Alzheimer’s Therapy: Beta-Amyloid Aggregation Inhibitors

By | April 15, 2015

Overview. Drugs in development to inhibit beta-amyloid aggregation include Praecis Pharmaceuticals’ Apan (PPI-1019), a compound developed by Senexis in preclinical testing, and Hoffmann-La Roche’s CPHPC. PPI-1019 is in Phase I development and has been shown in animal models to increase Aβ-40 levels in the cerebrospinal fluid (CSF), suggesting that the drug promotes the clearance of Aβ-40, the soluble form of the Aβ peptide, from the brain (although it is unclear how the drug affects levels of Aβ-42, the insoluble, plaque-forming form of Aβ). CPHPC, also in Phase I development, is an inhibitor of serum amyloid P component (SAP), a protein from the blood that contributes to amyloid aggregation by binding to the amyloid fibers. CPHPC causes SAP molecules to aggregate, leading to the clearance of SAP from the blood. The depletion of SAP from the blood suggests that the drug can potentially draw out the SAP residing within the brain, thereby preventing further Aβ plaque formation and perhaps reducing plaques that have already formed. Both of these potential Alzheimer’s disease therapies are in the early stages of development, and their proof-of-concept is still being tested. Neurochem’s Alzhemed (NC-531), which has a similar mechanism of action, is further along in development and shows potential to be the first disease-modifying therapy to be launched into the Alzheimer’s disease market.

Mechanism of Action. Amyloid beta (Aβ or Abeta) peptides aggregate to form amyloid fibrils in the brain. These fibrils are deposited on cell surfaces and at nerve terminals and form Aβ plaques, the characteristic extracellular pathology associated with Alzheimer’s disease. Amyloid beta () plaques are thought to be the cause of the neurodegeneration associated with the disease. Attacking the progression of the disease by interfering with the aggregation of the Aβ peptides before they form plaques is one avenue of therapeutic intervention.

Alzhemed (NC-531). Alzhemed () is in development by Neurochem, a company that specializes in drugs for age-related amyloid diseases. Alzhemed is a glycosaminoglycan (GAG) mimetic that prevents the aggregation of the Aβ peptide into amyloid plaques, a mechanism that suggests the drug’s potential to delay or prevent Alzheimer’s disease progression in its early stages. Importantly, in vitro data suggest multiple mechanisms that would endow Alzhemed with potent efficacy in early Alzheimer’s disease. First, in vitro data suggest the drug may prevent the formation of amyloid plaques and perhaps prevent small assemblies of Aβ peptides, known as amyloid-derived diffusible ligands (ADDLs), which are precursors to amyloid plaques. Some experts believe ADDLs are more toxic to neurons than the plaques themselves, and ADDLs have been shown to negatively affect cognition (). Second, Alzhemed might target both the plaque and tangle components of Alzheimer’s disease; GAG modifications have been found in neurofibrillary tangles (neurofibrillary tangles) in the Alzheimer’s disease brain and it is thought that GAG modifications on the tau protein promote NFT formation ().

Alzhemed is the most promising of the disease-modifying strategies that are expected to reach the market in the near term. Use of the drug may increase dramatically when the biomarker Pittsburgh Compound B becomes commercially available, because physicians will be able to select patients with early Alzheimer’s disease and MCI patients with amyloid plaques who are likely to progress to Alzheimer’s disease and who will benefit from Alzhemed treatment.

Alzhemed inhibits plaque formation in preclinical models, a mechanism that will presumably lead to stabilization of cognition in mild Alzheimer’s disease patients. The drug mimics a sugar modification on the Aβ peptide known as a GAG. The presence and temporal relationship of GAGs with plaques has led to the suggestion that GAGs contribute to amyloidogenesis, perhaps by influencing Aβ peptide-folding and/or by stabilizing plaques. The binding of Alzhemed to the Aβ peptide prevents the binding of natural GAGs to the peptide, thus preventing the formation of plaques. It is expected that Alzhemed’s ability to reduce beta-amyloid plaque load will lessen the plaque-induced oxidative damage and neuroinflammation in the Alzheimer’s disease brain. It is still unclear whether GAG modifications occur in ADDLs. If ADDLs are GAG-modified, Alzhemed should be capable of preventing their formation. In support of Alzhemed’s capacity to inhibit ADDL formation, the drug has been shown to slow fiber elongation by preventing Aβ from forming protofilaments in animal studies (). In addition, the drug interferes with the deposition of filaments on the cell surfaces and at nerve terminals in the brain in animal models (Garceau D, 2004).

