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Amyloid-Targeting Immunotherapy

Curator: Larry H. Bernstein, MD, FCAP

Possible Reasons Found for Failure of Alzheimer’s Treatment

By Staff Editor

http://www.healthnewsdigest.com/news/Alzheimer_Issues_680/Possible-Reasons-Found-for-Failure-of-Alzheimer-s-Treatment.shtml

(HealthNewsDigest.com) – Agglutinated proteins in the brain, known as amyloid-β plaques, are a key characteristic of Alzheimer’s. One treatment option uses special antibodies to break down these plaques. This approach yielded good results in the animal model, but for reasons that are not yet clear, it has so far been unsuccessful in patient studies. Scientists at the Technical University of Munich (TUM) have now discovered one possible cause: they noticed that, in mice that received one antibody treatment, nerve cell disorders did not improve and were even exacerbated.

Immunotherapies with antibodies that target amyloid-β were long considered promising for treating Alzheimer’s. Experiments with animals showed that they reduced plaques and reversed memory loss. In clinical studies on patients, however, it has not yet been possible to confirm these results. A team of researchers working with Dr. Dr. Marc Aurel Busche, a scientist at the TUM hospital Klinikum rechts der Isar Klinik und Poliklinik für Psychiatrie und Psychotherapie and at the TUM Institute of Neuroscience, and Prof. Arthur Konnerth from the Institute of Neuroscience has now clarified one possible reason for this. The findings were published in Nature Neuroscience.

Immunotherapy Increases Number of Hyperactive Nerve Cells

The researchers used Alzheimer’s mice models for their study. These animals carry a transgene for the amyloid-β precursor protein, which, as in humans, leads to the formation of amyloid-β plaques in the brain and causes memory disorders. The scientists treated the animals with immunotherapy antibodies and then analyzed nerve cell activity using high-resolution two-photon microscopy. They found that, while the plaques disappeared, the number of abnormally hyperactive neurons rose sharply.

“Hyperactive neurons can no longer perform their normal functions and, after some time, wear themselves out. They then fall silent and, later, possibly die off,” says Busche, explaining the significance of their discovery. “This could explain why patients who received the immunotherapy experienced no real improvement in their condition despite the decrease in plaques,” he adds.

Released Oligomers Potential Reason for Hyperactivity

Even in young Alzheimer’s mice, when no plaques were yet detectable in the brain, the antibody treatment led to increased development of hyperactive nerve cells. “Looking at these findings, even using the examined immunotherapies at an early stage, before the plaques appear, would offer little chance of success. As the scientist explains, the treatment already exhibits these side effects here, too.

“We suspect that the mechanism is as follows: The antibodies used in treatment release increasing numbers of soluble oligomers. These are precursors of the plaques and have been considered problematic for some time now. This could cause the increase in hyperactivity,” says Busche.

The work was funded by an Advanced ERC grant to Prof. Arthur Konnerth, the EU FP7 program (Project Corticonic) and the Deutsche Forschungsgemeinschaft (IRTG 1373 and SFB870). Marc Aurel Busche was supported by the Hans und Klementia Langmatz Stiftung.

Publication
Marc Aurel Busche, Christine Grienberger, Aylin D. Keskin, Beomjong Song, Ulf Neumann, Matthias Staufenbiel, Hans Förstl and Arthur Konnerth, Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models, Nature Neuroscience, November 9, 2015.
DOI: 10.1038/nn.4163
http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4163.html

Amyloid-Targeting Immunotherapy Disrupts Neuronal Function

Some antibodies designed to eliminate the plaques prominent in Alzheimer’s disease can aggravate neuronal hyperactivity in mice.

By Karen Zusi | November 9, 2015  http://www.the-scientist.com//?articles.view/articleNo/44435/title/Amyloid-Targeting-Immunotherapy-Disrupts-Neuronal-Function/

http://www.the-scientist.com/images/News/November2015/10_alzheimerbrain_b.jpg

Removing built-up plaques of amyloid-β in the brain is a long-sought therapy for patients with Alzheimer’s disease, but for a variety of reasons, few treatments have succeeded in alleviating symptoms once they reach clinical trials. In a study published today (November 9) in Nature Neuroscience, an international team examined the effects of two amyloid-β antibodies on neuronal activity in a mouse model, finding that the antibodies in fact led to an increase in neuronal dysfunction.

Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models

Marc Aurel Busche, Christine Grienberger, Aylin D Keskin, Beomjong Song, Ulf Neumann, Matthias Staufenbiel, Hans Förstl & Arthur Konnerth
Nature Neuroscience (2015)    http://dx.doi.org:/10.1038/nn.4163

Among the most promising approaches for treating Alzheimer´s disease is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies.

Marc Busche, a psychiatrist at Technical University of Munich in Germany, and others had previously found that neuronal hyperactivity is common in mouse models of Alzheimer’s disease. The chronically rapid-firing neurons can interfere with normal brain function in mice. “There’s evidence from human fMRI [functional magnetic resonance imaging] studies that humans will show hyperactivation early in the disease, followed by hypoactivation later on,” Busche told The Scientist. “It’s an early stage of neuronal dysfunction that can later turn into neural silencing.”

To investigate whether certain antibodies would alleviate this Alzheimer’s disease-associated phenotype, Busche and his colleagues first turned to bapineuzumab—a human monoclonal antibody that initially showed promise in treating mice modeling Alzheimer’s disease, but failed in human clinical trials. The dominant hypothesis for bapineuzumab’s failure is that it was administered too late in the disease progression, said Busche. “But it’s still a hypothesis,” he added. “There’s no real explanation for why these antibodies failed.”

The team’s latest experimenters used mice with a genetic mutation that caused them to overexpress the human amyloid-β protein; these engineered mice also displayed neuronal hyperactivity. The researchers injected 3D6, the mouse version of bapineuzumab, into the engineered mice, as well as into wild-type mice that had normal expression levels of the mouse amyloid-β protein. The team observed the effects using two-photon calcium imaging in a blinded study.

As expected, 3D6 decreased the amount of amyloid-β plaques in the engineered mice, while the control mice displayed no reaction to the injected antibodies. However, the mice engineered to overexpress human amyloid-β showed increased neuronal hyperactivity in response to the antibody, regardless of what stage of plaque development they were in. Even mice too young to have developed plaques showed aggravated hyperactive neurons. The team observed the same phenomenon when it tested a second antibody, β1, which went through early stages of drug development but was never used in human clinical trials.

The results surprised Busche. “When it turned out that the antibody group was worse than the control group, it was unbelievable. But we checked many times and there was no mistake,” he said. “We don’t see this effect in wild-type mice so it must be dependent on the interaction between the antibody and amyloid-β.”

Busche was quick to point out that the mouse model is not the same as a human Alzheimer’s patient. However, he said, “it gives a sense that we don’t understand the antibody’s action, and this might go on in the human brain as well.”

“I fully believe in their results, but I have some hesitation in saying that this result explains the failed clinical trials for amyloid-β immunotherapy,” said Cynthia Lemere, a neurologist and Alzheimer’s disease researcher at the Brigham and Women’s Hospital in Boston. “I think the major reason for clinical trials failing for immunotherapy is that up until now, they’ve been done in people with moderate-to-severe Alzheimer’s disease, and then mild-to-moderate. Now the studies are going further to include people with very early stages of clinical symptoms—and to my knowledge, they haven’t been stopped because patients are getting worse.”

Thomas Wisniewski, a cognitive neurologist at New York University, voiced a similar perspective. “I don’t think this is an explanation for why immunotherapy isn’t working—I think there are other more plausible reasons for that,” he said, citing clinical trials that treated patients during later stages of Alzheimer’s disease progression, as well as those that haven’t addressed tau-related pathologies, or didn’t target the key types of amyloid-β. “[The neuronal hyperactivity] is an interesting phenomenon to be studied,” he added, “but I think it’s a separate issue.”

M.A. Busche et al., “Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models,” Nature Neuroscience, doi:10.1038/nn.4163, 2015.

Figure 2: Worsening of neuronal dysfunction by anti-Aβ antibodies can occur independently of the effects on Aβ pathology.

