Over the past year, chatter has been building about combination drug therapy as the "New New Thing" in Alzheimer’s disease research. It is not idle talk. In the wake of anemic Phase 2 and 3 results, a movement has sprung up to turn ideas into action. Suggested by none other than Rusty Katz of the U.S. Food and Drug Administration, the topic of how the field could pull off clinical trials of two or more unapproved experimental drugs drew some 65 leading scientists and other stakeholders from across the country to Rockville, Maryland, last November. The occasion was the ACT-AD coalition’s fifth annual FDA/Alzheimer’s Disease Allies Meeting.

The scientists want to develop combination treatments with entirely new science. Rather than combine individually developed drugs in mild to moderate dementia, they are planning to test multiple experimental drugs in the preclinical stage of Alzheimer’s. “We are going to have to bite the bullet and be brave, and start combination trials as early as we can do it safely,” said Reisa Sperling of Brigham and Women’s Hospital in Boston, Massachusetts.

Dan Perry and Cynthia Bens of ACT-AD, the Washington, D.C.-based umbrella group for Alzheimer’s activist groups, hosted the meeting jointly with Diane Stephenson of the Critical Path Institute in Tucson, Arizona. C-Path is an applied research organization that engages regulatory with academic, industry, and other scientists to solve pre-competitive drug development problems.

After a day of discussion, the group parted with a pledge to take on the task. It is a large task, in part because testing drugs from more than one company in one trial or preclinical study will require a level of scientific and legal cooperation among companies that is nearly unprecedented in Alzheimer’s research. To facilitate such cooperation, the group agreed to whisk away leaders from the FDA, companies, universities, and other stakeholders for a three-day working meeting later this spring, where they would be charged with settling open questions and articulating a coordinated pathway that can be implemented. “Hermetically sealed room,” “Manhattan Project,” and “The Alamo” were some of the buzzwords that flew around, partly in jest, but partly in recognition of the size of the challenge.

Sperling urged that the spring meeting define specific action items that can be executed with current drugs and biomarkers. For his part, Katz said that the FDA wants to clarify with researchers exactly how a high-level draft guidance on combination trials that the agency published in 2010 can be applied to specific trial designs in Alzheimer’s. Michael Krams from Johnson and Johnson argued for a grander scheme, such as a jointly funded long-term biomarker observational study of up to 30,000 people. This study, “Framingham-on-steroids,” as Krams jokingly called it, would develop biomarker fingerprints for each disease stage going back to entirely asymptomatic, and then serve as a platform to spin off "sentinel" patient cohorts into a series of early-stage combination trials. Other speakers pointed to ongoing infrastructure in other indications that already enables multiple companies to jointly test combination therapies, or to contribute discontinued drugs to government repurposing initiatives (see Part 3 of this series). While people’s individual priorities varied, there was broad agreement that combination trials are both necessary and need a concerted effort to get off the ground. “We want to look back at today and say this is where it started,” said Stephenson.

Combination trials per se are nothing new. For years, researchers have tested two individually approved drugs together in one study, or added a single experimental drug to an approved one. For this approach, trial designs are established and the regulatory path is well trodden, said Owen Fields, a regulatory strategist at Pfizer. It also has yielded little improvement in Alzheimer’s treatment. For new AD drugs, this sequential approach of approving individually and then testing combinations is inadequate, scientists agreed. It is too slow, given that 10,000 baby boomers in the U.S. are turning 65 every day, said Stephen Salloway of Butler Hospital in Providence, Rhode Island. Other scientists expressed concern that some new drugs alone do not have robust effects on their own and would be discontinued even though they might well be effective when paired with another drug, especially in early disease stages.

Scientists are hoping to make a dent in the disease by combining two or even more disease-modifying therapies that are themselves in Phase 1 to Phase 3. This has never been done in Alzheimer’s research, though it is being done in cancer and being prepared in tuberculosis. And it can work. Last August, the FDA approved a combination treatment of four HIV drugs, two of which were previously approved but two that were new.

