Alzheimer’s Disease

General description for public users. This is the public user homepage for the Alzheimer’s Disease (AD) Therapeutic Area.  There are currently few approved drugs for the management of AD, and numerous high profile development failures have tempered enthusiasm for eventual treatment breakthroughs.  Nevertheless, AD remains a very busy pipeline area and there are more than 120 active development programs.

The STEPh REPORT for Alzheimer’s Disease reviews compounds and development programs currently under study from preclinical through NDA submission.  Information is reviewed in multiple formats:

  • mechanism of action
  • phase of development
  • projected year of approval

In addition, each compound has its own monograph that expands on the clinical efficacy and safety information reported during clinical trials.  Where available, links are provided to abstracts of relevant information such as published literature, SEC filings, and press releases.  The Alzheimer’s Disease STEPh REPORT is kept current as new information becomes available (e.g., new reports are uploaded every other month).  After downloading the STEPh REPORT, you can select the bookmark function from the PDF file for easy maneurverability through the document.

The Alzheimer’s Disease homepage also includes links to relevant resources, daily and archived AD news of interest, mini-reviews of Hot Topics, and a continuously updated Pipeline Table.

Access to the full Alzheimer’s Disease STEPh REPORT as well as the other informaiton in the AD homepage is available by subscription.  Please feel free to contact us for more information about becoming an active subscriber to this and other services offered by STEPh Inc.

Table of Contents

  • REPORT OVERVIEW
  • TABLE OF CONTENTS
  • TOPLINE SUMMARY
    • Background Information
    • Projects in Various Phases of Developement
    • Drug Targets
  • AD RESEARCH
    • Companies Involved in AD Research
    • Companies with a concerted Development Effort in AD Research
  • OVERVIEW OF B-SECRETASE INHIBITORS
  • OVERVIEW OF Y-SECRETASE INHIBITORS AND MODULATORS
  • OVERVIEW OF ACTIVE IMMUNOTHERAPY
  • OVERVIEW OF SEROTONIN ANTAGONISTS
  • OVERVIEW OF NICOTINIC AND MUSCARINIC RECEPTOR MODULATORS
  • OVERVIEW OF HISTAMINE ANGONISTS
  • OVERVIEW OF GSK3Β INHIBITORS
  • OVERVIEW OF DRUGS THAT TARGET TAU
  • OVERVIEW OF NEUROTROPHIC GROWTH FACTORS
  • OVERVIEW OF NMDA ANTAGONISTS
  • RECENTLY DISCONTINUED PROJECTS OF NOTE
  • DRUG MONOGRAPHS OVERVIEW
    • Individual Drug Monographs
    • Phase of Development of AD Compounds
    • Earliest Possible Approval Date for AD Compounds in Development
  • COMPOUNDS IN PHASE III DEVELOPMENT
  • COMPOUNDS IN PHASE II DEVELOPMENT
  • COMPOUNDS IN PHASE I DEVELOPMENT
  • COMPOUNDS IN PRECLINICAL AND DISCOVERY DEVELOPMENT

TOPLINE SUMMARY

Background Information

According to statistics recently made public by the Alzheimer’s Association (http://www.alz.org/downloads/facts_figures_2013.pdf ), an estimated 5.2 million Americans of all ages have Alzheimer’s disease in 2013.  This figure includes 5.0 million people age 65 and older, and 200,000 individuals under age 65 who have younger-onset Alzheimer’s.  One in nine age 65 and older has Alzheimer’s disease.  Of those with Alzheimer’s disease, an estimated 4% are under age 65, 13% are 65 to 74, 44% are 75 to 84, and 38% are 85 or older.

 

  • Theories on the pathogenesis of AD continue to evolve and this is reflected in the increase in the number of targets for drug therapy.  Patients with more severe disease are probably less likely to significantly benefit from treatment than those who are treated in the very early stages of the disease.

 

  • There are several treatment obstacles:  pathological changes are evident prior to development of cognitive decline and patient diagnosis; late onset AD is a heterogeneous disease and patients have mixed uncharacterized pathologies; single-target treatment approach is not very effective as noted by treatment failure in major phase III trials.  Current belief is that treatment must be initiated very early on in order to significantly impact the disease process.  Recent attention has been given to PREVENTION studies.

