Clinical:Bapineuzumab

Republished(by author self permission) from the following multimedia interactive articles.

Bapineuzumab (Pfizer, J&J, Elan) Review http://knol.google.com/k/krishan-maggon/bapineuzumab-pfizer-j-j-elan-review/3fy5eowy8suq3/119#

French

Le Bapineuzumab : enfin un remède contre la maladie d'Alzheimer ?

http://knol.google.com/k/krishan-maggon/le-bapineuzumab-enfin-un-remède-contre/3fy5eowy8suq3/123#

Abstract

Bapineuzumab is a fully humanized monoclonal antibody which targets beta amyloid protein involved in Alzheimer's Disease. There are 26 million patients in the world, half in Asia and the rest in N America/Europe with AD. It is the most advanced mAbs as well as the first new drug aimed at slowing, stopping the disease progression and degradation of the cognitive function. Johnson and Johnson paid over $ 1.5 billion for co-marketing rights to the originating company leading to mixed reactions from analysts. There are 14 ongoing Phase III trials in over 10,000 patients and results of some completed studies may be available in late 2012. The drug has fast track regulatory status with FDA. It must clearly show a beneficial and lasting effect through validated biomarker of underlying AD disease mechanism. If approved and marketed, this may be the first drug to stop disease progression and rate of decline in AD. It is hoped that clearing of beta-amyloid plaques results in slower rate of decline in cognitive and functional status of AD patients just like tumor reduction resulted in prolonged survival with cancer drugs. There are unconfirmed reports of clearing of plaques, progress in trials and return to "normal" of patients in early stages of AD and in clinical trials.

Other Names

Bapineuzumab is an investigation drug in Phase III trials in patients with Alzheimer's disease. It was discoverd and is being developed by Pfizer.

Uses

This article discusses the unlabeled and unapproved uses of Bapineuzumab. the drug has not been reviewed or approved by regulatory authorities in the US or Europe.

For the disease and disease related memory loss, please go to

Alzheimer's disease

Dimentia

How Bapineuzumab Is Taken

In clinical trials,the dose is given by iv infusion. The clinical effective dose is not known.

How Bapineuzumab Works

Bapineuzumab is a humanized mAbs for passive immunotherapy of AD and targets N terminus of the beta amyloid protein, one of the factor involved in disease pathogenesis. Johnson and Johnson agreed to pay $ 1.5 billion dollars to buy 18% stake in Elan and get majority share of its AD R&D portfolio including bapineuzumab.

Nomenclature

Bapi neu zu mab

Prefix neuro humanized monoclonal antibody

Bapineuzumab is a humanized monoclonal antibody for neurological disease.

Several analysts have rated the move risky due to high failure rates of new drugs in AD. On top J&J has to share market sales and profits with Pfizer and pay a royality to Elan.[31] If the drug works in AD, there is profit and Win Win situation for all the parties.

Research

There are no good animal models despite the prevalence of the disease in dogs, cats and animals in captivity. In the wild animals do not live sufficiently long for signs of the disease. The mouse model is used extensively but is not predictive of human AD. Both FDA and EMA have guidelines for new drugs testing in AD. FDA is evaluating the validity of an automatic non invasive, non threatening cognitive test for AD and histochemical test battery for efficacy and toxicity evaluation of new drugs as well as validity of new biomarkers for AD.

The history of new drug failures in Alzheimer's disease has been described in a previous book chapter by the author. At present there were ongoing 220 AD trials listed in Center Watch. Adis R&D database at the PhRMA site listed 9 drugs in Phase III, 20 in Phase II and 33 in Phase I in AD patients. There are 40 new molecular entities in trials involving over 10,000 AD patients. Newer drugs acting through AChE pathways for symptomatic relief of AD are not covered. During the past few years there has been a shift from acetylcholine target towards preventing or clearing plaque formation, protecting against oxidative damage to mitochondria and clearing or preventing neurofibrillary tangles. Active or passive stimulation of the immune system by vaccines and monoclonal antibodies. Some of the ongoing Phase III trials are studies to define the role of biomarkers, effect of music, resveratrol, thalidomide, vitamin E and epigallocatechin in AD. There is evidence to show that diabetes, depression, smoking and epsilon 4 allele of the apolipoprotein E gene (APOE e4) increase the risk of AD. Cognitive engagement and physical activities decreased the risk of AD. Mental stimulation, dietary supplements and exercise failed to prevent AD. There is a strong relationship between beta amyloid deposition and atrophy very early in the disease process and later by aggregated beta amyloid deposition. The use of MRI imaging may provide along with clinical tests and biomarkers better evaluation of AD for clinical trials. Genentech, GSK and Elan/Pfizer AC 001 vaccine are in early stage trials and results expected in late 2010.

