Emerging amyloid disease-modifying drugs for Alzheimer’s disease

1. Background

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, with a prevalence of 5% after 65 years of age, increasing to about 30% in people aged >85 years. To date, pharmacological treatment of AD includes acetylcholinesterase inhibitors for mild-moderate AD and memantine for moderate-to-severe AD. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.

According to the amyloid hypothesis, the deposition of amyloid beta (Aβ) is a crucial event, which starts a number of downstream pathogenic mechanisms, resulting in the end in neurodegeneration and neuronal death.

These events occur many years prior to the development of symptoms. In line with this evidence, new criteria introducing the use of biomarkers such as Cerebrospinal Fluid (CSF) analysis and positron emission tomography (PET) with an amyloid tracer have been developed [1], to anticipate the diagnosis at the phase of ‘prodromal AD’, that is, non-demented people with mild cognitive impairment because of AD.

2. Future pharmacologic agents

Many approaches have been developed in the last two decades to influence pathogenic mechanisms at the basis of the disease, primarily remove Aβ or interfere with its deposition, including mainly vaccination, passive immunization and anti-Aβ aggregation agents.

2.1. Vaccination

In the year 1999 Schenk et al. [2] demonstrated that immunization with Aβ as an antigen attenuated AD-like pathology in transgenic mice over-expressing the APP gene, by removing amyloid from the brain. Given these exciting preclinical results, a multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial using active immunization with Aβ42 plus adjuvant was started in 2001 on 300 patients using the Aβ peptide AN1792. Unfortunately, 6% of treated patients developed aseptic meningo-encephalitis, thus the trial was halted after 2–3 injections. The final results of the trial were published few years later.[3] Double-blind assessment was maintained for 12 months, demonstrating no significant differences in cognition between antibody responders and placebo.

In the year 2003, 80 patients who had entered the phase I AN1792 trial in 2000, gave their consent for long-term clinical follow-up and post-mortem neuropathological examination, which showed, in patients who received immunization, decreased Aβ load as compared with placebo. Despite this, no evidence of improved survival or an improvement in time to severe dementia was observed in such patients.[4] Therefore, plaque removal is likely not enough to halt neurodegeneration in AD, prompting some intriguing challenges to the amyloid hypothesis.

Years later, based on the hypothesis that the use of full-length amyloid peptide in AN1792 could have resulted in T-cell autoimmune response that caused the meningeal inflammation, subsequent efforts focused on second-generation amyloid vaccines design, in order to promote the humoral but not the cellular immune response. The first second-generation vaccine tested in AD patients is CAD106 (Novartis), that is composed of the Aβ amyloid 1-6 peptide coupled with a specific carrier. The Aβ1-6 peptide is derived from the N-terminal B cell epitope of Aβ and is able to avoid T cell activation. The first study with CAD106 included 58 patients with mild-to-moderate AD and proved that CAD106 has a favorable safety profile and acceptable antibody response.

In 2014, Novartis partnered with the Banner Alzheimer Research Institute to conduct a secondary prevention trial within the Alzheimer Prevention Initiative (API). This Phase II/III trial is set to run until 2023, with a 5-year treatment period. This study aims to enroll more than 1000 subjects homozygous ApoE4/4 carriers who are cognitively normal. About half of participants will be randomized to compare CAD106 to matching placebo injected intramuscularly at weeks 1, 7, 13, 24 and then quarterly. The other half will be randomized to compare once-daily CNP520, a beta-site APP-cleaving enzyme (BACE) inhibitor, to matching placebo. The primary outcome will measure the ability to delay diagnosis to mild cognitive impairment (MCI) or AD dementia. Additional primary and secondary prevention trial will likely be carried out in the next future (see [5] for review).

To date, other vaccines are under clinical investigation such as ACI-24, Affitope AD-02, Affitope AD-03, ACC-001, UB-311, V-950 and Lu AF20513, an Aβ1-12 peptide in which the T-helper cell epitopes of Aβ42 have been replaced with two foreign T-helper epitopes from the tetanus toxin, which stimulate existing memory T-helper cells to promote Aβ antibody production from B cells.[6] An additional approach, tested so far in preclinical phase, is represented by DNA Aβ protein immunotherapy.[7]

2.2. Passive immunization

Passive immunotherapy started being investigated in parallel with the active therapies because of serious side effects of vaccination.

