Treatment Options
Pipeline Treatments
Disease modifying treatment:
Disease-modifying drugs are substances that block or prevent the pathophysiological processes which trigger Alzheimer's disease. The disease-modifying treatment has a direct influence on the cause of the disease. Examples we will take a closer look at below are:
- β-amyloid (Abeta, Aβ) peptide aggregation inhibitors
- vaccines that induce an immune response against Aβ
- drugs that inhibit the enzyme that produces β-amyloid.
Figure 1. Prevention of β-amyloid pathway:
Amyloid precursor protein (APP) is sequentially cleaved by γ-secretase and then β-secretase to form soluble amyloid precursor protein β (sAPPβ) and the amyloid β 42 protein fragment (Aβ42). The Aβ42 fragments then aggregate and form the extracellular plaques common to Alzheimer's disease. (Modified from: http://www.sigmaaldrich.com/Area_of_Interest/Life_Science/Cell_Signaling/Product_Highlights/L685458.html)
Treatments hypothesized to prevent plaque formation:
γ-secretase inhibitors - Flurizan™ LY-450139
History of the Identification of Flurizan™ as Potential Disease Modifier in AD
An epidemiological study of 7983 patients indicated that long-term use of certain non-steroidal anti-inflammatory drugs or NSAIDs reduce the likelihood of developing AD by 80%. Further analyses revealed that decreased risk of AD appeared to correspond only with those NSAIDs which lowered the production of Aβ42. Preclinical studies have demonstrated that Flurizan lowers the level of Aβ42 more than other NSAIDs without inhibiting cyclooxygenase (COX).
Facts
Active compound: R-Enantiomer of NSAID Flurbiprofen (MPC-7869)
Company: Myriad Genetics (licensed by Encore Pharmaceuticals)
Mechanism of action: Modulator of γ-secretase (enzyme involved in the cleavage of the amyloid precursor protein (APP), see figure 1 above)
Effects
- Shift the cleavage site of APP from Aβ42 to Aβ38
- selective reduction of amyloidogenic Abeta42
- no cyclooxygenase (COX) inhibition
- good safety and tolerability profile expected.
Other Indications
Prostate Cancer
Colon Cancer (not approved)
Flurizan™ - Relevant trials in AD
| Trial | Comments / Results |
| 1. Phase I | - Flurizan is well tolerated in all kind of doses - no severe adverse events or dropouts |
| 2. Phase II | 1 year study which enrolled 200 patients with mild to moderate AD in Europe and in Canada - it compares memantine alone vs. memantine plus Flurizan - designed to show Flurizans efficacy in slowing and reversing cognitive decline (measure: ADAS-Cog score) in AD patients by lowering Aβ42 peptide levels - although a positive trend was observed Flurizan failed to achieve statistical significance in this study |
| 3. Phase III | 12 month, double blind, placebo-controlled, randomized, 100 center study which includes 750 patients with mild to moderate AD; enrolled in January 2005 - the major objective is to determine the ability to alter the course of cognitive decline and behavioural change under treatment (endpoints: ADAS-cog and ADL) - results are expected in 2007/2008 - after the failure of the phase II trial Myriad is considering modifying the study design to focus future enrollment on mild Alzheimer’s patients |
Additional information
in January 2005, Myriad announced that they are going to accelerated the development for Flurizan by starting a late-stage phase III trial before the end of an ongoing mid-stage study.
Conclusion
Interesting therapeutic approach. However, approval of Flurizan not expected in the next years.
Vaccination (AN-1792)
Facts
Active compound: Synthetic form of 42 amino acid beta amyloid peptide (Aβ42) (antigen).
Company: Elan Pharmaceuticals Inc., Wyeth.
Mechanism of action: Vaccine (hypothesis that the immunization can prevent and/ or reverse the development of Alzheimer`s disease)
Effects
- Immunization should result in the reactive generation of anti-Aβ-antibodies
- Should thereby prevent β-amyloid plaque desposition and destroy existing plaques
- Prevention of AD
Other Indications
MS
Crohn‘s disease (not approved)
Vaccination AN- 1792 - Relevant Trials
| Trial | Comments / Results |
| preclinical | - AN-1792 leads to an immune response - Transgenic mice treated with AN-1792 had no detectable amyloid deposits in their brains compared to controlled groups - Transgenic treated mice had significantly (>99%; p value=0.0002) less plaques and neuropathology than untreated animals |
| Phase I trials | AN-1792 is well tolerated and revealed a mechanism of action |
| Phase IIa |
2-year multicenter phase IIa study involving 375 patients began in September 2001 |
Conclusion
Results from trials using active immunization with AN-1972 support the hypothesis that anti-Aβ-antibodies might positively influence the disease progression in AD patients. This approach, however, is still at a very early stage.
Additional information
In March 2002, Elan discontinued treatment of patients with AN-1792 due to reports of encephalitis. The company continued clinical investigations on the effect of AN-1792 in patients which have been vaccinated. In patients who developed antibodies there seemed to be an effect on memory and a reduction in plaque load. Elan is currently working on the development of a substance for passive vaccination.
β-amyloid peptide aggregation inhibitors - Alzhemed™ (NC-531)
Facts
Active compound: 3-amino-1-propanesulfonic acid (3APS).
Company: Neurochem Inc.
Mechanism of action: Sulfated glycosaminoglycan (GAG) mimetic that inhibits amyloid beta fibrillogenesis.
Effects
- Expected to interfere with the formation of fibrils of β-Amyloid (Aβ) and should therefore prevent plaque formation.
- Favours clearance of soluble Aβ forms from the brain.
- Inhibits the inflammatory response associated with amyloid formation.
Other Indications
Stroke (not approved)
Additional information
The North American and the European phase III clinical trails are the first studies considered by the FDA to investigate neuroprotection / disease modification in AD First Disease modification studies
Data from the two trials expected not before 2007 / 2008.
Conclusion
No approval for AD expected in the next years.
Alzhemed™ (NC-531) - Relevant Trials
| Trial | Comments / Results |
| 1. Phase II |
3 month, multicenter, placebo-controlled, double-blind study in 58 patients with mild to moderate AD; completed in 2003
** in the groups with highest doses (200 or 300 mg/d) |
| 2. Phase IIb (Open-label-extention) | 18 patients of the phase II trial were followed another 17 months - the subset of mild AD patients (n=11) responded best to the therapy 70 % of these patients had now stabilized or improved scores of cognitive function test - no data available for the moderate cases - CSF levels of Aβ decreased; patients with best clinical response also had the largest decrease in CSF levels of Aβ-peptide - trial is still ongoing |
| 3. Phase III | 18-month, multi-centre, randomized, double-blind, placebo-controlled North American trial with 1052 patients with mild to moderate AD - patient enrolment completed in July 2005. In September 2005, approximately 470 and 210 patients had completed six and nine month of the trial respectively. - study is designed to demonstrate the disease-modifying potential of Alzhemed (assessed by the brain volume change from baseline as measured by magnetic resonance imaging(MRI)) |
| 4. Phase III | 18-month, multi-centre, randomized, double-blind, placebo-controlled and parallel-designed European trial with 930 patients with mild to moderate AD, launched in September 2005 - patients will be randomized to receive either placebo or one of two different dose levels of Alzhemed , in addition to their regular treatment with one of a number of AChEIs - study is designed to demonstrate the disease modifying potential of Alzhemed (assessed by the brain volume change from baseline as measured by MRI) |