The recipient research group, Alector, is to receive a $205 million USD up front payment, as well as future equity investments worth up to $20 million. Alector has seen a great deal of interest within the pharmaceutical world, raising a combined total of $80 million from Orbimed, GV, Polaris along with pharmaceutical companies including Merck & Co Inc and Amgen.
The deal with AbbVie involves research focused on the use of immunotherapy, a promising technique that has seen previous success in cancer therapy. Immunotherapy involves promoting the body’s immune system to attack a designated target.
In the case of Alzheimer’s therapy this target would likely be amyloid beta plaques. These plaques are formed from a chemically “sticky” molecule, Aβ-42, a cut derivative of the APP protein (a protein whose exact function is as of yet unknown, but due to its concentration in the synapses is thought to be involved in synaptic regulation). These plaques disrupt neuronal function and lead to neuronal cell death. This is thought to be one of the primary pathological mechanisms behind Alzheimer’s disease and is referred to as the “amyloid hypothesis”.
The amyloid hypothesis has thus far been the focal point of Alzheimer’s research. Despite numerous research institutions and pharmaceutical companies working on addressing the accumulation of amyloid plaques, no effective treatments have been developed in well over a decade.
Alzheimer’s research, hitting a hurdle it can’t cross
Alzheimer’s research has seen numerous stories of expensive medicines failing within the last year. The common factor linking all of these medications has been their focus on treating the accumulation of amyloid plaques.
High profile medical trials have been hailed by the media as a definite cure, or a “miracle treatment”. This has made disappointing findings in late stage human trials all the more devastating, often incurring significant financial loss for the company funding the research.
High profile failures included a potential medicine from Merck & Co Inc., Verubecestat, and Eli Lilly’s Solanezumab. More recently Axovant’s potential medication intepirdine, which focused on a different therapeutic target, also failed in late stage human trials.
It is a concern that an immunotherapeutic approach would also target amyloid plaques. In theory, this would mean it might suffer the same drawbacks as using conventional medications for plaque clearance. Alzheimer’s disease is complex, and its causes are more extensive than amyloid plaques alone.
Tau protein has also been implicated. Dysfunction of tau protein leads to it tangling within the neuron, disrupting neuronal signalling. This can also lead to the neuronal cell death common to Alzheimer’s disease. Immunotherapy will be an ineffective method of addressing this aspect of Alzheimer’s disease, as the tau protein is housed within the cell and inaccessible to the body’s immune system.
A previously researched concept seeing fresh investment
Immunotherapy, however, is not a new concept in treating Alzheimer’s disease. It has been shown to have some success in the past, but this success has never been translated to medical treatments.
Attempts have been made as far back as 1999 to use the body’s own immune system to combat Alzheimer’s. In a previous study, a vaccine was created to reduce amyloid deposition in a transgenic mouse strain that overproduced the APP precursor protein. The study showed that this strategy of passive immunotherapy was effective, restoring memory deficits in the mice resulting from amyloid deposition.
Further studies in mice revealed clear benefits to immunotherapy in the same kind of transgenic mice. Encouragingly, these benefits were also found in older mice, in which amyloid deposition had reached considerable levels.
Brief human trials confirmed the presence of an immune response to the vaccine. Following the vaccine there were instances of cognitive benefit in the patients as well as evidence of amyloid clearance.
Dangerous side effects?
Since this study, human trials have been infrequent due to findings that indicate the anti-amyloid vaccination has some dangerous side effects. Mouse models revealed the occurrence in some cases of microhemorrhage and vasogenic edema (dangerous small instances of bleeding in the brain and swelling in blood vessels). Also, while amyloid clearance was occurring in the brain, there was an increase in amyloid deposits in blood vessels.
These severe side effects primarily occurred in subjects with the apolipoprotein E4 genotype. This is a gene that is documented to contribute to Alzheimer’s, though its exact mechanism is yet to be established. This gene is uncommon in the vast majority of Alzheimer’s patients, and is largely found in those with familial Alzheimer’s disease. This form of the disease has established genetic causes and only affects between one and five percent of those with Alzheimer’s.
While the side effects may be largely limited to those with genetic causes for the disease, this may suggest the benefits may also be limited. In those with sporadic Alzheimer’s disease — the more common variant of the disease — the cause may not be primarily due to amyloid plaque accumulation, and so treatments that address this cause may have limited effect.
Immune response has also been implicated as a potential contributing factor to the damaging effects of Alzheimer’s. Microglia, a type of cell that mediates immune response within the brain, play a role in the removal of amyloid plaques. However, as the frequency of plaques increases, it is believed that the immune system of the brain becomes overwhelmed. This results in unregulated action by the microglia, which may cause damage to the fragile neurons that exacerbates the damage already caused by the plaques.
Harnessing the immune system to aid in combatting Alzheimer’s will be difficult. Immunotherapy in cancer is a more simple concept, in which the objective is to destroy tumour cells; in Alzheimer’s disease, plaques are already cleared by the immune system. It is the inability of the body to control this function that contributes to the illness.
Immunotherapy, a tried and tested strategy
The difficulty of solving this unregulated immune response has not escaped many in the scientific community. Some of whom remain sceptical of Alector’s attempts at using immunotherapy. Dr Mary Sano, director of the Mount Sinai Alzheimer’s Disease Research Center points to the many fruitless attempts that have previously occurred, and says that the results of the trials will be little more than a guess.
The hypothesis of Alector is that by altering the immune system, plaques could be cleared more efficiently, and nerve cells could be better protected. “We want to rejuvenate the immune system so it is able to clear a-beta and other debris, and to control nerve protection.” says Arnon Rosenthal, chief executive of Alector.
Details of how this will be achieved are currently elusive as the therapies are in their initial stages. Alector is hoping to get five drug targets into human trials over the next two years. This would indicate that there are numerous approaches already in development.
How these strategies differ from previous attempts is yet to be established. Whether the therapies are effective is also unknown as of yet. However, the amyloid hypothesis is already questionable as the sole cause of Alzheimer’s disease, and immunotherapy may simply be a more novel approach at reaching the same target as many drugs that have already failed.
However, immunotherapy could be used to address other potential contributors of the disease, such as metabolic dysregulation resulting from the unregulated immune response. Until more details arise regarding the therapies their effectiveness will be, as Dr Sano says, a guess.
It is encouraging that companies continue to be willing to invest in new kinds of Alzheimer’s treatments despite the numerous failed trials.