Alzhemed’s mechanism of action, as hopeful as it is, is still somewhat controversial and may not necessarily have a clinical benefit. Scientists do not yet completely understand the link between Aβ levels and cognition as measured by Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores. Clearing plaques may not alleviate patients’ cognitive defects. So far, Phase II trial data are insufficiently powered to reach significant conclusions as to cognitive improvements with Alzhemed using psychometric tests. However, amyloid plaque clearance will likely be associated with cognitive stabilization, and preliminary data from Ay vaccine trials suggest that patients who responded to the vaccine had cognitive stabilization and were later found at autopsy to have reduced amyloid plaque levels ().

A Phase II dose-finding trial showed that Alzhemed, at the highest dose administered, reduced Aβ-42 levels in the CSF of patients with mild to moderate Alzheimer’s disease (a secondary end point) by as much as 70%, but it did not improve cognition or global functioning at three months as measured by ADAS-cog scores. (Nevertheless, the dose-finding study was not powered to detect the drug’s efficacy; nor was efficacy an end point of the study.) More than half of patients were also taking acetylcholinesterase inhibitors; however, the effects on Aβ-42 levels in the CSF are attributable to Alzhemed and not the acetylcholinesterase inhibitors, which do not affect Aβ levels. Amyloid beta () levels in the CSF are still in dispute as an indicator of amyloid burden in the brain because of the high variability of the levels between patients. In addition, the reduction in Aβ-42 levels in the CSF is hard to interpret because an Aβ aggregation inhibitor would have been expected to increase Aβ-42 levels in the CSF if it were promoting the clearance of plaques, composed of Aβ-42, from the brain. Nevertheless, a reduction in plasma Aβ-40 and Aβ-42 levels was observed in transgenic mouse models of Alzheimer’s disease and associated with a reduction in brain amyloid plaques (), so a similar reduction in amyloid plaques may be occurring in the Phase II treatment group. However, the trial results were variable — one of the eight participants in the highest dose group had higher levels of beta-amyloid compared with baseline measurement.

The Phase II trial was a randomized, double-blind, placebo-controlled, parallel-design study investigating the safety and pharmacokinetic profile of the drug and optimizing the dosing regimen (). At the beginning of the trial, approximately 70% of the participants were concurrently using a memorγ-enhancing drug (mostly donepezil [Eisai/Pfizer’s Aricept]). The 58 patients in this small trial were randomized to the “placebo” group (i.e., acetylcholinesterase inhibitors and placebo) or Alzhemed (with or without an AChEI), in one of three dosing groups (100, 200, and 300 mg daily) for 12 weeks. Results showed dose-related levels of Alzhemed in the CSF of trial participants, suggesting that the drug successfully crosses the BBB, an important hurdle for therapeutic efficacy.

In an open-label extension of this Phase II trial, however, Alzhemed-treated patients with mild to moderate Alzheimer’s disease did show stabilization or mild decline in cognition as measured by ADAS-cog, as compared with historical controls. In the open-label extension, trial participants continued on drug treatment with the 300 mg dose for an additional thirteen months. Eighteen of the 58 patients who had completed 16 months of treatment showed cognitive function stabilization during the open-label extension, as measured by ADAS-cog. The ADAS-cog scale measures cognitive function, with a score of zero representing normal individuals and a score of 70 reserved for individuals who are severely demented; thus, an increase in ADAS-cog scores correlates with a decline in cognitive function. The data at 16 months (presented at the 8th Montreal/Springfield Symposium on Advances in Alzheimer’s Disease Therapies in April 2004 in Montreal, Canada) showed that patients with mild to moderate Alzheimer’s disease treated with Alzhemed had a score of 2.33 points on the ADAS-cog, compared with 9.65 (indicating a worse cognitive decline) expected from historical controls.

Data after 20 months of the open-label extension (presented at the 9th International Conference on Alzheimer’s Disease and Related Disorders [ICAD] in July 2004 in Philadelphia) also indicate Alzhemed’s efficacy. The data showed that the 19 patients with mild to moderate Alzheimer’s disease had an average change of 6.2 points from baseline in their ADAS-cog scores, compared with 11.9 seen in historical controls, indicating only a mild cognitive decline for the Alzhemed-treated patients.

The stabilization data in mild to moderate patients receiving Alzhemed treatment is similar to the clinical trial data that support the current use of acetylcholinesterase inhibitors in Alzheimer’s disease; however, future trials of Alzhemed are expected to show a continued stabilization of cognitive function over one to two years, a slightly longer duration of stabilization compared with acetylcholinesterase inhibitors’ results. In the pivotal trial studies of acetylcholinesterase inhibitors after one year of treatment (), the ADAS-cog scores declined between 0 and 2.46 points. This result is comparable to the 2.33-point decline in the ADAS-cog score after 16 months of Alzhemed treatment in patients with mild to moderate Alzheimer’s disease. Many patients in the Alzhemed trial are also treated with an AChEI (70% were on an AChEI at the beginning of the study; however, it is unclear how many are on the combination of Alzhemed and an AChEI at the open-label stage of the study); therefore, these results do not demonstrate an additive effect of Alzhemed to the performance of acetylcholinesterase inhibitors (AChEIs). However, as mentioned, Alzhemed’s effect on cognitive stabilization is expected to be longer-lasting than that of acetylcholinesterase inhibitors (AChEIs). Alzhemed results are significantly better than those obtained in historical controls, where an 8-point decline in ADAS-cog scores of untreated patients is expected after one year ().

