There is a great unmet need for simple, inexpensive, and non-invasive tests that could be applied on a large scale to screen for Alzheimer’s disease (AD).

Finding a biomarker in AD that translates into clinical meaningfulness has been a real challenge for the field of biomarkers in the central nervous system (CNS).

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacologic responses to a therapeutic intervention. The current way to definitively diagnose AD is through brain scans and tests of cerebrospinal fluid (CSF), which must be collected via lumbar puncture. However, these procedures are invasive and expensive.

These challenges have created opportunities for biomarkers that can be measured in a simple way and that are also less invasive and less expensive. The eye is easy to access, possesses clear optics, and shares many vascular and neural similarities to the brain. Specifically, the retina, which is a projection of the CNS, has been considered a “window to the brain” and a new potential biomarker for AD.

Given these strong connections between the brain and the retina, researchers thought that neurodegenerative disease may also have a similar pathology in the optic nerve and retinal ganglion cells (RGCs).

The development of modern imaging techniques has improved the visualization of the detailed structures and functions of the retina, and has allowed clinicians and researchers to potentially diagnosis and differentiate AD early.

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At the 14th International Conference on AD and Parkinson’s disease (PD) 2019 in Lisbon, Portugal, detection of apoptotic retinal cells (DARC) was presented by University College London (UCL) as a novel imaging technology that can monitor RGC apoptosis and might be a potential biomarker in neurodegenerative diseases. DARC uses fluorescently labelled annexin V to identify apoptosis in retinal cells, as well as binds to actively apoptotic and sick cells to enable single imaging in the retina.

In early apoptosis, the cell membrane changes in structure and phosphatidylserine, which is bound with the fluorescent labelled annexin V, moves from the inside to the outside of the cell. Furthermore, individual apoptotic cells are visualized as white spots on the retina, and experimental studies show DARC as an early marker of glaucoma.

A Phase I clinical trial of DARC in both healthy and glaucoma subjects has been completed. Results showed that DARC counts were significantly greater in patients who later showed increasing rates of disease progression. A Phase II clinical trial in glaucoma, age-related macular degeneration (AMD), AD (Down’s syndrome), and multiple sclerosis (MS, optic neuritis) has been recently completed. DARC is considered to be a promising new retinal biomarker/diagnostic tool comprising fluorescently labelled annexin V, with the potential for early detection of neurodegeneration and prompt treatment response in many CNS indications. However, it needs clinical validation with multiple trials.

The development of imaging technologies for eye and brain diseases could help in the diagnosis of early neurodegeneration, the assessment of disease progression, the response of treatment, and significantly reduced clinical trial length.

Preliminary data on Crenezumab showed it was unlikely to meet the primary endpoint

New data from trials testing the efficacy and safety of Roche’s crenezumab, a humanized anti-amyloid β (Aβ) immunoglobulin (Ig) G4 monoclonal antibodies (mAb) in prodromal to mild AD were presented at the 14th International Congress on AD and PD 2019. Crenezumab is designed to neutralize Aβ oligomers by blocking the interaction of oligomers with neurons and promoting the phagocytic removal of oligomers by microglia. It also localizes to the periphery of amyloid plaques, which are proposed to be rich in Aβ oligomers. Crenezumab’s ability to bind to all forms of the peptide is thought to contribute to its relatively low risk of amyloid-related imaging abnormalities (ARIA).

Crenezumab was being studied in one Phase III trial, CREAD1, in 750 participants with prodromal or mild AD. CREAD1 began despite crenezumab’s failure in its Phase II trial, ABBY, because the Phase II dosing was limited to 15mg/kg but was increased to 60mg/kg in Phase III. In March 2017, Roche initiated a second Phase III trial with an identical study design to CREAD1, called CREAD2, which recruited 750 new participants with prodromal and mild AD. The CREAD trials were two-year, global, randomized, double-blind, placebo-controlled, parallel-group, Phase III studies that were designed to investigate the safety and efficacy of crenezumab at a dose of 60mg/kg intravenously (IV) every four weeks in patients with early prodromal or mild AD with confirmed evidence of cerebral beta amyloid pathology via CSF or amyloid positron emission tomography (PET).

