By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team

There are few who have Steve Paul’s perspective, experience and track-record in the neurosciences. A former scientific director at the NIMH/NIH, Paul was formerly President of Lilly Research Laboratories and an accomplished entrepreneur at Third Rock Ventures. Additionally, he co-founded two CNS-focused companies, Sage Therapeutics and Voyager Therapeutics (a gene therapy company). Now, Paul is CEO and Chairman of Karuna Therapeutics.

Throughout his multi-decade career, Paul’s interest in the neurosciences and drug discovery, particularly for psychiatric and neurological disorders, never diminished – despite a shrinking emphasis on neuroscience worldwide.         

His latest entrepreneurial endeavor is with Karuna, a neuroscience startup developing first-in-class therapeutics to improve quality of life for people living with schizophrenia, Alzheimer’s disease and pain. Rich Soll and the WuXi content team recently caught up with Paul to discuss Karuna and the revitalization of the neuroscience field in general.

“In the neurosciences, antipsychotics and Selective Serotonin Reuptake Inhibitors (SSRIs) once dominated the commercial pharmaceutical market; they dwarfed oncology and most other therapeutic areas,” explained Paul. “However, the collapse of the CNS market was attributable to several factors, including limited efficacy, tough clinical trials due to large placebo effects, and nothing better in the pipeline—a dearth of innovation.”

That has been changing in recent years. There’s an incredible amount of basic genetic and biological understanding of the etiology of many neurological disorders, especially diseases such as Parkinson’s disease, Alzheimer’s disease, MS, ALS, and Huntington’s. For psychiatric disorders, there’s little that is well understood with respect to genetics, and even those that are clearly inherited are highly polygenic disorders, which makes it very difficult to identify and validate drug targets based on genetics alone.

“Our knowledge about the intricacies and complexity of chemical neurotransmission, on the other hand, has advanced considerably over the last decade,” exclaimed Paul. “And we have capitalized on this knowledge with my first company, Sage Therapeutics, where we have developed a rich pipeline of drugs targeting GABA and glutamate receptors, including a recently launched drug for treating postpartum depression, and now with Karuna. These developments are happening primarily in small companies who work in the neurosciences.”

Karuna’s lead compound, xanomeline, was originally developed at Lilly in the 1990s for improving cognition in advanced Alzheimer’s patients. Although cognition was only modestly improved in this Phase 2 study, other neuropsychiatric symptoms, for example agitation and psychotic symptoms such as hallucinations and delusions (observed in 40-50 percent of advanced Alzheimer’s disease patients) were substantially improved, and this was accomplished without many of the troublesome side effects of traditional antipsychotic drugs, such as sedation and weight gain. However the elderly population did not tolerate the drug well due to peripheral cholinergic side effects. In another Phase 2 study in another form of psychosis that occurs in patients with schizophrenia, the drug once again appeared to be active.

“The drug stimulates preferentially two of the five G-protein coupled muscarinic receptors, M1 and M4 receptors, which led to both the beneficial and side effects. Although xanomeline was not developed further by Lilly, the drug nevertheless had a remarkable antipsychotic profile,” said Paul. “A simple, but elegant solution to this dilemma unfolded: Formulate xanomeline with a generic, non-brain penetrating, peripherally-acting muscarinic antagonist, specifically trospium.”

Trospium had other favorable features, including a long elimination half-life enabling it to cover the presence of xanomeline around the clock. Moreover, it’s not metabolized by the same liver enzymes as xanomeline, which meant likely fewer drug-to-drug interactions. The combination product is tagged KarXT.

Two Phase 1 studies have been conducted with KarXT and the combo has shown good tolerability. Currently, a large Phase 2 schizophrenia study is ongoing and by year’s end we will know if we see the same antipsychotic effects of xanomeline while attenuating its side effects.

“Based on feedback from three independent safety monitoring reviews of our unblinded Phase 2 data, we are cautiously optimistic that we have improved the tolerability of xanomeline through this reformulation,” proclaimed Paul. “We are very focused on M1 and M4 receptors and hope to eventually have other exciting drugs that stimulate these and other GPCRs and in different ways.”