Anti-Aβ treatment aggravates abnormal brain activity in a mouse model of Alzheimer’s disease

Nature Neuroscience   Nov 10, 2015

http://www.natureasia.com/en/research/highlight/10316

Therapies that reduce deposits of amyloid-β (Aβ) in the brain are ineffective at repairing neuronal impairment in mice and actually increase it, finds a study published online in Nature Neuroscience. Aβ deposits aggregate into clumps in the brain which are a pathological hallmark of Alzheimer’s disease.

Expression of mutant human amyloid protein in animals results in deposits of Aβ plaques that induce abnormal increases in neuronal activity and impair the normal function of neuronal circuits.

Arthur Konnerth, Marc Busche and colleagues explored whether they could reverse these impairments by treating mice that overexpress the human mutant amyloid precursor protein with either of two different antibodies targeting Aβ (14 mice) or a control antibody (19 mice). They found that, although treatment with the Aβ targeting antibodies reduced the amount of plaques in the animals’ brains, it also increased the amount of hyperactive neurons.

This was true whether the treatment was given to older mice (14 treated, 19 control) or younger mice in which the accumulation of Aβ had yet to occur (10 treated, 13 control). The same therapies had no effect on neuronal activity in a group of normal mice (5 treated, 3 control), suggesting that the observed exacerbation in mutant mice is dependent on the presence of Aβ and cannot be explained by incidental effects of inflammation in response to the antibodies.

The authors note that, although other research has shown that anti-Aβ treatment can prevent the weakening of neuronal connections and memory impairments in animal models of Alzheimer’s disease, these benefits are not enough to repair neuronal dysfunction.

They suggest that their findings provide a cellular mechanism that may explain, in part, why treatments targeting Aβ in human clinical trials have failed to improve cognitive deficits. However, the authors point out that future studies are needed to determine whether the increase in abnormal neural activity seen in their animal models is related to the poor efficacy of Aβ therapy in patients.

 

ANAVEX™ 2-73

ANAVEX™ 2-73 is an orally available drug candidate developed to potentially modify Alzheimer’s disease rather than temporarily address its symptoms. It has a clean Phase 1 data profile and shows reversal of memory loss (anti-amnesic properties) and neuroprotection in several models of Alzheimer’s disease.

Successful Phase 1 Clinical Trial

A Phase 1 single ascending dose human clinical trial of ANAVEX 2-73 was successfully completed in healthy human volunteers. It was a randomized, placebo-controlled study. Healthy male volunteers aged 18 to 55 received single, ascending oral doses over the course of the trial. The trial objectives were to define the maximum tolerated dose, assess pharmacokinetics (PK), clinical and lab safety.

Results:

• Dosing from 1-60 mg.
• Maximum tolerated dose 55-60 mg; above the equivalent dose shown to have positive effects in mouse models of Alzheimer’s disease.
• Well tolerated below the 55-60 mg dose with only mild adverse events in some volunteers.
• Observed adverse events at doses above the maximum tolerated single dose included headache and dizziness, which were moderate in severity and reversible. These side effects are often seen with drugs that target central nervous system (CNS) conditions, including Alzheimer’s disease.
• No significant changes in blood safety measurements.
• No changes in ECG.
• Favorable PK profile.
  • Rapid absorption into blood.
  • Dose proportional kinetics.

The trial was conducted in Germany by ABX-CRO in collaboration with the Technical University of Dresden. ABX-CRO and the Technical University of Dresden are well regarded for their experience with clinical trials and CNS compounds.

 

ANAVEX 2-73,

Clinical-stage biopharmaceutical company Anavex Life Sciences Corp. is working on an investigational oral treatment for Alzheimer’s disease called ANAVEX 2-73, with full PART A data and preliminary PART B data from its ongoing Phase 2a clinical trial to be presented during the Clinical Trials on Alzheimer’s Disease (CTAD) conference, November 5 and 7 in Barcelona, Spain.

The trial’s Principal Investigator, Stephen Macfarlane, who also serves as director and associate professor at Aged Psychiatry, Caulfield Hospital in Melbourne, Australia, will represent the company and host a late-breaking oral session entitled “New Exploratory Alzheimer’s Drug ANAVEX 2-73: Assessment of Safety and Cognitive Performance in a Phase 2a Study in mild-to-moderate Alzheimer’s Patients.” During the presentation, which will take place Saturday, November 7, at 9:45 a.m. CET, at the Gran Hotel Princesa Sofia, in Barcelona, Macfarlane will focus on the the multicenter Phase 2a clinical trial of ANAVEX 2-73. The study includes two separate phases and includes 32 mild-to-moderate Alzheimer’s patients. While PART A is a simple randomized, open-label, two-period, cross-over, adaptive trial of up to 36 days, PART B is an open-label extension trial for an additional 52 weeks.

