACI-24 and ACI-35.

ACI-24 is a liposomal therapeutic anti-amyloid vaccine. In preclinical research, data demonstrated significant activity in plaque reduction and memory restoration. And, the vaccine had a favorable safety profile, characterized by a lack of observed local inflammation and a mechanism of action independent of inflammatory T cells. The Phase I/IIa study is complete, and results are scheduled to be published in 2019.

A Phase II study of ACI-24 started in August 2018 to assess the vaccine’s safety, tolerability, immunogenicity and target engagement of the vaccine’s formulations in patients with mild AD. This trial seeks to confirm the positive trends on amyloid PET imaging observed in the previous Phase I/IIa study.⁸

ACI-35 is a liposomal therapeutic anti-tau vaccine. In preclinical testing in patients with mild to moderate AD, the vaccine induced an antibody response that was highly specific to misfolded and phosphorylated tau, which resulted in a significant reduction of phosphorylated tau and an improvement in cognitive clinical parameters. The PhaseIb study was considered safe and well-tolerated with no events related to central nervous center inflammation.

A Phase Ib/IIa study was announced in August. Based on the results of the Phase Ib study, in which a T-cell independent antibody response was indicated but lacked the boosting response desired for an optimal long-term and potentially preventive application, a new generation of the anti-tau vaccine was developed that demonstrated a high and boostable antibody response, which will be tested in this study.⁸

According to Andrea Pfeifer, CEO of AC Immune, “These two promising vaccine candidates were developed using the active immunization approach of our proprietary SupraAntigen vaccine discovery platform. This, along with the Morphomer small molecule discovery platform, forms the foundation of AC Immune’s broad and robust pipeline. AC Immune’s vaccines target AD through active immunization, where the immune system is stimulated to make its own antibodies against pathological proteins. The advantages of the SupraAntigen platform include a high selectivity for conformational targets and a favorable safety profile due to a T-cell independent mechanism of action, which does not trigger T-cell correlated inflammation. We are looking forward to further developing ACI-24 and ACI-35 through clinical trials, building on the promising results thus far.”

CAD106

Novartis Pharmaceuticals Corp. is developing a vaccine called CAD106 designed to stimulate the production of antibodies against beta-amyloid while avoiding inflammatory T-cell activation. CAD106 is composed of a short fragment of beta-amyloid that includes only the amino acids 1 to 6. It is hoped the antibody response triggered by the vaccine will break down beta-amyloid plaques in a patient’s brain and prevent new plaques from forming. Preclinical evidence gathered in animal studies suggests CAD106 can reduce beta-amyloid accumulation in the brain by inducing antibodies that interfere with beta-amyloid deposits and by binding to beta-amyloid aggregates.

Results of a Phase I study showed that, in people with mild to moderate AD, CAD106 induced titers that met prespecified responder criteria for an immune response while being generally safe and well-tolerated. Results of a Phase II study indicated antibody maturation and continued safety.

In November 2015, Novartis embarked on a Phase II/III study, called the Generation Study. This study is currently enrolling participants at sites across the U.S., Canada and Europe to test if CAD106 and another investigative medication, CNP520 from Amgen, can prevent Alzheimer’s in people ages 60 years to 75 years who are cognitively healthy but have two APOE4 genes. APOE4 is a variant of the APOE gene found in a number of Alzheimer’s patients. People with two copies of the APOE4 gene variant are considered to be at high risk of developing mild cognitive impairment (a slight decline in cognitive ability, including thinking and memory skills) and/or dementia due to AD. One part of the study will compare 430 individuals given CAD106 as an injection to 260 individuals who will receive a placebo; another will compare 390 people treated with oral CNP520 against a placebo. The study will follow participants for at least 60 months (five years) and up to 96 months (eight years), and is expected to conclude in May 2024.^9,10

According to Antonio Ligi, director of global external communications at Novartis, “We have recruited a sufficient number of subjects (65) for the CAD106 cohort to evaluate the effects on amyloid in the brain. We expect to conduct this assessment after two years of treatment at the latest. This is expected to take place in 2020. In parallel, we are working with Banner Alzheimer’s Instituteto evaluate whether there are further development options for CAD106.”

DNA AB42

Scientists at the University of Texas Southwestern Peter O’Donnell Jr. Brain Institute led by Roger Rosenberg, MD, and Doris Lambracht-Washington, PhD, have developed a DNA vaccine called DNA AB42 that is on a short list of promising antibody treatments aimed at protecting against both types of proteins that kill brain cells as they spread in deadly plaques and tangles on the brains of AD patients. The idea for the vaccine was to start with DNA coding for amyloid and inject it into the skin rather than the muscle to produce a different kind of immune response. The injected skin cells make a three-molecule chain of beta-amyloid (AB42), and the body responds by producing antibodies that inhibit the buildup of amyloid and, indirectly, also of tau.¹¹

The latest study, which consisted of four cohorts of between 15 and 24 mice each, showed a 40 percent reduction of Aβ 42 peptide and a 25 percent to 50 percent reduction of total tau and different phosphorylated tau molecules in mice compared with nonimmunized control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase activation. The vaccine did not induce inflammatory T-cell responses.¹²

