Disease modifying Therapy against Alzheimer
WHO WE ARE Alzheimer
is a devastating disease that robs the life of patients and their
families. Currently, 50 million people are affected by dementia worldwide.
This number doubles every 20 years reaching 131 million in 2050. In fact, AD is
the 6th leading cause of death in industrialized countries. Patients
lose their memories and independence. Facing the loss of a beloved person
leaves the relatives with guilt, grief and anger. The socio-economic burden of AD is enormous. Total worldwide cost of
dementia was estimated to US$ 818 bio in 2015. Most of these costs are devoted
to social (40%) and informal (40%) care. The availability of a
disease-modifying drug would transform
the market from one that reacts to a debilitating disease to one that helps
preserving the affected individual’s personality and Independence.
WHO WE ARE
MARKET FOR AD THERAPEUTICS
Marketed drugs are the
acetylcholine esterase inhibitors donepezil, galantamine and rivastigmine and,
the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. They are symptomatic drugs only, and are indicated
for mid-to-severe AD. There is no drug
approved for earlier disease stages nor one that would exert disease-modifying
activity. All of the approved drugs are now also available as generics.
Costs spend on these
symptomatic drugs globally are US$ 10 bio, thus representing only 1-2% of the
total societal cost of the disease. This indicates the absence of an effective
therapy and showcases the opportunity.
The AD drug pipeline is rated
modest: 105 agents were tested in 139 clinical trials in 2017 (Phase I: 25
agents, Phase II: 52 agents, Phase III: 28 agents). This compares to 836 agents
tested for cancer in 2016. The comparatively fast development timeline based
on the repurposing strategy and the intervention point are offering a unique
market opportunity for ADvantage.
AD04 program is based on results made in a Phase II study primarily assessing
another drug candidate in early AD. Data obtained suggest AD04 to slow
shrinkage of the hippocampus, the part of the brain that harbors memory
function(s). This was demonstrated by measuring its volume with a fully
automated, MRI-based system. Importantly, reduced loss of hippocampal volume
correlated with less decline in memory (as compared to controls). Other
disease-driven parameters were also positively affected (e.g., quality of life
of caregivers). Concerning the mode-of-action, AD04 reboosts natural homeostatic pathways involved
in recognition of oxidation-modified lipoproteins and in resolution of
inflammatory responses. Similar mode of action has been shown in animal models
to prevent atherosclerosis. AD04 likely triggers shared pathways involved in
the amelioration of AD as of atherosclerosis.
The clinical development plan
is driven by the repurposing strategy
and integrates AD04’s stage of development and specific indication, early AD.
To achieve marketing authorization, the following principal milestones need to be considered: (1) POC in humans by defining the spectrum
of AD04-triggered biomarker changes, (2) dose/
schedule optimization by correlating the biomarker profile to positive
changes in clinical endpoints, (3) demonstration
of efficacy of the optimal dosage. Given the eligibility of AD04 for fast track designation, dose/schedule optimization and efficacy testing
may be done in one pivotal trial using an adaptive design saving precious time.
ADvantage will run a small
study designed to define the spectrum of biomarker changes to deliver POC, i.e.
principal milestone (1) [2-arm study, classical AD04 dosage vs saline, n=20/arm,
endpoints: hippocampal volume, inflammation markers (PET, CSF)]. In parallel, ADvantage
will further validate the mode of action in AD using specific biomarker assays.
After the POC study, ADvantage can be sold in a trade sale process.