The initial conclusion of CREAD1 and CREAD2, which was presented at the conference, indicates that the Phase III studies are being discontinued based on a pre-planned CREAD interim analysis that indicated crenezumab was unlikely to meet the primary endpoint of change from the baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. Results from the post-hoc analysis in secondary endpoints (Alzheimer’s Disease Assessment Scale- Cognitive Subscale [ADAS-Cog] 13, Mini-Mental State Examination [MMSE], and Activities of Daily Living [ADL]) and in subgroups (earlier versus later stage AD, APOE E4 carrier status) were consistent with the primary outcome. Target exposures were achieved, and no safety signals for crenezumab were observed in the analysis. Additionally, the overall safety profile was similar to that seen in previous trials. Furthermore, the safety data of the trials showed that the majority of adverse events (AEs) were of mild to moderate intensity, and small imbalances between the treatment arms have been observed in infections, neurologic, psychiatric, and gastrointestinal AEs, as well as AEs related to injuries and to investigations. There were no meaningful differences with regards to treatment emergent AEs overall, AEs of interest (pneumonia an ARIA), serious AEs, or AEs leading to treatment discontinuation or deaths. Moreover, incidence of treatment-emergent anti-drug antibodies was low (n=2 in crenezumab arm; n=1 in placebo arm). However, the presented data were preliminary, as patients are still completing their post-treatment visits and data review and analysis are ongoing.

Roche discontinued its CREAD clinical programme of crenezumab in January 2019, and another AD drug targeting the amyloid pathways—Biogen/Eisai’s aducanumab, which was once the most promising drug in the AD pipeline—failed last week. Several clinical trials have been discontinued due to failure to reverse or even slow the cognitive decline associated with AD, leading some researchers to question if they are pursuing the right target. However, scientists and researchers still have hope in amyloid as a potential treatment of AD, even though they all agreed that the approval of a new drug for this indication is still far away.

Crenezumab is still being investigated in an Alzheimer’s Prevention Initiative (API), Autosomal Dominant Alzheimer’s Disease (ADAD) trial in Colombia, South America.

A new way to treat AD with a bacterial pathogen

Data from trials testing the safety, pharmacokinetics (PK), biomarkers, and cognitive readouts of a Phase Ib study of Cortexyme’s COR388 were presented at the 2019 International Congress on AD and PD. The drug is a small-molecule, orally available inhibitor of gingipains, which are the cysteine proteases of the periodontal pathogen Porphyromonas gingivalis (Pg). Chronic periodontitis (CP) has been identified as a significant risk factor for AD, and mouse studies have indicated that Pg can translocate to the brain after oral infection in mice. In a key publication from University of Illinois, researchers showed that oral infection of Pg in wild mice results in brain infection and AD pathology. Specifically, Pg brain infection increased APP/Bace1 gene expression, Abeta42 production and plaques, tau phosphorylation, and tangle formation.

COR388 is an optimized new chemical entity that is first in class and orally administered. In the Phase Ia SAD study, the drug was shown to be well tolerated in healthy volunteers with infrequent AEs, no subcortical arteriosclerotic encephalopathy, no dose-limiting toxicity (DLT), and no clinically relevant changes in laboratory tests, electrocardiogram (ECG), or vital signs. The Phase Ib trial was a randomized, placebo controlled, repeat dose trial that enrolled 33 subjects in four cohorts. Cohorts 1–3 enrolled healthy volunteers with no dementia who received 25mg, 50mg, and 100mg of COR388 or placebo every 12 hours for 10 consecutive days. Cohort 4 enrolled subjects with AD who received 50mg of COR388 or placebo every 12 hours for 28 days as outpatients.

Results showed that COR388 was safe and well tolerated in all four cohorts, drug related treatment-emergent AEs were mild and transient, and no dose-limiting toxicities or serious AEs were reported. COR388’s PK profile was consistent with twice daily dosing, and CSF levels of the drug were similar to those seen in nonclinical studies where levels were associated with high brain penetration.

After these positive results, Cortexyme plans to conduct a Phase II/III study, GAIN, which will start in Q2 2019. Topline results are expected at the end of 2021. The GAIN study will be a randomized, double-blind, placebo-controlled, parallel group trial that will recruit 570 patients with mild to moderate AD and will last 48 weeks, with six weeks safety follow up. The primary endpoint will be ADAS-Cog 11, 90% powered to detect 2.5 points/year change in slope. The study will be conducted in US and in eight EU countries.

The AD pipeline has been characterized by big failures, and the latest discontinuations of crenezumab and aducanumab have cast doubts about the amyloid hypothesis. The amyloid hypothesis has been the major explanation for the pathogenesis of AD for more than 20 years, but after Aβ-targeting drugs for the treatment of AD ended in failure, researchers are exploring other potential treatment options such as tau proteins, vaccines, and also bacterial pathogens.

An update on efficacy, safety, and biomarker of the AMBAR study showed positive results in the Aβ hypothesis

New data from Grifols’ AMBAR trials testing the efficacy and safety of short-term plasma exchange followed by long-term plasmapheresis with infusion of human albumin combined with intravenous immunoglobulin (IVIG) in patients with mild and moderate AD were presented at the 14th International Congress on AD and PD. AMBAR is based on the hypothesis that most of the Aβ protein is bound to albumin and circulates in plasma. Extracting this plasma may remove pathological substances, such as Aβ, from the brain, thereby potentially limiting the disease’s impact on the patient’s cognitive functions.

