Digital Therapeutics and the Song of the Future of Healthcare

Scientific progress typically involves the construction of models and paradigms and their iterative elaboration, punctuated by surprising, disruptive developments that shatter those paradigms and open windows into unprecedented opportunities. Seattle-based biotech EMulate Therapeutics is working hard on the latter, developing technology that leverages magnetic fields to emulate the information inherent to therapeutic molecules and replicate their therapeutic effects without ever administering the molecules to patients. Pharma’s Almanac’s David Alvaro, Ph.D., met with EMulate’s Chris E. Rivera and Xavier A. Figueroa, Ph.D., to discuss the idea behind a molecule’s digital signature or “song,” the company’s disruptive technology, and how it may help usher in a true digital transformation in healthcare.


David Alvaro (DA): I usually go into this kind of interview with a pretty good handle on the field and the history leading up to the newest innovation, but I must admit that your approach and technology are entirely new to me. Can you begin with the root of the idea that radio frequency energy (RFE) could have real therapeutic effects and walk me through how that developed into the work that EMulate is doing today?

Chris Rivera (CR): The company was founded by John and Mike Butters, two brothers from the Seattle area. There had been some literature published in the mid-to-late 1990s around the electrostatic surface potential of molecules, and it piqued their interest and led them to meet with physicists from national labs around the country. They started to develop a novel hypothesis: if they could capture that energy as information and then recapitulate it in some form or fashion, could they emulate the electrostatic potential of a molecule without the molecule being present? The physicists and the scientists and engineers they spoke with said, “Hypothetically. Maybe.”


With that, they founded the company in 2002, moving to the San Diego / La Jolla area, where they connected with a group of physicists and engineers called Tristan Technologies. Tristan was one of only a handful of leading experts in the world about superconducting quantum interfering devices (SQUIDs), which are ultrasensitive magnetometers that were developed by the U.S. government and primarily advanced during the Cold War and which were located on a submarine nearby in the Pacific Ocean. Together, Tristan and EMulate built on this technology to develop our acquisition system, which we call the Magnetic Interrogation Device System (MIDS).


Today, our fifth-generation MIDS, which sits in our lab just south of Seattle, is a 4’ 3’ square lead box in which we “record” a molecule using its RFE. Rather than high-energy ionizing RFE, we are using the ultralow end — below 22,000 Hz. In fact, in the last couple of years, we’ve discovered that most of the energy performing biological work is probably below 10,000 Hz. To record the electrostatic surface potential of a molecule, we supercool the inside of the MIDS with liquid helium to about 4.4 Kelvin and introduce a sample of the molecule in a little tube. Incidentally, the inside of the lead-lined MIDS was and may still be — the quietest place on earth.


Over time, as the molecule begins to tumble and turn naturally in solution, it leaves a minute magnetic wake, like a canoe traveling down a canal. The SQUID magnetometer sits right below it, and it can measure and record that magnetic wake as a time domain series with millions of data points, which is converted into a WAV file. In many cases, this is done multiple times, after which we select the recording that contains the most information.


The analogy I like to use is that this recording is the “song” of that molecule. Over time, we’ve discovered that every song is unique, meaning that each molecule has its own unique signature or fingerprint. We then simply download that WAV file to a controller device, where it can be played in a manner targeted to the organ or tissue where we want to see the therapeutic effect,


In one important case, we applied this to the treatment of patients with glioblastoma multiforme (GBM), for which temodar, radiation, and surgery are the current standard of care. Unfortunately, patients diagnosed with GBM only live 15 months on average. We recorded the song of paclitaxel and used it to treat about 150 patients with GBM, which is a rapidly dividing tumor that is sensitive to our WAV file of paclitaxel. We connected the controller to a coil that each patient could wear on their head. Playing the WAV file through the coil creates a magnetic field representative of paclitaxel that has the circumference of the coil and expands vertically about 15 centimeters in each direction, bathing the entire brain in the song of paclitaxel.


Noncovalent drugs that don’t bind or block receptor sites actually come to within angstroms of the receptor or cell protein that they target, and we believe that there’s an information exchange that ultimately causes the confirmation change or protein folding. We believe that the song for a given molecule is able to emulate that information exchange.


We have demonstrated this effect in dozens of in vitro and in vivo models and now in human clinical trials. We’re ready to enter phase III studies, both in GBM and in a rare pediatric brain tumor called diffuse intrinsic pontine glioma (DIPG), for which we are again emulating paclitaxel. And our work today isn’t limited to cancer —  we’ve explored the technology in pain models, as well as with psychedelics for mental health concerns. The data set is quite broad and deep.


