Category: Med Device

Secant Group has developed a biomaterial platform technology that provides a resorbable, implantable polymer to drive further innovation in the medical device, pharma, and biopharma markets. Secant Group President Jeff H. Robertson discussed the company’s innovative approach with Pharma’s Almanac Managing Editor Emilie Branch.

Product Design History

Building on decades of experience engineering textile structures for industrial, fashion, and aerospace applications, Secant Group, LLC, was formed in 2016 as the parent company for Secant Medical Components and Secant Technical Materials. Secant works closely with sister company SanaVita Medical, LLC — a U.S. FDA–registered contract manufacturer for medical devices — to provide end-toend contract manufacturing and process services for customers developing medical devices and combination products. Through this partnership, Secant leverages its research capabilities to extend its biomaterial drug delivery platform, while SanaVita Medical conducts validation and scale-up activities for commercial production for their pharma customers. Secant also works very closely with another sister company, Charter Medical, Ltd., to provide essential products and services to life science companies.

Biomaterials Innovation

Secant Group’s R&D team focuses on invention and innovation, whether that means creating new textile geometries that challenge current manufacturing technologies or developing an advanced biomaterial platform on the cutting edge of regenerative medicine. The R&D group brings a range of experience encompassing medical devices, polymer chemistry, analytical chemistry, and cell biology to their efforts spanning biomedical textile technology development, polymer processing, implantable polymer research, textile formation, and multiple extrusion methods, both internally and through academic and industrial collaborations and strategic partnerships.

Biomedical textile structures are already used in cardiovascular, general surgery, neurovascular, and orthopedic applications. Secant is bridging the technologies for traditional biomedical textiles with regenerative medicine to create high-performance materials that will support innovative medical technology to improve the quality of life. These new biomaterials have the potential for use in many additional areas, including novel implantable drug-delivery devices.

Secant’s implantable medical components cover applications, including endovascular aneurysm repair, heart valve replacement and repair, spine repair, neurovascular aneurysm repair, soft tissue repair, and a range of orthopedic applications. The company’s implantable drug delivery platform enables the controlled and localized release of active pharmaceutical ingredients.

Novel Bioresorbable Resin

Secant’s bioresorbable resin platform Regenerez^®, based on the elastomer poly(glycerol sebacate) (PGS), offers a unique combination of attributes, including multiple nonpharmacological modulating properties. PGS is a synthetic polymer manufactured from two benign materials that are metabolized naturally in the body via the Krebs cycle and thus do not accumulate, a differentiator compared with other available synthetic materials.

Regenerez also has antimicrobial properties and may reduce the incidence of local infection when used as a polymer coating or implant in medical device applications. Regenerez further elicits tissue-appropriate mechanobiological responses, stimulating regeneration and growth of native tissue. It is also nonimmunogenic and has immunomodulatory properties that promote healing without chronic inflammation, leading to reduced scar tissue formation.

“This combination of properties makes Regenerez ideal for the production of implantable devices for sustained drug release, which can lead to improved patient compliance. Notably, the surface erosion degradation rate of Regenerez can be tailored by tuning the physical and chemical characteristics of the polymer,” says President Jeff Robertson.

Similarly, modifying the polymer morphology of the PGS elastomer by changing the initial reaction stoichiometry allows for tailoring of the mechanical and elastomeric properties of Regenerez to match the physical properties of different tissues in different medical device and pharma target applications, such as cardiovascular, nerve, and bone tissue. PGS can also be shaped into many forms. Regenerez has potential use in functional bioresorbable coatings, biomedical textiles, and medical devices, as well as in novel drug-delivery solutions, tissue engineering, and regenerative medicine.

Combining Strengths to Generate Powerful Innovation

“We are focused on providing clients with consistent value, quality, and technical expertise while continually advancing biomaterials technology into practical applications for the medical device and pharmaceutical industries,” stated Robertson. “Within the next 18 months to two years, Secant expects to launch the first of many new innovative biomaterial products, with more innovations and products reaching the market every subsequent one to two years.” 

Originally published on PharmasAlmanac.com on July 1, 2020.

The poly(glycerol sebacate urethane) (PGSU) polymer platform Hydralese™ is a biodegradable drug delivery marvel that outperforms all commercially available equivalents. Secant Group is focused on implementing this new technology across indications, from ocular micro-implants that treat ophthalmologic disorders to orally administered gastroretentive rings that deliver antivirals to subcutaneous implants and injectables that treat neurological disorders, prevent HIV, and deliver contraception— but its potential does not stop there. Stephanie Reed, Ph.D., Director of Translational Product Development, spoke with Pharma’s Almanac regarding Secant’s legacy as an aerospace textile provider to its expansion into pharma and medical device, as well as the future applications of this impressive biomaterial.

DAVID ALVARO (DA): Can you give me a primer on the history of Secant, including the original vision, focus, and technology upon which the company was founded, and how it has expanded from there?

STEPHANIE REED (SR): Secant is an 80-year-old company that has been evolving for many decades. We originally began working in the aerospace industry in the production of textiles for astronaut spacesuits and satellite antenna meshes — and we continue to support the aerospace business today. In the 1980s and throughout the 1990s, Secant expanded into the medical device world. We have very deep roots and a lot of maturity and penetration with our current medical device customers, and we continue to supply high-quality, lifesaving implantable textile components to these original equipment manufacturers (OEMs).