Several recent trends have converged to encourage researchers to try their hand at combination trials in Alzheimer’s. Setbacks in the clinic have reinforced the idea that it may take attacks on different pathways simultaneously to change the course of a disease as complex as Alzheimer’s. Research in tau and inflammation is rising in prominence and bringing these pathways to the fore as drug targets. Genetics research in AD is highlighting cholesterol management, endocytosis, and innate immunity as implicated in AD. “The risk genes tell us it’s not one gene, it’s not one target, and it’s going to take a multiple-target approach to be successful,” said Stephenson.

More narrowly, researchers who have conducted anti-amyloid trials say they have learned that hitting multiple targets even within just the amyloid pathway may be necessary to reduce amyloid levels earlier, safer, and more drastically than drugs have done to date. These researchers would start combination testing by adding a BACE inhibitor to an antibody. That is partly because for this type of combination, several Phase 2 or 3 drugs of both classes exist already.

Regulatory leaders have wanted to see combination trials ever since the FDA started the Critical Path initiative in 2004. Nine years later, both the will and the necessary tools appear to be in place. “We are very eager to develop combinations,” the FDA’s Bob Temple told the audience. Both Temple, a senior leader who oversees clinical science at the FDA, and Katz, who directs the agency’s Division of Neurology Products, spoke at this meeting (see Part 2 of this series).

The challenges are considerable. Starting with the scientific ones, Sperling noticed that it is unclear how trials can pick up combination drug effects, particularly in early disease stages, where the disease moves slowly. Biomarkers? They are proving their worth for selecting patients and indicating whether a drug hits its intended target. “But in terms of predicting clinical benefit, biomarkers are behind where we hoped they would be,” Sperling said. She was referring to the apparent dissociation between biomarker and clinical responses in the solanezumab and bapineuzumab Phase 3 results (see ARF related news story).

To Sperling’s mind, this problem can be solved by collecting biomarker information not only from small subsets of trial participants, but also from all participants in several more drug trials, such that scientists have more data to tell how each marker tracks with the subsequent clinical outcome. More sensitive cognitive measures are needed to detect the subtle changes that occur in early AD (see upcoming ARF Webinar on research in this area).

Getting Started with COMBAT
Gaps in those tools notwithstanding, Sperling has started planning a trial, to be called Combination Therapy in Early AD (COMBAT). The title is intentional. “After all, it is a war, and we are losing,” Sperling said. COMBAT could combine a secretase inhibitor and an immunotherapy to decrease Aβ production and facilitate clearance. In theory, such a trial could start in a few months, Sperling said. Alternatively, the trial could boost clearance by combining several antibodies that go after soluble, oligomeric, and fibrillar forms of Aβ. It could combine an anti-Aβ with an anti-tau drug to try to stem neurodegeneration, or add other neuroprotective or anti-inflammatory agents to any of the above. “I would love to build COMBAT to be a platform where we add COMBAT 2 and 3 as arms when these other drugs become available,” Sperling said.

The trial will contain adaptive features. Alas, which ones? Given the current lack of theragnostic power in the available biomarkers, it is unclear what short-term markers the trial could use to adapt dosing, randomization, or other parameters. One option would be to build early monitoring for ARIA-E into the model, because that side effect is known to happen soon after dosing, if it does. Another option might be to first run a small, continuous CSF monitoring study in some volunteers to determine when CSF biomarkers first respond to the given drugs—hours? days?—and build a lumbar puncture at that time point into the model as a basis on which to adapt. Importantly, the question of what markers to adapt on could be a deliberate objective of the trial, according to Don Berry, a leader in adaptive trial design at the MD Anderson Cancer Center in Houston, Texas. “You build the trial so it will answer that question along with other questions,” said Berry.—Gabrielle Strobel.

This is Part 1 of a three-part series. See also Part 2, Part 3. Read a PDF of the entire series.


