Clinical Research: Phase 1 - Phase 4

Better Days Ahead? The Emerging State of CNS Drug Development

Experts describing recent advances in drug development often drift into hyperbole — but really, can you blame them? Gene therapies and drugs that weaponize the immune system against tumor cells are among recent breakthroughs that were unthinkable even a decade ago.

But therapies for central nervous system disorders have been a stubborn exception. “We recognize that progress across different therapeutic areas has been uneven, including for complex neurological diseases,” former FDA Commissioner Scott Gottlieb wrote in a recent statement about how his agency is working to advance CNS drug development. But recent signs suggest that things are changing.

Central nervous system disorders are a diverse group of conditions that include psychiatric, neurological, and substance abuse disorders. Treatment options for these conditions have traditionally been limited or nonexistent, and development of new drugs has lagged other therapeutic areas — this despite the fact that one in four American adults today suffers from at least one CNS condition.

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Treating these patients costs more than $317 billion annually, and CNS disorders are expected to make up 14.7 percent of the global disease burden by 2020 — the largest burden of any disease group.

Still, patients have few treatment options. CNS drugs historically have cost far more to develop than other medications, yet have been among the least likely to receive FDA approval. In addition, management – and minimization – of the placebo effect remains an especially daunting challenge. Investors are understandably shy about taking such a big gamble, and consequently, many major pharmaceutical companies have scaled back CNS drug development or left the field altogether.

Now, one of the biggest biotech companies sees things turning around. “We believe that all the signs point to neuroscience as the next oncology,” Mike Ehlers, R&D chief at Biogen Inc., told investors last summer. He cited recent research breakthroughs that have improved the industry’s understanding of central nervous system disorders like Huntington’s disease and ALS. In addition, the FDA has recently granted Breakthrough designation to MDMA, currently in development for treatment of PTSD, and esketamine, in development for treatment-resistant depression.

It’s been a long road. “Perhaps no field in the life sciences has been as heartbreaking, from a drug development standpoint, as Alzheimer’s disease and dementia,” Fortune magazine reported in February. “The past two years alone have seen devastating setbacks for experimental Alzheimer’s drugs from a compendium of major pharmaceutical companies,” including Eli Lilly’s very public Phase 3 failure of solanezumab, which cost the company hundreds of millions of dollars and resulted in job cuts.

Even still, big pharmas and small biotechs alike are ambitiously pursuing new treatments for Alzheimer’s disease, depression, multiple sclerosis, PTSD, and migraines, among other conditions. Alzheimer’s, the biggest and most potentially lucrative target, has a poor track record to say the least. The FDA still has approved no drugs to treat the disease’s underlying causes, even as the world’s elderly population continues to grow.

In its 2018 Pipeline Report of drugs under development, Medical Marketing & Media lists Azeliragon, Lanabecestat, Crenezumab, and seven other Alzheimer’s treatments, most of them in Phase 3 trials.

There’s reason for optimism in a recent proclamation by Scott Gottlieb, the FDA commissioner. In a statement issued in February, Gottlieb announced a new focus on advancing treatments for neurological disorders that are not adequately addressed by available therapies. FDA guidance documents specifically target Alzheimer’s, Duchenne muscular dystrophy, migraine, epilepsy, and ALS.

“The guidance documents … are an important step in facilitating efficient development of treatments for patients with serious neurological conditions,” Gottlieb wrote. “These changes … will improve our ability to engage with sponsors, patients, and researchers, and adapt quickly to an environment where the science is changing at a breathtaking speed across many disease areas.”

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