In a previous presentation at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) Congress in October 2018 in Barcelona, Grifols showed that the re-specified cohort of moderate AD patients demonstrated a statistically significant (61%) reduction in disease progression in both ADAS-Cog and the AD Cooperative Study (ADCS)-ADL scales of treated patients compared to placebo at 14 months.

The new data presented from Grifols showed that there were statistically significant improvements in memory, language, processing, speed, and quality of life (QoL) in the high albumin + IVIG arm compared to placebo at 14 months. In the mild AD cohort, there were also statistically significant improvements in language and processing speed with high albumin + IVG, while in the moderate AD cohort there were statistically significant improvements in memory and QoL. Safety data show a low rate of AEs rate through the whole study related to plasma exchange. AEs were largely accumulated during the conventional therapeutic plasma exchange (TPE) period with a progressive decrease during the low-volume PE (LVPE) period. Patients treated with plasmapheresis without IVIG had more infections than patients treated with IVIG and also than those in placebo arm, however the rate of infections not related with caterer was lower in patients receiving IVIG.

Furthermore, CSF Aβ42 biomarkers showed stabilization in treated patients and a decline in the placebo arm, particularly for moderate AD, while CSF tau and phospho-tau (P-tau) showed less increase in the treated patients compared to the placebo arm, particularly for moderate AD.

After all the failures in the AD pipeline, especially in AD drugs targeting the amyloid pathways such as crenzumab and aducanumab, this finally represents positive clinical data that gives hope to the treatment of this disease. Albumin may represent a multi-modal approach to the management of the disease due to its binding capacity, antioxidant properties, immune modulatory properties, and anti-inflammatory properties.

However, this drug is not yet approved, and it will take many years to explore whether or not patients will really benefit from the treatment. The company has not yet decided how to submit approval to regulatory advisors, as this can be done in two different options. The first option is to submit it as a plasma changes procedure, which is regulated by medical regulations, American Society for Apheresis (ASFA).

The second option is to submit the approval of the drug to the FDA. Grifols will continue its clinical program and will conduct a large new trial even though it is not that clear which cohort they will study, mild or moderate AD. At the Alzheimer’s Association International Conference (AAIC) held from July 14–17 in Los Angeles, California, US, the company will present another update about the clinical endpoints and all biomarkers of the study. It will also complete all protocol data by the end of this year.

New opportunities for anti-Amyloid mAbs for the treatment of AD

At the 2019 International Congress on AD and PD, scientists and researchers presented new opportunities and lessons learned in trials with mAbs after all the failures that affected the AD pipeline, especially in AD drugs targeting the amyloid pathways, such as crenezumab and aducanumab.

Several clinical trials of mAbs were conducted in the past few years with clear no success in terms of efficacy. The list of investigated drugs includes Pfizer’s bapinezumab and ponezumab, Eli Lilly’s solanezumab and donanemab, Roche’s crenezumab and gantenerumab, and Biogen/Eisai’s aducanumab. Through these trials, scientists and researchers learned that the most neurotoxic species of Aβ is the soluble oligomer, which has emerged as the central target for disease modifying treatment (DMT) including mAbs.

Clearance of fibrillar Aβ is perhaps not an essential goal of treatment, but may occur as an epiphenomenon to clear oligomers and reduce fibrillar Aβ at the cost of augmenting soluble species, which could actually be harmful. As such, mAbs directed against the N-Terminus of Aβ may be most effective in clearing toxic aggregated species of Aβ, including oligomers and protofibrils.

In clinical trials of these amyloid-lowering therapies under development for AD, ARIA-edema (ARIA-E) has been reported with increased incidence in patients with mild to moderate AD. Scientists hypothesized that if ARIA-E is caused by clearance of fibrillar Aβ from cerebral vessels, then mAbs with conformationally specific epitopes selective for soluble aggregated species (oligomers and protofibrils) may avoid ARIA-E.

In fact, if ARIA-E is more related to inflammation, then humanized mAbs lacking the microglia activating the fragment crystallizable (Fc) region could emerge as promising therapies, even though it is unclear whether the infrequency of ARIA-E seen with crenezumab is related to its IgG4 structure or its mid-domain epitope.

Currently, there are still questions to be answered, as it is still unclear whether early interventions are necessary for treatment benefit. These questions include whether an Aβ cascade is initiated such that deterioration can no longer be slowed, or whether modest Aβ clearance is irrelevant in the advanced Aβ deposition setting. Empiric trial evidence for this viewpoint is limited in the post-hoc analyses from the Phase III solanezumab program and the Phase II crenezumab trial.

