Alzheimer’s disease: when the cure?

ALZHTo answer this question we should list some significant facts about the disease. There are 36 millions patients with the disease in the world, a diagnosis of Alzheimer disease is made every three seconds in the USA, the costs of the disease in the world are 600-800 billions of dollars and there is convergent evidence that indicates that the asymptomatic phase (before the onset of symptoms), last 15-20 years. Up to now, there is not a cure for the disease, although we know a lot on the genes and the proteins, which are involved.
The current available drugs (three acethylcholine-esterase inhibitors and one NMDA antagonist) show some efficacy only for 2/3 of patients and this effect lasts generally 6 months. Some studies regarding the effects of the association of these drugs are ongoing.
The CERE 110 is a phase I study that provided evidence that bilateral stereotactic administration of genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF)in to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression. Phase II and III studies are needed.
EVP-6124 (Encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III studies under the title COGNITIV AD are ongoing.
Most phase III studies targeting Aß amyloid with monoclonal antibodies (Solanezumab, Crenezumab, Gantenerumab) did not show significant results. However, some positive trend n patients with mild or moderate disease was observed, data, which seems sufficient to extend these phase III trials to patients with the mildest form of the disease. Results will be available in few years.
The A4 trial will enroll normal individuals with amyloid accumulation, who are at increased risk for cognitive decline due to AD. 5000 clinically normal older individuals will be screened to identify those with increased amyloid accumulation on PET imaging; those individuals will be randomized into the anti-amyloid treatment arm with solanezumab or placebo arm. Individuals who do not show evidence of elevated amyloid accumulation may be eligible in an observation arm that will run parallel to the A4 treatment arm with identical cognitive assessments. A4 and LEARN study participants will be followed for 168 week treatment and observation periods.
The multicenter Dian-tu and API ADAD trials will enroll large samples of individuals who are carriers of different genetic variants of AD and will treat them with anti-amyloid monoclonal antibodies during the asymptomatic phase of the disease. The last two studies will give results after 2020.
Studies of drugs against secretases (MK/8931) are in phase II/III and results are expected on 2020.
Human studies on vaccines inducing immune response against Aß amyloid are still in phase I and II.
Therapies targeting tau proteins are for the moment only studied in animal models.
TTP488 is an orally active antagonist of RAGE (receptor for advanced glycation end-products). A phase II study did not provide significant results and showed concerns for safety of higher doses.
Pioglitazone, an insulin sensitizer of the thiazolidinedione class of peroxisome-proliferator activated receptor γ (PPAR-γ) agonists is under study on a phase III trial.
A Phase II study of saracatinib (AZD0530), a small molecule inhibitor with high potency for Src and Fyn, a family of kinases intervening in the synthesis of amiloid and tau, is ongoing.
In conclusion, there is nothing substantially new regarding a cure for the disease. Some optimism should be expressed for the future phase III studies including asymptomatic patients with the genetic variants of the disease and who will be trailed with monoclonal anti-amyloid antibodies. We have to wait still 5 years and probably even more for the results of such studies. However, it seems evident, from biological data we have, that Alzheimer disease is a multiple-mechanism disease requiring probably for a cure the combination of multiple drugs.

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