Alzhemed does appear to delay the time at which the ADAS-cog of treated patients drops below their baseline level (and cognitive decline begins). Results in mild Alzheimer’s disease patients (MMSE between 19 and 25) showed no worsening in ADAS-cog from their baseline up to 16 months (with an ADAS-cog score of — 0.09 [n = 11], the negative score indicating cognitive improvement), comparing favorably to the decline of ADAS-cog scores under baseline in donepezil-treated patients at 9 months (although this latter study also included moderate patients, so that this group likely declined at a more rapid rate than mild patients alone). Data on the effect of donepezil in mild Alzheimer’s disease patients at 16 months are not yet available; however, the delay in the worsening of Alzhemed patients is potentially attributable to Alzhemed.

Because of its mechanism of action, and because Aβ-42 levels in CSF decrease with Alzhemed treatment (suggesting a drug-induced reduction of amyloid plaques, if results are comparable to preclinical studies in transgenic mice), Alzhemed may be expected to slow the rate of amyloid plaque buildup. This effect could be demonstrated from continued cognitive stabilization of mild to moderate patients over longer time periods than those assessed in the Phase II trial so far. This extended stabilization would be greater with Alzhemed than with acetylcholinesterase inhibitors because the treatment window for acetylcholinesterase inhibitors will only last while cholinergic neurons are alive (cholinergic neurons will die as the disease progresses and plaque and tangle burden increases), whereas Alzhemed slows amyloid plaque buildup, so that all CNS neurons will be protected for a longer period of time. However, the drug may not be capable of preventing plaque deposition beyond a certain threshold, so that Alzhemed’s effect will be reduced over time as the disease progresses.

With 58 patients, the Phase II trial was insufficiently powered to reach significant conclusions as to cognitive improvements using psychometric tests; such conclusions await the completion of larger Phase III trials. Phase III efficacy data must demonstrate cognitive and functional stabilization or improvements if the drug is to show a therapeutic advantage over acetylcholinesterase inhibitors (AChEIs). An effect of Alzhemed on plaque numbers (and possibly neurofibrillary tangles if Alzhemed does indeed prevent NFT formation) remains to be demonstrated in humans. In the absence of widely accepted amyloid plaque markers, this may only be accomplished by autopsy of patients on long-term treatment with the drug.

Alzhemed’s market potential hinges on the results of ongoing Phase III trials. These trials were initiated in the United States in June 2004 for patients with mild to moderate Alzheimer’s disease, and in Europe in September 2005. The trials will evaluate the safety and efficacy of Alzhemed in combination with AChEI treatment in 950 patients with mild to moderate Alzheimer’s disease over the course of 18 months. The trial will investigate the efficacy of one of two doses of Alzhemed (200 mg and 300 mg daily) combined with AChEI treatment compared with AChEI treatment alone. Efficacy will be measured by the ADAS-cog and the Clinical Dementia Rating-Sum of the Boxes (CDR-SB). Changes in brain volume (most likely the hippocampus or entorhinal cortex) by structural MRI will constitute a secondary end point.

Neurochem is seeking partners for the late-stage development and marketing of Alzhemed. The company had formed an alliance with Lundbeck in June 1999 to develop anti-amyloid agents for Alzheimer’s disease, including Alzhemed; however, this agreement was terminated in October 2001.

Alzhemed is the drug furthest along in the development process for Alzheimer’s disease that targets the aggregation of Aβ plaques, and, if successful, Alzhemed has the potential to significantly alter the Alzheimer’s disease therapeutic landscape and drive sales in a market that would otherwise be limited by the genericization of the acetylcholinesterase inhibitors (AChEIs). Because Alzhemed is disease-modifying (as opposed to acetylcholinesterase inhibitors, which address only the symptoms of the disease), appears to have a benign side-effect profile, and can potentially stave off cognitive decline for a longer period of time than acetylcholinesterase inhibitors, physicians are likely to prescribe Alzhemed over acetylcholinesterase inhibitors, even if the drug does not show a much larger magnitude of stabilization over that of acetylcholinesterase inhibitors (AChEIs).