Baxter iv Human Globulin has shown positive outcome in function and cognition in 14 patients (on active drug) who completed 18 months of treatment. MRI analysis showed treated patients had lower enlagement of the brain and brain atrophy as compared to control group. ( http://www.baxter.com/press_room/press_releases/2010/04_13_10_gammagard.html ).

Senile plaques are mainly formed of beta-amyloid a peptide with 42 amino acids. Drugs in clinical trials include AD vaccine from Elan, Bapineuzumab is the most advanced mAbs targeting beta-amyloid followed by Solanezumab (Lilly). Slanezumab was moved into phase III trials on the basis of Phase II safety and biomarker data without the results of any efficacy data. Lilly claims that it has identified rapid marker for target binding and bioactivity of its mAbs and additional biomarkers for indicating disease status. Semagacestat (Lilly) inhibitor of gamma-secretase is in Phase III trials followed by several other new compounds acting on the same enzyme. Stimulators of alpha-secretase are in R&D with 1 project in Phase II trials. Potent inhibitors of beta-amyloid aggregation in development include a leading compound in Phase III (EHT 0202). [14][15][16][17]. There are reports of reduction or clearing of amyloid plaques in AD patients treated with Bapineuzumab and stabilization of the disease in web chatter. Other reports say that bapineuzumab clinical trials showed a reduction in plaques but no improvements in cogntive functions? Clinical trials in AD now measure CSF AB levels, brain amyloid load, CSF tau, brain volume by MRI and FDG PET scan

Clinical Trials

The results of the double blind placebo control Phase II study in 234 mild to moderate AD patients were published. Patients were given a 6 dose schedule every 13 week of 0.15, 0.5, 1 and 2 mg/kg body weight or placebo. Primary predetermined efficacy points were Alzheimer's Disease Assessment Scale for cognition( ADAS-cog) and functional Disability Assessment Scale for Dementia (DAD). The mAbs failed to meet primary end points of efficacy and was no better than placebo. A post study subset analysis showed that significant reduction in cognitive and functional scale was achieved in non carriers of Apolipoprotein E є 4 allele. This observation justified moving to Phase III trials.

The effect of bapineuzumab on reduction of cortical fibrillar beta amyloid load in AD patients was studied with carbon 11 labelled Pittsburg compound B as a biomarker. Patients were randomly assigned to receive 6 infusions of 0.5, 1 or 2 mg/kg or placebo every 13 week and had PET scan at baseline and weeks 20, 45 and 78. All study staff, patients and caretakers were masked or blinded to the study through an interactive voice system. Out of the 28 enrolled patients, 20 received study drug mAbs and 8 were on placebo. Two patients at the highest dose reported vasogenic edema. Treatment with bapineuzumab reduced cortical 11 C PiB retention as compared with both baseline and placebo. PiB C11 PET scan may be used as a biomarker for cortical fibrillar beta amyloid load.[35]. Bapineuzumab treatment reduced CSF tau levels therby indication the mAbs was bioactive in the brain and may modify the underlying disease process. CSF AB levels increase within a day after treatment.

The 14 ongoing clinical trials are listed, some are completed and others recruiting AD patients. due to the incidence of vascular edema treatment with the highest dose 2mg/kg was removed ( during 2009) in the amended protocol with only the 0.5 and 1 mg/kg dose schedule. Johnson and Johnson has taken over the management of Phase III trials from Elan and decided to enroll additional patients for better statistical outcome. The results of these studies will be disclosed in 2012. Some of the Phase II-III trials are to validate and identify biomarkers, histological screen and automated cognition test as surrogate end points for AD. Pfizer is responsible for 4 safety and efficacy Phase III trials in over 4000 patients with mild to moderate Alzheimer's disease. There is a parallel with the anti-tumor drugs where reduction in tumor size correlated with anticancer effect resulting in stable disease and then increased progression free survival. Bapineuzumab efficacy in clearing beta amyloid plaques may similarly result in stable disease, slower decline or eventual improvement in cognitive and functional status of AD patients.

If the drug passes the safety and efficacy criteria in Phase III trials to be completed in 2012.The regulatory filing is expected during 2Q 2013 and approval by 4Q 2013. If the data monitoring board order early termination of studies due to seperior efficacy data in 2011, it may come a year earlier to the market. On the other hand if any safety or efficacy issues are raised or FDA/EMA ask for additional information, its approval and marketing may be delayed.

Immunotherapy of AD disease must avoid proinflammatory response and cytokine release cascade as well as vasogenic edema and microbleeds. AD patients have to spend 6 hours for ADAS and other AD assessments, sign a 18 page informed consent form?.

Immunotherapy of AD disease must avoid proinflammatory response and cytokine release cascade as well as vasogenic edema and microbleeds. AD patients have to spend 6 hours for ADAS and other AD assessments, sign a 18 page informed consent form?

To b added

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