DA: That’s absolutely amazing. What can you tell me about how rapid the onset of effects is upon turning the coil on and how quickly they end when it’s turned off? Also, are you able to tweak the gain to adjust the intensity of the effects?

CR: That’s a great question, and it’s perhaps best illustrated in an assay that Xavier and others have replicated dozens of times: tubulin polymerization in response to the paclitaxel song. Tubulin will polymerize by itself over time, but we see rapid acceleration once we have activated the song. Mike Butters, one of our founders, has developed a technique to accelerate both the onset and the effect by about 25%. We’ve since replicated this enhancing effect in independent studies in pain and in mental health and psychedelic models. Within just the last couple of weeks, we believe that we have created another technique to improve the onset and the effects by another 10–15%.


As another example, we recorded the WAV file of the psilocybin molecule, which is derived from psychedelic mushrooms. The Chief Medical Officer of a publicly traded company working in the psychedelic space — a psychiatrist by training who is very familiar with psychedelics — was in our Seattle office a couple months back. He put the device on and turned on the RFE signature for psilocybin, and he reported that he started to feel the effects within 5–10 minutes and that they plateaued over time. Then, when he turned it off, the effects dissipated within 10–15 minutes. For some therapies — and psychedelics are a perfect example — the ability to be able to shut things down quickly if adverse effects arise and have those effects wear off quickly will be a huge benefit. Additionally, this has advantages from a reimbursement standpoint. With some of these therapies, patients are under the influence for several hours, during which they have to stay in the doctor’s office, and neither the therapist or the insurance likely enjoys paying for several hours of treatment if that time could be significantly and predictably reduced. Furthermore, we believe that patients could potentially take the device home and use it therapeutically at home as well.


In a similar vein, we had a veterinary oncologist treat about 300 dogs with various cancers, of which a handful experienced mild neutropenia and alopecia; once he took the device off, those side effects resolved fairly quickly.


DA: How generalizable do you think this technology will be across in different types of molecules, at least among those that work noncovalently?

Xavier Figueroa (XF): One area where we have strong evidence of efficacy is small inhibitor RNAs; RFE can replicate the effects of small nucleotides. We are still trying to determine the upper limit of the length of a nucleotide string that will be possible. On the other hand, we can’t replace vitamins or any structural components.


Molecules involved in signaling are likely to be our sweet spot, but we have yet to figure out what the absolute limit will be. For example, our spinoff company Hapbee Technologies Inc. has a product that uses adenosine and melatonin as a sleep aid. Adenosine will activate adenosine receptors, while caffeine blocks them, and we see some of those effects using our RFE caffeine song. So, there must be some informational or confirmational change in the adenosine receptors that our caffeine signal produces that somehow slightly inhibits the adenosine produced by the brain from interacting too strongly with them. While we don’t believe that our approach can block a receptor completely, we have evidence suggesting that we can alter these receptors and decrease the probability of adenosine interacting appropriately.


DA: Have you explored the nature of the information in that digital signature to the point where you have an understanding of how it represents the molecule’s information and what elements of the signal translate to different aspects of the structure, such that at some point in the future you might be able to create a song predictively rather than by recording?

XF: That’s currently a big part of our internal development. We’ve discussed it for years, but it has just been a matter of resource limitation and bandwidth. EMulate was originally founded on commitment to a vision to treat cancer, and then we were suddenly presented with an opportunity to significantly expand our technological base. But we’re still a biotech startup today. Interrogating the nature of the signals themselves will be a priority for us so that we can understand how to transition from recording the magnetic field to entirely in silico work.


CR: We are still at a relatively early stage of understanding the technology, which is why we have focused on signal enhancement over the last few years. At some point, we believe that we can probably create these signals in silico, likely using artificial intelligence (AI). We’re currently trying to take the company public, and we will likely use some of those resources for continued signal development and enhancement.


DA: I’d like to circle back to the benefits of this technology compared with a more conventional therapeutic in which the molecule is actually administered into patients. Some of the benefits are quite obvious, but are there others that merit mention?

XF: One clear advantage, as we discussed, is relatively fast onset and clearance, as seen from the pain data, as well as the ability to reduce pain sensation itself with a pretty good tail in which the pain relief continues before the pain returns.


The possibilities are really significant, and we believe that we can penetrate a lot of markets. I think that our strength is going to be in working cooperatively in combination with existing therapies. Perhaps we can eventually replace them, but right now we want to work cooperatively to enhance therapies that work.