Paul was a senior author on the initial Lilly paper describing xanomeline’s antipsychotic effect in Alzheimer’s disease.

“People ask me all the time ‘Why didn’t you think of this or do this when you were back at Lilly?’” Paul shared. “It’s interesting. I think we, in our zest to get the purest and cleanest kind of molecules, sometimes ignore data that’s sort of sitting right in front of us. Even if we had thought of this combination strategy, I don’t think we would have pursued it. It was just too inelegant for a large company. What we did was to go back to the labs to try to come up with a single molecule that had fewer of these peripheral cholinergic side effects and still retained the therapeutic benefits. We worked on that for 20 years, and we couldn’t do it.”

Paul believes Karuna’s approach has the potential to produce a differentiated therapy relative to current D2 dopamine receptor-based antipsychotic drugs, whose roots date back to the 1950s, and to beneficially impact the lives of millions of patients with schizophrenia and other psychotic and cognitive disorders.

Antipsychotics are often used by physicians to address a wide range of neuropsychiatric disorders but are associated with modest efficacy and significant side effects. Karuna believes the preferential stimulation of M1 and M4 muscarinic receptors in the CNS may also address the negative symptoms of schizophrenia, such as apathy, reduced social drive and loss of motivation, as well as cognitive deficits in working memory and attention, all of which currently lack any approved treatments.

Other beneficial properties of xanomeline have also been uncovered. It has been known for years that nonselective muscarinic agonists have analgesic properties. Scientists at AstraZeneca published a paper a few years ago showing that xanomeline has very potent analgesic effects across a broad range of animal pain models.

“We know that the pathway that mediates the analgesic effects are mediated via muscarinic receptors, instead of opiate receptors,” said Paul. “The drug reduces pain in various animal models distinct from the opiate receptor, so this could be a non-opioid pain medicine. To me, that’s remarkable that you can take an old drug that has been ignored, but you need to ask the right questions at the right time. If it works, we’ll also have good IP protection on the co-formulated product.”

Karuna, initially a PureTech-incubated biotech, completed its IPO in early July, raising approximately $102.6 million. So far, it has built its pipeline on the broad therapeutic potential of its lead product candidate KarXT as an oral modulator of muscarinic receptors. However, its intent is to commercialize in the U.S. and partner for all other regions. In five years, Paul’s plan is to have launched its first medicine, KarXT for acute psychosis in schizophrenia and Alzheimer’s disease, to have something in pain, and to have a very full mid-stage and early stage pipeline.

All of these plans are being conducted from a virtual organization, no labs.

“In today’s ecosystem, this is possible because of organizations like WuXi AppTec, where many parts of the value chain can be accessed with high quality and with people every bit as good as we had in the glory days of big pharma,” stated Paul.

“Currently, there are literally hundreds of smaller companies discovering and developing medicines in a very different way than we had traditionally done at big pharma. Gaining access to these critical components was not possible 20 years ago but now they are available, and they are cost-effective solutions.”

Paul also discussed two potentially game-changing technologies. The first relates to the availability of reliable, high throughput, in-silico chemistry approaches where biological targets with structural information, including crystal or Cryo-EM structures, are used to find chemical hits and leads much quicker; in many cases the compounds have already also have been prescreened for drug-like properties.

The second relates to screening behaviorally complex disorders such as depression or schizophrenia, essentially using phenotypic screening in mice, coupled with artificial intelligence and machine learning analytics, which allow for the design molecules that can modulate complex behavioral biology in a predictable way.

Paul concluded with this thoughtful insight: “Looking to the industry’s future there will definitely be more effective CNS drugs approved and more affordable drugs to boot. In the case of Karuna, we’re focusing on psychotic disorders and hope to introduce the next generation of antipsychotic drugs, arguably the first new generation in half a century. That makes me feel good.”