  1. Questions for thought leaders:

    • Why are we putting most of the diagnostic and treatment dollars into the amyloid basket?
    • Isn’t it generally acknowledged that amyloid deposits are a feature of the late stages of the disease?
    • Do we really know which forms of amyloid Aβ are pathogenic?
    • What about small blood vessel damage and inflammation as either causative or contributing factors?
    • And what about oxidative damage as one of the primary causes?
    • Do we know what the targets are that initiate the earliest, asymptomatic stages of the disease??

    It’s hard to see how combinations of existing ”treatments” deal with these issues.

  2. Proposal for a Public-Private Consortium to Develop Combined Immunotherapy Targeting Aβ,Tau, α-synuclein, and TDP-43 as Disease-Modifying Interventions for Alzheimer’s Disease

    We propose the creation of a public-private consortium of centers without walls in academia and biotech/pharma to investigate mechanisms of Alzheimer’s disease (AD) transmission. Specifically, the consortium should evaluate the potential efficacy of immune therapy comprising a combination of monoclonal antibodies (MAbs) specific to pathological species of tau, Aβ, α-synuclein, and TDP-43 as disease-modifying interventions for AD.

    The misfolding and aggregation of disease proteins to form the hallmark lesions of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and related disorders culminate in the relentless accumulation of disease protein deposits that trigger the dysfunction and death of affected neurons (see Table below for representative examples).



    Examples of aging-related neurodegenerative diseases, hallmark lesions that enable their diagnosis, and peptide/protein building blocks of their pathological signatures. The lesions of some of these diseases, such as Lewy bodies (LBs) in PD, and those shared by ALS and FTLD such as TDP-43 inclusions, co-occur in AD. Thus, AD is the most common α-synucleinopathy and the most common TDP-43 proteinopathy. SPs = senile plaques; NFTs = neurofibrillary tangles; GCIs = glial cytoplasmic inclusions.

    Although little is known about the mechanisms underlying the onset and progression of these diseases, growing evidence suggest these may occur through the cell-to-cell spread of pathological disease proteins (for recent reviews, see 1-3). How transmission occurs in most neurodegenerative disorders is unclear, but prion diseases provide insights relevant to AD, PD, and other related disorders. Briefly, normal prion proteins undergo templated conversion to pathological species that spread from cell to cell and are linked to neurodegeneration. With respect to non-prion disorders such as AD, it is known that tau and Aβ pathologies progress in a stereotypical pattern consistent with the cell-to-cell transmission of an unknown pathogen. However, AD also is characterized by the accumulation of pathological α-synuclein in Lewy bodies (LBs) and TDP-43 protein deposits in about 50 percent of AD patients, making AD the most common α-synucleinopathy and TDP-43 proteinopathy. Despite growing evidence of the transmissibility of tau and Aβ pathology, the exact nature of the transmissible agent or agents underlying AD remained enigmatic until very recently, when experimental studies demonstrated that fibrils formed by synthetic α-synuclein, Aβ, and tau were sufficient to transmit neurodegenerative disease characterized by LBs, plaques, and tangles, respectively (4-6). The mechanisms underlying the transmission of pathologic α-synuclein, tau, and Aβ, as well as their contributions to disease progression, remain largely unexplored, and it is not known if synthetic TDP-43 fibrils can transmit disease, as do α-synuclein, tau, and Aβ fibrils. The figure below summarizes the hypothetical role that the transmission of tau pathology may play in AD, based on the studies of Iba et al (6) and current understanding of tau-mediated neurodegeneration (7).



    Hypothetical processes whereby normal tau is converted into pathological tau that fibrillizes and deposits into NFTs of affected neurons in AD. Genetic abnormalities and environmental factors may accelerate this process. Normal quality-control systems (chaperones, ubiquitin proteosome and phagosome/lysosome systems) that prevent/reverse protein misfolding or eliminate misfolded proteins are overwhelmed. Remarkably, recent data suggest that the progression of AD, PD, and related disorders may be linked to the cell-to-cell spread of pathological species of tau, Aβ, and α-synuclein, as illustrated in the upper right of the figure. The toxic consequences of pathological tau are illustrated in the lower right.