One strategy still being tested for clinical benefits involves producing the antibodies in the lab and injecting them into the body. Allowing the body to produce its own antibodies through active immunization would be the preferable strategy since the vaccine would be more accessible and less expensive. It also produces a wider variety of antibody types than the preformed antibodies containing only one specific antibody.¹¹

According to Dr. Rosenberg, “The DNA AB42 vaccine differentiates itself from other AD vaccines currently being researched in that it targets both amyloid and tau, it elicits a different immune response that might be safe for humans, and it produces its own antibodies through active immunization. I’m hopeful this vaccine can prevent or slow the progression of AD, and plans are now underway to obtain funding to test it in humans.”

UB-311

United Neuroscience is developing an anti-amyloid endobody vaccine called UB-311. This synthetic peptide vaccine couples a helper T-cell epitope designed with United Biomedical’s UBITh platform to the amino acids 1-14 in the beta amyloid protein, packaged in a proprietary delivery system. The approach aims to stimulate a T-helper type 2 regulatory immune response over a Thelper type 1 pro-inflammatory response, and to avoid cross-reactivity with similar endogenous antigens.¹³

A peer-reviewed paper on preclinical studies in small animals, baboons and macaques reported the vaccine generated N-terminal anti-amyloid antibodies, which neutralized amyloid toxicity and promoted plaque clearance. The paper also claimed the vaccine evoked no anti-amyloid cellular responses in a transgenic mouse model for AD, and both acute and chronic dosing were safe and well-tolerated in cynomolgus macaques.

In a Phase I clinical trial, the UB-311 vaccine was tested on patients with mild to moderate AD to determine safety, tolerability and immunogenicity. Results concluded the vaccine was safe, well-tolerated and produced a specific antibody response in all participants tested. In a Phase II clinical trial, patients with a clinical diagnosis of mild AD were assessed for the primary outcomes of safety, tolerability and immunogenicity and the secondary outcomes of cognitive, functional, global and neuropsychiatric.¹⁴ Results showed UB-311 generated antibodies to specific beta-amyloid peptides and fibrils, and there was no decrease in antibody levels in patients who were older. Results also showed PET imaging of beta-amyloid clumps and genetic screening for the APOE4 gene can help identify people with mild cases of AD.¹⁵ In addition, results of a top-line Phase IIa study showed UB-311 met the primary aims of safety and immunogenicity with a 96 percent response rate.¹⁶

A Research Paradigm Shift?

Unfortunately, as promising as the results of these vaccines sound, many in the field are not convinced all or even any of these AD vaccines will be effective for humans. To date, there has not been a single vaccine that either targets the toxic proteins amyloid or tau that has made it beyond a Phase III clinical trial. In fact, a recent study found “the attrition rate for AD treatment is high, with 72 percent of agents failing in Phase I, 92 percent failing in Phase II and 98 percent failing in Phase III in the period observed [from 2002 to 2012].” Further, “the failure rate since 2002 (excluding agents currently in Phase III) is 99.6 percent.”¹⁷

What’s needed in AD research is a paradigm shift, says Zaven Khachaturian, former director of the Office of Alzheimer’s Research at the National Institutes of Health, former director of the Division of Neuroscience at NIA, and now senior science advisor of the Alzheimer’s Association, Editor-in-Chief of Alzheimer’s & Dementia, the journal of the Alzheimer’s Association, and president of the Campaign to Prevent Alzheimer’s Disease by 2020. “The current research on Alzheimer’s disease, based on current prevailing ideas, theories, paradigms and promising leads, have not yielded any positive results in the last 40 years. The problem is that this is a very complex disease, and this field does not have any single theory that encompasses all of the well-documented facts about the spectrum of Alzheimer’s disease. Therefore, novel research projects need to be developed to find a primary intervention that will reverse, prevent or cure Alzheimer’s disease.”

In the current approach to conducting AD research, Khachaturian says, “The traditional approach, based on reductionistic logic, to untangle the complexity of a biological system, is not adequate by itself to explain the behavior of the higher levels of organization of the system.” In addition, says Khachaturian, novel approaches to conducting AD research are needed to discover new, novel primary interventions: “Current models and/or modeling systems used to understand the complex neurobiological mechanism that underlie the neurodegenerative processes associated with dementia-Alzheimer syndrome are not adequate for developing effective treatments. There is a need for new or different modeling systems that incorporate concepts derived from systems theory.”¹⁸

“After 40 years of consistent therapy development failures, I am skeptical about any positive reports based on early preliminary animal studies or early clinical trials. There have been too many promising ideas that did not come to fruition. However, I remain optimistic about any potential promising interventions, pending successful demonstration of efficacy in a well-powered and controlled clinical trial,” adds Khachaturian.

Until the crucial missing piece of the AD puzzleis found, it could be several years or even decades before a vaccine is developed that will prevent, cure or slow the progression of this fatal disease.