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Exploring the State of the Science

Multimodal therapeutic approaches have been used successfully to treat some complex neurological diseases such as pain and epilepsy for many years. Indeed, combination therapy is the standard of care for the treatment of PD, said Fiske. For example, levodopa, which is converted to dopamine in the brain and is the first-line treatment for PD, is nearly always given in combination with carbidopa, a levodopa enhancer that enables the use of a lower dose of levodopa and thus reduces the side effects of nausea and vomiting.

These examples not only provide lessons for future multimodal therapy development, but also illuminate the research gaps that need to be addressed in order to move ahead into new disease areas as efficiently and synergistically as possible, said Timothy Strauman. The theoretical considerations of seemingly simple approaches—using two drugs at the same time—are useful and apply to more complicated multimodal therapies, such as those that coadminister drugs with psychosocial intervention or neurostimulation, added Hildebrand.

CO-DELIVERY OF PHARMACOLOGICAL INTERVENTIONS FOR ALZHEIMER’S DISEASE

Currently, more than 35 million people worldwide are estimated to have AD, with these numbers expected to triple by 2050 unless an effective treatment is found to slow or prevent the disease (Alzheimer’s Association, 2014; Prince et al., 2013). Pharmaceutical drug development across all disease areas is risky, but drug development for AD has been particularly disappointing with only about 0.5 percent of compounds successfully proceeding from the preclinical phase to an approved drug (Calcoen et al., 2015), said Hendrix.

Emerging interest in using combination therapy to treat AD derives not only from the urgency to find new treatments, but also from experience in other disease areas such as cancer and HIV/AIDS, where cocktails of drugs have proven to be required for successful treatment (Hendrix et al., 2016). Moreover, the complex neuropathology of AD (Holtzman et al., 2011) suggests that it may be necessary to attack multiple pathways in order to slow the disease, said Hendrix. Indeed, treatments currently in the pipeline are being tested in combination with cholinesterase inhibitors, which are one of only two classes of drugs currently approved for the symptomatic treatment of AD. For example, one of these drugs, AVP923, is being tested in a Phase III trial for the treatment of agitation in AD. AVP923 combines dextromethorphan and quinidine, and is a possible example of super synergy. By itself quinidine has no effect, but it changes the way dextromethorphan is metabolized so it can reach the brain, said Hendrix. The product, marketed under the name Nuedexta, has already been approved for the treatment of pseudobulbar affect in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS).

Drugs being considered for possible combination therapy in AD span a wide variety of mechanisms, said Hendrix, including those that target amyloid β and tau, the proteins that aggregate as plaques and tangles in the AD brain, and those that are potentially neuroprotective (see Figure 3-1). For each of these targets, there may be multiple intervention possibilities, for example, stopping production or improving clearance of amyloid β or preventing the accumulation of tau. So a combination therapy could potentially attack one pathology in two different ways, attack two different pathologies, or attack one pathology in combination with a neuroprotective agent.

Of course, combining drugs introduces many other challenges related to pharmacokinetics, pharmacodynamics, dose finding, drug interactions, and other adverse events, said Hendrix. The routes of administration and dosing regimens could further complicate a trial, for example, if one drug is administered by infusion every third week while another is taken orally each day. Finally, regulatory and business issues should be considered, Hendrix said, adding that possibly the biggest barrier is that few companies are large enough and have the capacity and breadth of experience in AD to take on a combination trial. This is where an organization such as the Alzheimer’s Association comes in, building collaborative partnerships with multiple stakeholders. It was with this in mind that they convened a workgroup of regulators, academicians, and industry representatives to map out a path forward for AD combination therapy (Hendrix et al., 2016). The workgroup recommended proceeding with a 2 × 2 factorial four-arm design combining an anti-amyloid and anti-tau drug, where one arm would test the anti-amyloid drug alone, one arm would test the anti-tau drug alone, one arm would combine the two drugs, and one arm would be the placebo.