Preclinical evidence suggests that peripherally administered antibodies can enter the central nervous system and bind to Aβ, where it is eliminated through Fc receptor-mediated clearance by microglial cells.[8]

Two humanized mAbs have been first developed: bapineuzumab (Pfizer), directed against the N-terminal region of Aβ peptide [9] and solanezumab (Eli Lilly), directed against Aβ central region.[10]

Prior to the completion of the Phase II study, a phase III trial with bapineuzumab was initiated. The results of these trials did not show overall efficacy but a small subset of patients, namely the ApoE E4 non-carriers, responded well. Subsequently, two Phase III trials, one in carriers and one in non-carriers, were carried out but, disappointingly, gave negative results.[11] AAB-003 is a humanized derivative of bapineuzumab (AAB-001), modified to differ from bapineuzumab in its Fc fraction to reduce the antibody’s effector function on microglial activation, linked to Amyloid Related Imaging Abnormalities (ARIA), a complication of bapineuzumab. The drug has been so far tested in Phase I.

Solanezumab is instead directed against the central region of Aβ and does not enter in central nervous system, acting through peripheral sink mechanism, as showed by its ability to increase plasma Aβ in treated patients.[10] Despite promising results in Phase II, two large Phase III clinical trials failed to show any significant effect on cognition.[12]

Two Phase III trials of gantenerumab (Roche), the first fully human anti-Aβ monoclonal antibody directed to both N-terminal and central regions of Aβ, in patients with prodromal or mild AD are ongoing.[13]

Another promising antibody is aducanumab, a high-affinity, fully human IgG1 monoclonal antibody against a conformational epitope found on Aβ. After successful Phase I-II trials, on August 2015, Phase III began with two efficacy trials (221AD301 ENGAGE and 221AD302 EMERGE) on people with MCI because of AD or mild AD as ascertained by a positive amyloid PET scan.

Additional antibodies are in Phase I and II, including some directed to Aβ oligomers (crenezumab) and soluble protofibrils (BAN2401).

A problem with Aβ antibodies is that in brain parenchyma they only reach 0.1% of the antibody concentration in serum because of the low passage of antibodies across the blood–brain barrier. Antibodies also have to pass through further barriers to reach intracellular compartments. Consequently, intraneuronal Aβ antibody concentrations may not be sufficient to reduce intracellular Aβ, impacting efficacy. This also makes it difficult to optimize dosing.[8]

2.3. Amyloid deposition inhibitors

The most studied is named tramiprosate (Alzhemed^TM, Neurochem, Inc.), a glycosaminoglycan (GAG) mimetic. Despite promising Phase II studies, Tramiprosate failed in two large Phase III clinical studies in AD. Limitations included the lack of clinical and disease-modification outcome measures, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.[14]

A possible evolution of tramiprosate is the small organic compound ALZ-801, developed by Alzheon.

A promising future approach include the design of BRICHOS domains, shown to inhibit fibril formation and toxicity of the Aβ peptide.[15]

3. Open questions

Despite a number of disease-modifying compounds tested after promising preclinical results, no effective drugs have reached the market so far. This is possibly because of several weaknesses.

First, plaque removal may not be sufficient to halt progressive neurodegeneration in AD. In this regard, the neuropathological analysis of brains from patients who received immunization showed that, although mean Aβ load was lower than in the placebo group, there was disappointingly no evidence of improved survival or improvement in time to severe dementia. Thus, mechanisms at the basis of the pathogenesis of AD need to be further investigated before developing new claimed ‘disease-modifying’ compounds.

The second issue is that treatments for AD could be effective only in certain phases of the disease or in patients carrying a particular ApoE genotype. Many trials probably failed because the intervention was too late. Considering that Aβ deposits even decades before symptom onset, therapeutic trials should be carried out as early as possible during the course of the disease. However, while subgroup analysis of the solanezumab Phase III studies in mild AD patients and initial results of aducanumab in mild and prodromal AD seem to support this hypothesis, the recent failure of the gantenerumab Phase III study in prodromal AD does not confirm it.

Third, outcome measures, represented by neuropsychological testing, are rough indicators of clinical benefit. Therefore, surrogate outcome measures (surrogate biomarkers) are needed in order to have: (i) substitutes for clinical endpoints (to date limited to neuropsychological testing), (ii) tools able to predict clinical benefit, or the opposite and (iii) demonstrate whether there are disease-modifying properties. So far, none among biomarkers proposed for early diagnosis have such characteristics.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.