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Ken Mariash, CEO of Sinaptica, sat down with Onyx for a feature-length interview.
Why did you become the CEO of Sinaptica?
I studied biochemistry and business economics. After a lab internship, where I spent a lot of time pipetting, I realized that while I loved research and science, I was more interested in dedicating myself to the business side of medicine.
I started off as a consultant and got a 50,000-foot view of the industry, working on strategy projects for blockbuster drug launches with big pharma clients like BMS and Janssen. Then I moved into industry, joining CSL, Australia's largest biotech, where I helped launch intravenous immune globulin (IVIG).
After CSL, I joined Baxter's BioScience division. We collaborated with Dr. Norman Relkin on a phase three study of IVIG for Alzheimer's disease, aiming to reduce amyloid levels in the brain. However, the study failed. It was the early days of the amyloid hypothesis. Nowadays we know that Alzheimer’s isn’t just about the build-up of amyloid, for one thing, it affects the electrical network of the brain.
Later, I was recruited to Boston Scientific's neuromodulation division. I formed the strategy group there and helped grow the spinal cord stimulation and others businesses from around $300 million to $900 million total. While there, we expanded into deep brain stimulation (DBS) for Parkinson's disease.
Neuromodulation excites me because it's targeted and precise. Electrical stimulation can modulate organ systems. In the brain, It’s all about targeting the correct network – that’s how we’ve seen new treatments become approved for Parkinson's, essential tremor, dystonia, epilepsy - and hopefully Alzheimer's soon.
A lot of Alzheimer's assets are, or were, being built on shaky phase two data. And so when I saw Sinaptica's data—it was profound: There was bright-line efficacy across all endpoints with strong biological confirmations. Cognitive endpoints all looked good. Functional endpoints all looked good. Virtually no confounds. But there was something else, indicating to me, and others, that there was also a remarkable biological phenomenon… transformative changes in the gray matter as well at the micro- and connectome- levels.
It was unlike anything I'd seen in 20 years. And so I joined Sinaptica.
How does neuromodulation work?
What sometimes people don't realize: every cell in your body is electrically connected to every other cell. And organ systems can be modulated by stimulation. So the vagus nerve, for example, works for epilepsy. The splenic nerve can release a population of T cells that are anti-inflammatory for rheumatoid arthritis. The sacral nerves for overactive bladder work really well. In pain management, modulated electrical pulses can mask pain signals traveling up the spinal cord. In epilepsy, rhythmic stimulation can reduce hyper-oscillatory activity, which helps restore balance to the brain’s signalling patterns. DBS works for Parkinson's, although we don't really know how.
Our approach at Sinaptica focuses on neuroplasticity— in other words, the process by which stimulating nerves strengthens them and builds new connections. Specifically, we look at long-term potentiation (LTP). LTP-like plasticity is crucial for memory formation–for creating new neural connections. When one delivers electrical energy to a brain network, it induces neuroplasticity. By inducing neuroplasticity, we strengthen the network that drives human memory. Alzheimer's is often thought of as a disease of dysfunction of the default mode network (DMN), and this leads to inability to form new episodic memories. Not by accident, the DMN is the first and biggest network to go down in Alzheimer's.
And it's well known already that the brains of Alzheimer's patients often exhibit epileptiform activity. There is a pattern of oscillatory imbalance. It results from excitation/inhibition imbalances. This oscillatory dysfunction is being restored in Alzheimer's through neuromodulation as well.
How does your Alzheimer’s neuromodulation work?
What we’re doing at Sinaptica is using precision neuromodulation stimulating the DMN, which we call “nDMN”. The key with our neuromodulation at Sinaptica is that we're pairing a very well-known stimulation technique, transcranial magnetic stimulation (TMS) concurrently with electroencephalography (EEG). That combination is like active sonar: we get very revealing feedback data for every pulse we send.
We're able to ‘ping’ the brain with single pulses, and then ‘listen’ with 64-channel EEG, which tells us which networks we've just ‘lit up’. This approach reveals so much about the unique structure of a patient's brain. We're able to stimulate, listen, and learn. This mapping allows us to accurately target the therapy to the right network, the DMN, and not the wrong network, e.g. the Dorsal Attention Network.
Sinaptica was founded based on a groundbreaking six-month Phase 2 study in mild-to-moderate Alzheimer’s, the toughest patients. The results from this study by our scientific co-founders showed 82% slowing of Alzheimer’s progression. We have another Phase 2 readout after one year of treatment coming out on October 31st (addendum: you can read more about this readout here). It’s worth remembering that Alzheimer's is 100% fatal: patients are essentially given a death sentence. But if we can slow the progression and give patients additional years of quality life, that's the best outcome we can hope for right now. I've lost two grandparents to Alzheimer's, and it's tragic how it affects everyone, but I would’ve loved to have had a few more quality years with them.
What does the future for Sinaptica look like?
We have the 52-week Phase 2 study results. We have another study starting in Italy, a multicenter study in mild Alzheimer's using a second-generation modality. We're also planning a phase three study in mild to moderate Alzheimer's next year. We haven’t seen any major side effects to our neuromodulation and have seen very positive results to date in this very challenging disease.
We’re also open to combined therapy using Sinaptica neuromodulation with pharmaceuticals. We believe that combinatorial approaches, like we’ve seen in HIV or cancer treatments, will eventually beat Alzheimer’s.
In the future, our platform technology could apply to many conditions. Our patents cover using TMS-EEG in any brain disease. Anywhere there's a brain circuit, we can illuminate it with TMS-EEG—conditions like Parkinson's, stroke, traumatic brain injury, autism, OCD, and depression—and we're developing algorithms to analyze and decode brain signals and learning how to target different diseases based on the relevant networks we need to target. In early studies, our technology also showed memory boosting effects of 60% to 80% in healthy volunteers. At Sinaptica, we're building a platform for neuromodulation with personalization and precision to treat Alzheimer’s and improve brain health.