    Thus, we see a compelling rationale for targeting transmissible species of tau, Aβ, and α-synuclein using passive immune therapy to treat AD. It is plausible that targeting TDP-43 in a similar manner will have potential therapeutic benefit for AD patients, since 50 percent of AD patients harbor TDP-43 pathology. Accordingly, we believe it is warranted to invest in the high-risk but potentially highly therapeutically beneficial effort to generate MAbs specific to pathological tau, Aβ, α-synuclein, and TDP-43, and combine them into a single infusate as therapy for AD. This is similar to what has been undertaken with passive immune therapy for AD using Aβ-specific MAbs alone, except that we propose here the combined use of MAbs specific to pathological tau, Aβ, α-synuclein, and TDP-43 because AD is a multi-proteinopathy of plaques, tangles, LBs, and TDP-43 inclusions.

    This is not an entirely new approach, since intravenous immunoglobulins are in clinical trials for AD (8). In parallel with efforts to develop immune therapy to AD that combines a mixture of MAbs specific to pathological tau, Aβ, α-synuclein, and TDP-43 in a single passive immunization protocol, it is timely and critical to investigate the mechanisms underlying the transmission of these disease proteins in AD, and how one disease protein may cross seed the fibrillization of another disease protein (9). Finally, although fibrillar species of tau, Aβ, and α-synuclein transmit disease similar to prions, they differ sharply from prions in that they do not show evidence of infectivity (10). Hence, studies to understand the differences between proteinacious infectious particles such as prions and transmissible non-infectious species of pathological tau, Aβ, and α-synuclein are warranted.

    Thus, the consortium envisioned here would include investors and contributing participants from academia, pharmaceutical companies, biotechnology companies, venture philanthropies, and state and federal governments who would contribute funding, expertise, model systems, MAbs, preclinical testing capabilities, toxicology, etc., according to their interests and abilities. Models for such partnerships include the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Parkinson’s Progression Markers Initiative (PPMI) that focus on biomarkers for AD and PD, respectively (11,12). However, since ADNI and PPMI work in precompetitive space, a new “compact” for governance of this consortium would need to be designed to develop an algorithm for rewarding participants in accordance with their respective contributions, should this consortium lead to successful treatments for AD that generate commercial revenues. This challenge notwithstanding, the funding target for this proposal would be $10 million per year for 10 years, for a total of $100 million, with the deliverable being one or more MAbs specific to pathological tau, Aβ, α-synuclein, and TDP-43 that are shown to block progression/transmission of tau, Aβ, α-synuclein, and TDP-43 pathologies in appropriate animal models that could be combined into a single infusate for testing as therapy for AD.


    . Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol. 2011 Oct;70(4):532-40. PubMed.

    . Protein aggregate spreading in neurodegenerative diseases: problems and perspectives. Neurosci Res. 2011 Aug;70(4):339-48. PubMed.

    . Cell biology. A unifying role for prions in neurodegenerative diseases. Science. 2012 Jun 22;336(6088):1511-3. PubMed.

    . Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012 Nov 16;338(6109):949-53. PubMed.

    . Purified and synthetic Alzheimer's amyloid beta (Aβ) prions. Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):11025-30. Epub 2012 Jun 18 PubMed.

    . Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci. 2013 Jan 16;33(3):1024-37. PubMed.

    . Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb Perspect Med. 2011 Sep;1(1):a006437. PubMed.

    . Intravenous immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence. Drugs. 2010 Mar 26;70(5):513-28. PubMed.

    . Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. PubMed.

    . Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 2013 Apr;70(4):462-8. PubMed.

    . The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception. Alzheimers Dement. 2013 Sep;9(5):e111-94. PubMed.

    . The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol. 2011 Dec;95(4):629-35. Epub 2011 Sep 14 PubMed.

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News Citations

  1. CTAD: New Data on Sola, Bapi, Spark Theragnostics Debate

Webinar Citations

  1. New Frontier: Developing Outcome Measures for Pre-dementia Trials

Other Citations

  1. Part 3

External Citations

  1. combination treatment of four HIV drugs

Further Reading