In 2019, disheartened by the lack of progress and innovation in the space, Dr. Amit Etkin decided to leave Stanford University to pursue new treatments for conditions like depression and post-traumatic stress disorder.
In the same year, he founded Alto Neuroscience, a biotech company that uses biological measurements (biomarkers), to develop tailored treatments for those suffering from mental health conditions.
The novel approach has already shown promising results, with the company recently announcing positive findings for a phase 2 trial of lead candidate ALTO-100, a drug to treat major depressive disorder (MDD). Alto said the treatment demonstrated ‘clear evidence of efficacy and favorable safety in patients with MDD’.
“I was a tenured professor of psychiatry at Stanford and leaving that position was no small feat. You have your whole life set – to some degree. I had a big lab and from many perspectives – my career was in a great place. Stanford is one of the most preeminent institutions in the world, but I realized the limits of that environment and the reality is – you can’t create new treatments, at least in humans, in academia,” Etkin tells Bio Pharma Reporter.
“I almost saw it as graduating from school as an adult. I’d reached the end of that phase. It was very fruitful, but I now feel vindicated for that decision because our work at Alto has been so productive and we’ve made progress much faster than I could ever have imagined.”
Background and moving out of treatment stagnation
Outlining the timeline of mental health treatment, Etkin says while the rise of selective serotonin reuptake inhibitors (SSRIs) in the 1980s and 1990s seemed to ‘fix a lot of problems’, a couple of seminal studies in the 2000s exposed key limitations, causing ‘deflation’ after the hype died down.
“The reason we’re now building out of from that, is because at the time there was no real science of humans with diseases as much as there was animal models that didn’t translate to humans. So when things got hard, big pharma just pulled back instead of relying on the science that had been slowly building in the background – understanding people and their brains and how they differ,” he says.
Crucially, Etkin rejects the notion that the brain is ‘too complex’ and research will never be able to shed light on how to improve patients ‘subjective internal world’ and their mental well-being.
“It's true that the brain is a complex organ but that doesn't mean that you can't make advances and make them in very simple and actionable ways – by starting somewhere. The mistake that’s been made in this field is the idea that you first have to solve the brain, and that comes way in the future, and then we’ll finally be able to create new therapeutics and diagnostics,” he says.
“In reality, all clinical trials to date have assumed that our target population falls under this one-size-fits-all label of depression or schizophrenia and then not actually measure or research anything about the biology of these folks.”
How is Alto offering something new?
Alto’s AI-enabled precision psychiatry platform measures brain biomarkers such as behavior electroencephalogram (EEG) activity, wearable data, genetics, and sleep and activity patterns. By analysing this data, the company believes it can predict drug response and match each patient with the correct Alto drug.
A biomarker is a measurable signal in the human body that can be used to track and assess disease. Etkin defines them as ‘anything objective that is based in biology that you can measure about a person that could be meaningful.’
“A biomarker doesn’t have to be blood-based. It could be an EEG, which is a brainwave signal that tells you how one part of the brain is more or less active or connected than other parts. It could also be a behavioural test, like a reaction time or cognitive test, or a wearable which tells us about a patient’s sleep. All of these things tell us about biology and are objective and measurable,” he adds.
However, Etkin stresses that his work is not intended to replace subjective, personal experiences of mental illness, but instead complement them with objective data.
“Speaking as a psychiatrist, personal experiences of a disorder are very important to understand and honor. However, if I see a patient with depression and just speak with them clinically, I wouldn’t necessarily be able to tell what their cognition is like – unless I measure it using objective tools,” Etkin says.
“That is where biomarkers come in, to give us an extra layer of insight that is simply not possible from the subjective. We can collect data about cognitive difficulties in certain patient populations and then start to develop drugs to improve that cognitive issue.”
In fact, Etkin explains that the inspiration for ALTO-100 came after the realisation that a segment of the depressed population suffers from poor cognition, whereas the rest of this demographic has a cognitive performance that is similar to healthy individuals.