Earlier intervention with a DMT, including mAbs, is advantageous. This is why there are additional studies of preclinical AD to join the ongoing secondary prevention trials: Anti-Amyloid Treatment in Asymptomatic AD trial (A4) for solanezumab, AD Prevention Initiative for crenezumab, and Dominantly Inherited AD Network for solanezumab and gantenerumab.

Anti-amyloid mAbs that bind different epitopes and conformations of Aβ and N-terminal antibodies have demonstrated safety but have failed in clinical endpoints in mild-dementia and prodromal AD. However, it remains unclear whether Aβ plaque clearance is a necessary feature of an effective anti-amyloid antibody, or whether early intervention is necessary for any treatment benefit.

These mAb trials indicated that mild patients may respond better, and that ARIA must be monitored when studying mAbs. Clinical effects can be shown and more sensitive approaches may be useful, such as the AD Composite Score (ADCOMS). Design innovation, such as adaptive design, can address some of the issues of AD drug development including dose, duration, and AE management. The use of biomarkers can support the downstream effect.

After the discontinuation of aducanumab, scientists and experts are hopeful about Biogen’s/Eisai’s BAN2401, which entered a Phase III trial last week and is currently considered to be the most promising drug in the AD pipeline. Several clinical trials have been discontinued due to failure to reverse or even slow the cognitive decline associated with the disease, leading some researchers to question if they are pursuing the right target.

However, scientists and researchers still have hope in target amyloid as a potential treatment of AD, even though they also think that amyloid should not be the only target but instead used in combination. Experts agreed that the approval of a new drug for this indication is still far away. Future antibodies may be designed to dissociate efficacy from ARIA-E, and a combination of therapies could be seen as a more common trend in the field, specifically mAbs + bace inhibitors and mAbs + anti-tau therapies.

Progress and prospects in leveraging biomarkers in AD clinical trials

The search for AD biomarkers that translate into clinical meaningfulness has been a challenge. The current way to definitively diagnose AD is through brain scans and tests of CSF, which must be collected via lumbar puncture. These procedures are invasive and expensive. However, blood tests seem to be the new horizon for AD biomarkers, as they are less expensive, less invasive, and make it easier to collect samples.

Biomarkers have important roles in AD clinical trials and may be useful for subject selection, monitoring of disease progression, or therapeutic efficacy. In the early diagnosis of AD, CSF tests to detect Aβ are invasive but also highly accessible and cheap. They provide information on other biomarkers, such as P-tau, and can detect very early changes. Amyloid PET tests are have limited accessibility and are very expensive, but they are also less invasive than CSF tests, provide topographical information, and can detect early changes.

Results from studies investigating blood Aβ have been conflicting, as plasma measures of Aβ are complicated by its short half-life compared to CSF, and sample matrix effects. Recent improvements in technology have shown promising results, as studies have demonstrated that the ratio of plasma Aβ42/40 correlates well with CSF Aβ42/40 and amyloid PET, as well as predicts future conversion to positive amyloid PET. The plasma Aβ42/40 ratio could potentially be a prescreening tool, as prescreening with a blood test to calculate plasma Aβ42/40 ratios could hypothetically reduce the number of individuals who would require lumbar punctures or PET screen by more than half.

The diagnostic confirmation of amyloid positivity through PET, CSF, and blood show both advantages and disadvantages. For example, an advantage for PET is its significant diagnostic accuracy, while its disadvantages include the fact that it is very expensive, requiring a radioactive probe injected into the bloodstream, logistical challenges due to tracer half-life, and the need for a PET scanner.

CSF is a positive direct measure of molecular pathology, has lower protease activity, and can measure various biomarkers, but patients are sometimes reluctant due to the invasive nature of a lumbar puncture. It is simple to collect samples of blood, and utilizing blood would reduce the number of patients requiring confirmation via CSF or PET, but there is lack of standardization in collection and analytical procedures, and blood has not yet been validated as a diagnostic tool.

Aβ biomarkers can be used for subject selection, allow early diagnosis, are disease specific and reliable. Amyloid PET and CSF Aβ have comparable diagnostic accuracy. The CSF Aβ42/40 ratio may be more disease specific and more reliable compared with Aβ42, while the plasma Aβ42/40 ratio may have a future role in prescreening patients.

Furthermore, biomarkers can also be used to monitor disease progression even though conflicting result exist. Some non-specific biomarkers correlate with disease progression and predict cognitive decline. Changes in synaptic proteins precede neurodegeneration markers. However, these biomarkers cannot serve as surrogate markers yet.

While Biomarkers in AD are increasingly used in drug development, they are not yet uniformly used for AD confirmation. Predictive biomarkers would allow enrichment strategies for clinical trials and future treatment options, such as fast versus slow progressors. Core AD biomarkers are needed for subject selection and predictive biomarkers are needed for enrichment strategies, even though surrogate biomarkers, which are intended to substitute for a clinical endpoint, are still lacking in AD.