CR: To give you another example: we had a brainstorming session in November 2020 in which one of our advisors suggested that psychedelics for mental health was a really hot area for investment and interest. In March 2021, we recorded psilocybin, ketamine, and a number of other psychedelic agents as part of a collaboration with a CRO that specializes in these preclinical animal models. In September, we began to test efficacy in this model and safety in animals, and we’re now ready to begin human clinical trials. So, in less than a year, we went from an idea to validated objective preclinical data and are ready to enter phase I for $300,000–500,000. Time and cost are extremely efficient in the technology.


In addition to onset and clearance, another huge advantage is our ability to localize the therapy. For example, we now have validated pre-clinical data with fentanyl, and I’ve actually used the fentanyl WAV file myself. I had a knee replacement in August, but I do not personally like taking prescribed opioids and try to limit them as much as possible. With our technology, I can put the coil playing the fentanyl signature song over my knee, and it rapidly reduces my pain from an eight or nine out of 10 to a five or six.


And then finally: the reason why we’re ready for phase III studies in both GBM and diffuse midline glioma is that crossing the blood–brain barrier (BBB) is not an issue for our approach as it is for so many drugs, so we can deliver the effect of drugs to the brain very efficiently.


DA: There really are so many potential advantages to this technology, and there are many directions in which you could take things. What else can you share about what this moment in time is like for EMulate, in terms of how far you’ve come and your key short- and intermediate-term milestones?  

CR: I think we’ve really turned a corner. I also think it’s kind of ironic, but the recent upheaval associated with COVID had a long-term benefit for us. The week before COVID hit, I received terms from a global radiation oncology company for both a major investment and an option to acquire the oncology technology or business. Then COVID hit, and heir market cap went down 40%, so they had to pause the deal. Later that summer, they came back and still wanted to pursue the deal, but then a few weeks later, they announced they had been acquired.


Those events let us to reposition EMulate Therapeutics as the parent company of a group of focused subsidiaries: Mensana Therapeutics for mental health; Indolor Therapeutics for pain, and Zoesana Therapeutics for animal health. Xavier already mentioned Hapbee, our subsidiary focused on wearable tech. The Hapbee device is essentially the coil that we already discussed, but with a Bluetooth chip, so that instead of using a controller you can download an app to your phone. Hapbee shipped their first product to customers in September 2020 and went public in October 2020. We aim to recreate or emulate that model going forward.


Right now, we are very excited about the opportunity to take EMulate public. We have engaged E.F. Hutton as our underwriter. We hope to go public and raise enough capital that we can begin the phase III study in DIPG and two phase I studies –– one in mental health and one in pain. At EMulate, we are experts in the technology –– we can create the WAV files and establish the initial preclinical models very easily and efficiently. But we’re looking for strategic partners that are experts in vertical areas that can help rapidly advance the technology in a more efficient, strategic, and focused way.


We can do straight licensing transactions, and we have two licensing partners right now: Teijan Pharma has licensed the right to GBM in Japan, and Sayre Therapeutics has licensed the rights to brain cancer in both adults and children in India. We can also create a joint venture or a totally separate publicly traded company, like Hapbee.


DA: I don’t know if I’ve ever discussed a technology that has more transformative potential than this does. When you look into the future past the milestones we discussed, how big of an impact do you imagine this having on healthcare, drug development, and beyond?

CR: There are quite a few areas where I see us having an impact. The drug industry model is broken it takes way too long and is way too expensive, both in terms of development and the experience of the patient and our healthcare system just can’t sustain that model. As Xavier mentioned, I don’t know if we’ll replace drugs entirely, but I think we can work conjunctively with them to increase efficacy and reduce the overall costs. Reducing the time and cost for the development of a therapeutic will have a huge impact.


I remember sitting in a conference about 12 years ago where a speaker from one of the phone companies was discussing the future of the cell phone, how it was going to be our cash, our banks, and our tickets for everything, and that seemed unbelievable at the time. But today, most everyone has a cell phone, and all those things came to pass. There continue to be challenges getting vaccines or therapeutics to the developing world safely and efficiently without temperature excursions or anything like that. If the only thing that needs to be transferred is a digital file, those challenges disappear.


Eventually, I think that this technology will be acquired by a digital company someone like Google, Amazon, Apple, or Microsoft and it will really change the world in terms of how we treat human diseases and our sense of health and wellness itself.


At the end of the day, we believe that we are the only true digital therapeutic company, and we are changing biological systems with ones and zeroes.