Draft Guidance

FDA issued (February 2013) a Draft Guidance for Developing Drugs for the Treatment of Early Stage Disease (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338287.pdf ).  The guidance addresses FDA’s current thinking regarding the selection of patients with early AD, or patients who are determined to be at risk of developing AD, for enrollment into clinical trials.  It also addresses selection of endpoints for clinical trials in these populations, as well as the manner in which disease modification might be demonstrated including the role of biomarkers. 

Recent Treatment Failures

It has been 10+ years since the last new drug was approved for the treatment/management of AD patients.  In the interim, there have been several high profile developmental failures, such as semagacestat (ᵞ-secretase inhibitor, tarenflurbil (ᵞ-secretase modulator), and more recently, bapineuzumab and solanezumab (monoclonal antibodies), and avagacestat.  There are several prevailing postulates that attempt to decipher the most likely reasons for the apparent difficulties in drug development for AD.  These include: treatment traditionally occurs too far along in the disease process to bring about meaningful benefits; the disease process is more complicated than previously thought and targeting a single receptor or disease process is insufficient to evoke a meaningful clinical response; investigational agents either do not sufficiently penetrate the blood-brain-barrier or do not stay long enough at the intended drug target; and, animal models do not accurately predict clinical effects in humans.  Future research may indicate that treatment should be initiated before clinical symptoms appear and that a multi-targeted approach may be necessary to prevent significant cognitive decline.  In this regard, preventive strategies (such as immunization against disease) may prove to be the most effective way to manage this disease condition.

A recent publication reviewed why a cure for AD has yet to be found: “It is unlikely that attacking a downstream phenomenon, like apoptosis or amyloid-β accumulation, can cure AD, or prevent the progression of the disease.  It is probable that senile dementia is the result of a combination of several processes, working differently in each person.  Epidemiological studies have identified many risk factors for “senile dementia of the Alzheimer type”, some genetic but most environmental and therefore modifiable.  Thus, a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age.” [Korczyn AD.  Why have we failed to cure Alzheimer’s disease?  J Alzheimers Dis 2012;29:275-82. doi: 10.3233/JAD-2011-110359. http://www.ncbi.nlm.nih.gov/pubmed/22258512 ].

National Alzheimer’s Plan

The Department of Health and Human Services (HHS) released the first National Alzheimer’s Plan in May 2012, which was updated in 2013.  The 2013 Update includes a new timeline for achieving its first goal—prevent and effectively treat Alzheimer’s disease by 2025—and a review of progress over the past year.

 

The Update includes the following changes:

  • Creation of milestones to facilitate achievement of the goal to prevent and effectively treat Alzheimer’s disease by 2025.
  • Creation of an Alzheimer’s disease curriculum for primary care practitioners.
  • Special attention to examine unaddressed needs of patients in late stages of disease.

Prevention Studies

The NIH announced (May 2012) a major initiative to seek new treatment by 2025 for AD.  Two therapies were selected for study for prevention of AD:  the crenezumab trial was one of two announced as part of the National Plan to Address Alzheimer’s Disease. The other one is a five-year, $7.5 million trial headed by Suzanne Craft at the University of Washington, Seattle, to test whether an intranasal insulin spray improves cognition in 240 people diagnosed with mild cognitive impairment.  Most of the participants in the crenezumab trial will be drawn from an extended family of 5,000 people who live in Medellin, Colombia, and villages outside that city.  That family is believed to have more members who suffer from Alzheimer’s than any other in the world. Those who possess a specific genetic mutation begin showing cognitive impairment around age 45 and full-blown dementia around 51.  The $100 million study will run for five years, but results on sophisticated tests may indicate in as little as two years whether the drug is helping to delay memory decline or brain changes.  Although a relatively small percentage of people with Alzheimer’s have the genetic early-onset form that affects the Colombian family, the trial is expected to answer questions that could apply to a broader population. The crenezumab study will also include a small number of Americans with gene mutations guaranteed to cause early-onset Alzheimer’s.