“We know that people experiencing depression with poor cognition respond pretty badly to standard care treatments. So we can identify them objectively and recognise that they’re underserved – which makes them the ideal population to go after. The question is, what do you do to improve their clinical state?” he says.
With this in mind, Alto’s research identified that poor cognition is a reflection of low brain plasticity, meaning the ability of the brain to adapt with input.
“So we went out and found ALTO-100 which is a drug that enhances brain plasticity as its mechanism of action. We then tested it in this phase 2 study and found that those with worse cognition saw their depression symptoms improve more than the group with better cognitive ability,” Etkin says.
Alto is currently in the midst of a phase 2b trial to determine the difference between drug and placebo in these populations. Moving forward, it is hoping to conduct a phase 3 program with FDA input.
“We're pretty well along that path. Our approach has simply been to measure something, stick with it and do it systemically. In drug development terms, we are around the corner from having this get out there – maybe in the next five years. Which sounds like a long time but from my academic frame where you can get really nothing done over five years – that’s very exciting,” Etkin adds.
Is Alto’s approach a step in the right direction?
At its core, Alto subverts the idea that mental health treatment has to rely on trial and error. Rather than relying on symptoms, it is pioneering a more precise and data-driven approach.
“I think patients and providers are both super frustrated with the status quo, so anything that gets them out of that is welcomed. Right now, people will go and seek their own solutions. These aren’t evidence based and sometimes they’re grossly misleading – like measuring urine serotonin levels. People will do all sorts of things and spend real money when they feel like they're at the end of their road and trying to find some answers,” Etkin says.
“So having something that is properly developed and validated and part of a drug approval process - I think creates a very different perspective.”
It is no secret that antidepressant use has risen sharply in recent years. Etkin believes there is no ‘due diligence’ in the process, as there is no test to be done, so doctor’s simply do what is logical and give the person a treatment at random.
“You might tell a story about why you're giving one treatment or another but truly it's just trial and error. So people do what they can. Providers are trying to get their patients better in every way they can so nobody's happy with the current system, as no one is benefitting from it,” he says.
“We also have the challenge in the US, and I assume in the NHS, that most of these prescriptions are done by primary care doctors and they are overloaded with patients – so it’s hard to have meaningful interactions and insert diagnostics on a regular basis. We have to develop our ecosystem beyond the narrow bandwidth of primary care docs and a narrow view of psychiatrists. Patients are frustrated and they’re looking for something different – so there is a real opportunity there.”
By adjusting the approach to mental health treatment, Etkin also believes that Alto’s work may reduce stigma and help patients that may find it difficult to talk about how they are feeling, as the company's method is evidence-based rather than relying on symptoms.
“Our goal is not to change or replace diagnoses, as the reason we have them is just as common language, it’s a place to start. But it’s not a place to end. Think of it like a physical condition, if you come to your doctor with shortness of breath and mobility issues, you may get diagnosed with congestive heart failure. But that’s just saying you have problems in your heart pumping blood and you get exhausted essentially,” he says.
“Then you do a bunch of tests that tell you what the causes of the problem are. You still hold the same diagnosis but you also have data explaining the issue which guides treatment. It’s very similar in depression or any other psychiatric disorder, that the experience is captured by a diagnosis – but further tests can guide a therapeutic as opposed to being a diagnostic by itself.”
Alto is certainly making promising strides in advancing a novel approach to psychiatric treatment. After making the jump from Stanford University to the world of biotech, Etkin encourages other academics to consider taking their research from the lab to a potentially more impactful, commercial setting.
“People have come to me because of my path to get advice and there are several folks right now that I'm speaking to who are making that decision to leave or struggling with that decision. It’s almost a Silicon Valley mindset – the idea that you go with the vision, even if that comes at some personal risk in terms of your career. The act of trying and even having failed will make you better at whatever comes next, be it another business or being a different role in academia, than if you'd stayed and not tried.”