Recent failures in Alzheimer’s Research and Development (R&D)

27th March 2017 (Last Updated March 27th, 2017 18:30)

No new Alzheimer’s drug has made it to market in the last 14 years. However, given the huge demand and sales potential in this therapy area, manufacturers continue to invest in costly clinical trials.

No new Alzheimer’s drugs have made it to market in the last 14 years. However, given the huge demand and sales potential in this therapy area, manufacturers continue to invest in costly clinical trials. Their efforts have been further emboldened by the recent improvements in biomarkers allowing for better patient identification in a variety of diseases.

As 99% of Alzheimer’s drug trials have failed in the past decade, it is vital for manufacturers to learn from previous mistakes when moving forward.

The table below summarises pivotal trials for Alzheimer’s treatments that have failed in the last 10 years.

Drug

Manufacturer

Description

Phase

Termination Date

What Went Wrong?

Idalopirdine

Lundbeck/

Otsuka

A 5-HT6 antagonist as a symptomatic adjunct to Chl.

III

February 2017

Dosage was changed from 30mg thrice daily in Phase II down to once daily 30mg or 60mg doses in Phase III in an attempt to reduce the dropout rate. This is likely to have contributed to the insufficient pharmacological effect.

Solanezumab

Eli Lilly

A monoclonal antibody against Aβ (It was the most advanced drug in the pipeline until November 2016).

III

November 2016

Eli Lilly stated that in the first two trials, some patients did not have the Aβ pathology, which the drug targets, thus weakening the outcome results. However, in the final study, despite ensuring the presence of Aβ in all participants, solanezumab still failed to improve patients’ cognition compared to placebo, calling into question whether Aβ is in fact the right drug target or not.

 Bapineuzumab

Pfizer/

Johnson & Johnson

The first monoclonal antibody to show reduction in total and phosphorylated tau.

III

August 2012

Bapineuzumab failed to show change in cognitive or functional performance in two Phase III trials. The risk of amyloid related imaging abnormalities (ARIA) or brain swelling associated with amyloid clearance meant that the dosing of bapineuzumab was kept low, limiting the amount of antibody that could get into the brain.

 Latrepirdine (Dimebon)

Pfizer/

Medivation

An inhibitor of cholinesterase and N-methyl-D-aspartate receptor (NMDA) receptors, which has been used as an antihistamine in Russia since the 1980s.

III

March 2010

Although positive preclinical and Phase II results were reported, three pivotal Phase III trials showed no cognitive benefits over placebo. A mechanism of action (MOA) for cognitive benefit is unclear, and the failure may partly be due to insufficient understanding of its MOA.

Intravenous Immunoglobulin/IVIG (Gammagard)

Baxter

An intravenous infusion of antibodies from human plasma and a US Food and Drug Administration (FDA)approved treatment for a wide range of immune-deficiencies.

III

May 2013

Intravenous immunoglobin (IVIG) failed to show benefits in cognitive and functional abilities, but secondary analyses showed a hint of beneficial effect in moderate Alzheimer’s patients. It is still unclear whether IVIG is effective in treating Alzheimer’s disease or not.

Semagacestat

Eli Lilly

Semagacestat blocks the enzyme, γ-secretase, and reduces the production of Aβ40 and Aβ42.

III

August 2010

The treatment arm showed worse performance than the placebo arm. Semagacestat’s failure is likely to be due to the inhibition of all γ-secretase’s 40-plus substrates (such as the notch receptor), which could have affected safety and pharmacology.

Tarenflurbil (Flurizan)

 

Myriad Genetics & Laboratories

A first generation γ-secretase modulator.

III

June 2008

The efficacy curves of treatment and placebo almost completely overlapped. The failure is mainly attributed to insufficient penetration in the brain and engagement with the target protein.

Tramiprosate (Alzhemed)

 

Bellus Health (Formerly Neurchem)

An Aβ aggregation inhibitor that acts through the inhibition of glycosaminoglycans.

III

November 2007

Tramiprosate failed to induce any cognitive improvement and caused moderately severe gastrointestinal (GI) side effects.

Source: GlobalData
ARIA = amyloid related imaging abnormalities; CHI = cholinesterase inhibitor; GI = gastrointestinal; IVIG = intravenous immunoglobulin; MOA = mechanism of action; NMDA = N-methyl-D-aspartate

 

Future clinical trials in Alzheimer’s disease can benefit from the lessons learned from these trials, which include the following:

  • Earlier intervention is likely to increase the clinical effect. Amyloid-targeting drugs such as idalopirdine would likely have shown stronger benefits in a pre-symptomatic population. It is increasingly relevant to consider effective patient stratification using a multitude of biomarkers and testing drugs in prodromal or Alzheimer’s patients.
  • More stringent preclinical evaluation is needed. Insufficient knowledge of the mechanism of action (MOA) largely contributed to the failure of latrepirdine. Although regulators are most focused on clinical outcomes, thorough understanding of compounds through mechanistic studies and target identification will reduce the risk of costly errors at later stages of development.

Related report:

GlobalData (2017). PharmaPoint: Alzheimer’s Disease – Global Drug Forecasts and Market Analysis to 2026, to be published