The research intends to assess the maximum dose of treatment tolerated by patients, and to explore cognitive efficacy using mini-mental state examination score (MMSE), dose response, bioavailability, Cogstate and electroencephalographic (EEG) activity, including event-related potentials (EEG/ERP), as well as the preformance of ANAVEX 2-73 as an add-on therapy to donepezil (Aricept).

ANAVEX 2-73 is Anavex’s lead investigational treatment for Alzheimer’s disease, in line with the company’s goal of finding effective therapies for Alzheimer’s disease, other central nervous system (CNS) diseases, pain, and various types of cancer. The novel drug targets sigma-1 and muscarinic receptors, which are thought to decrease the amount of protein misfolding, beta amyloid tau and inflammation through upstream actions.

Last November, the biopharmaceutical company presented encouraging results from their phase 1 clinical trial for Anavex 2-73, during the CNS Summit 2014 in Boca Raton, Florida. The phase 1 study demonstrated that the treatment is safe and well tolerated, suggesting a favorable pharmacokinetics profile. During the randomized, double-blind, placebo-controlled study no severe adverse events were registered, while the adverse events reported included moderate and reversible headache and dizziness, which are common symptoms associated with drugs that target central nervous system (CNS) conditions, such as Alzheimer’s.

New Exploratory Alzheimer’s Drug ANAVEX 2-73: Assessment of Safety and Cognitive Performance in a Phase 2a Study in mild-to-moderate Alzheimer’s Patients

Steve Macfarlane, MD1 , Paul Maruff, PhD2 , Marco Cecchi, PhD3 , Dennis Moore, PhD3 , Anastasios Zografidis, PhD4 , Christopher Missling, PhD4 (1)

Caulfield Hospital, Melbourne, Australia (2), Cogstate, Melbourne, Australia (3), Neuronetrix, KY, USA (4), Anavex Life Sciences, Corp., New York, NY, USA

Background: Despite major efforts aimed at finding a treatment for Alzheimer’s disease (AD), progress in developing compounds that can relieve cognitive deficits associated with the disease has been slow. ANAVEX 2-73 is a sigma-1 and muscarinic receptor agonist that in preclinical studies has shown memory-preserving and neuroprotective effects. In our ongoing phase 2a clinical study we are assessing ANAVEX 2-73 safety in subjects with mild-to-moderated AD, and measuring drug effects on MMSE, EEG and Event Related Potentials (ERP) cognitive measures, and Cogstate test batteries to optimize dosing.

Methods: Thirty-two subjects that meet NINCDS-ADRDA criteria for probable AD are being recruited at up to seven clinical sites in Melbourne, Australia. Subjects are between 55 and 85 years of age, and have an MMSE of 16 to 28. In PART A of the study, participants are administered ANAVEX 2-73 orally and IV in an open-label, 2-period, cross-over trial with adaptive study design lasting up to 36 days for each participant. In PART B of the study, all participants are administered ANAVEX 2-73 daily orally. MMSE, EEG/ERP (P300) and Cogstate tests are performed at baseline and subsequently at weeks 12, 26, 38 and 52 of the PART B open label extension.

Results: The primary outcome of the study is safety, and ANAVEX 2-73 was well tolerated. In the secondary outcome endpoints preliminary analysis of data from subjects shows an average improvement of the MMSE score at week 5. A majority of all patients tested so far improved their respective MMSE score. The average EEG/ERP (P300 amplitude) signal also improved and also the average Cogstate test improved across the test batteries.

Conclusions: Data collected so far indicate that ANAVEX 2-73 is safe and well tolerated. Interim results also show improved cognitive performance after drug administration in subjects with mild-to-moderate AD. The current results seem to justify a prospective comparison with current standard of care in a larger clinical trial study. A more complete set of results will be available at the time of the conference.