In addition to the crenezumab trial, the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN TU) at Washington University School of Medicine in St. Louis is conducting a major prevention trial with active drug therapy (solanezumab, gantenerumab).  The DIAN Prevention Study is a phase II/III randomized, double-blind, placebo-controlled multi-center study of 2 potential disease modifying therapies in individuals at risk for and with dominantly inherited Alzheimer’s disease.  The trial is the result of collaboration between academia, industry, and advocacy groups.  Roche and Lilly have agreed to make the treatments available at no cost to investigators and will provide supporting grants.  The trial is also supported by a $4.2 million grant from the Alzheimer’s Association.  The researchers have applied for support through the NIH.  The trial began December 2012 and will enroll 210 patients, which will include those who have inherited mutations and participants who did not inherit the Alzheimer’s mutations.  Patients will receive solanezumab 400 mg IV once monthly, gantenerumab 225 mg subcutaneously once monthly, or placebo.  All subjects will be within 10 to 15 years of the anticipated age when symptoms of cognitive decline and dementia are expected to appear.  The first part of the trial is planned to last for 2 years and will be expanded and extended if one or more of the drugs are effective in slowing or stopping indicators of presymptomatic AD.  The projected study end date is December 2016.

CURRENT RESEARCH STATUS

There are more than 120 active compounds in development and ~200 development programs.  In some cases, companies have indicated that they have an active program in AD but have not identified specific compounds that they have under study.  The greatest clinical focus centers on immunotherapy, which is usually administered early on in the disease process where they may eventually prove to halt disease progression.

Companies appear willing to advance compounds to phase III based on marginal clinical effects observed in phase II trials.  Pfizer was by far the most active company in AD research.  At one point, Pfizer had at least 9 active AD projects across 8 mechanisms of action but has since terminated several programs (lack of efficacy and/or strategic refocusing).

Projects in Various Phases of Development

More than 120 active projects/agents are currently in development.  There are few compounds in phase III and the likelihood of success of these agents is tempered by the recent failure of much hyped agents that were either terminated early or failed to show significant clinical effects.  Given the financial rewards to be gained for new therapies that improve cognition and daily functioning, it appears companies are willing to gamble that marginal clinical benefit observed in phase II trials will translate to successful results in phase III.

Drug Targets

As more theories about the pathogenesis of AD continue to emerge, so too have the number of drug targets increased.  The β-secretase theory seems to have fallen out of favor and this is reflected in the paucity of active projects in this area.  Gamma secretase inhibition continues to generate interest but only those agents that alter the ɣ-secretase substrate and have no effect on Notch have any chance to be commercialized.  Semagacestat reached phase III but was discontinued due to safety concerns and worsening of cognitive and daily living functions.  Similarly, avagacestat was dropped in phase II due to worsening in cognition.  Flurizan, an isomer of the NSAID flurbiprofen, had marginal activity in a phase II trial but progressed to phase III where trials were a failure.  A similar number of development projects are currently targeting histamine, serotonin, nicotinic/muscarinic receptors, and Tau.  By far, the greatest interest centers on immunotherapy with an equivalent number of vaccines (active immunotherapy) and monoclonal antibodies (passive immunotherapy).  To be effective, immunotherapy should be administered early in the course of illness before a patient has progressed to more moderate/severe disease.  Many of the agents in development have either multiple mechanisms of action or their precise mechanisms are not clearly understood and thus not included in the above totals.

Link to Diabetes?

Diabetic patients have been demonstrated to have an increased risk for development of Alzheimer’s disease.  However, many questions are left to be answered, such as whether cognitive impairment observed in diabetic patients is the result of excess pathological features of AD or vascular disease, whether cognitive impairment in diabetic patients is less severe than those with dementia but no diabetes, and impact of diabetes in AD patients who are ApoE carriers.  Also, how will treatment with anti-diabetic agents impact the pathological course of Alzheimer’s disease.  To help address the latter question, a phase III trial with pioglitazone is currently in progress.

Combination Therapy

Combination therapy may be an approach that gains in popularity, given the heterogeneity of the disease and the growing number of different mechanisms of action of compounds in development.  In addition, as the FDA appears to be receptive to combination studies, companies that have multiple development programs are increasingly more likely to initiate combination drug trials in an attempt to increase the likelihood of treatment success.  An initial preclinical combination trial was conducted by Roche with R7129 (BACE inhibitor) and gantenerumab (MAb), which showed promising results.  However, Roche has noted that R7129 has been dropped from further human clinical trials.

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