Within the last few years, Secant moved toward diversifying beyond textiles into fields that would complement our textile capabilities and healthcare focus, which prompted our parent organization, Solesis, to acquire Charter Medical. Charter Medical focuses on single-use technologies for the production of cell and gene therapies as well as for bioprocessing and blood management. That intersects well with what we do in textiles and biomaterials — there’s a lot of room for innovation to bring all of these facets together, like different points on a triangle.

When the novel biomaterial that we’re developing — poly(glycerol sebacate) (PGS) — is layered on top of that, it highlights the cross-functional nature of all these applications and the potential that arises from combining our proficiencies in device architectures, cell interactions, and polymer properties. Secant Group is unique because we play in all these major fields, and we’re not afraid to cross boundaries to tie concepts together to bring better solutions to market.

DA: Can you explain the fundamental science and what’s unique about PGS?

SR: PGS itself has been around for a long time, but it originally gained popularity in the early 2000s at MIT for tissue engineering in medicine. Even now, when you look in the academic literature, most of the PGS work is in the tissue engineering space. Secant, being a medical device company with a textile legacy, identified PGS about 10 years ago when scouting polymers to bring in-house because of its bioregenerative potential and synergies with medical products.

At that time, PGS was coined as “bio-rubber” because it’s a flexible elastomer that is bio-friendly and biodegrades; it’s soft, stretchy, and compliant and can mimic the mechanical properties of native tissues. There are advantages at the cellular level, in terms of mechanotransduction and biocompatibility, to a flexible material that can match the compliance of native tissues as opposed to the hard plastic common polymers currently in use.

Since then, Secant developed a variation on PGS with enhanced properties for improved processing and shelf-life storage called PGS urethane (PGSU), which comprises our Hydralese™ platform today.

Aside from having optimal and tunable mechanical properties, Hydralese is a biodegradable polymer that can slowly degrade in the body over the course of two months to two years — there simply aren’t viable options on the market that are both flexible and biodegradable like PGSU. Hydralese degrades through surface erosion as opposed to bulk degradation. Bulk degradation is the common breakdown process of commercialized biodegradable polymers. Other polymers don’t degrade at all and either reside as a permanent implant inside the body or require removal from the body at the end of treatment.

To paint a better picture, imagine bulk degradation as cereal sitting in milk; the material swells up and gets soggy before eventually falling apart into multiple pieces or a pulpy mass. Hydralese is more like a cough drop that slowly diminishes in size over time. It erodes primarily through the interaction with water, as well as with exposure to enzymes, cells, and biological fluids. This main mechanism of hydrolysis is very controllable and predictable.

When it breaks down, PGS is degraded back into its starting components — glycerol and sebacate — which then are metabolized by and even act as nutrients for cells. Hydralese fully bioerodes within the body through metabolism and excretion pathways. PGSU degradation does not exhibit the same acidity in the local tissue microenvironment as other biodegradable polymers. We’ve completed a lot of animal testing and comprehensive biocompatibility tests per ISO 10993 guidelines, which show that it’s a largely inert material and is thus very innocuous and safe. These same traits make Hydralese attractive from a drug product formulation standpoint, as it has a sustained drug release rate and allows a larger amount of drug to be delivered over a longer period, with greater linearity and control.  

DA: What can you share about the end-use applications that exist for Hydralese and any future uses that you anticipate?

SR: There’s a push to move away from animal-derived products in medical devices and to replace collagen or gelatin with a substitute material that is preferably synthetic. Our PGSU-based platform, Hydralese, has ideal elastic properties for devices that may require transcatheter deployment or may experience pulsatile or other mechanical forces at the anatomical site. In addition, Hydralese offers predictable and controllable degradation and the ability for ambient shelf-life storage, bypassing the need for fixatives and cold-chain storage and transport. This means a device could be stable at room temperature and humidity without requiring any formaldehydes or refrigeration, like animal products do to maintain their shelf-life.

Hydralese is a water-impermeable polymer, which enables it to surface erode — water can’t access the interior. This lends itself to application as a coating on medical devices and to make previously porous textiles water- or blood-tight. We’re working on many projects in the vascular device space using Hydralese as a blood-tight coating. The material itself is very hemocompatible, making it suitable for heart valve leaflets and vascular stent grafts.

We’re also highly focused on controlled release of pharmaceuticals using Hydralese implants, microspheres, coatings, films, and gastroretentive devices. One therapy area of interest is ocular drug delivery. In this end-use application, materials are either implanted or injected into the eye, so patient comfort and tolerability are paramount. Hydralese can deliver more drug over a longer period such that an injection could be spaced out from weekly to twice annually, which would be a tremendous advantage for patients. Secant is working to create solutions for retinal diseases, glaucoma, and other sorts of inflammatory issues in the eye to help realize this goal and advance these programs.

We’re also highly active in HIV prevention and treatment, as well as the co-delivery of HIV prophylactic agents alongside contraceptive agents. These dual-delivery strategies that simultaneously prevent the spread of infectious disease and prevent unwanted pregnancy using a single product are called “multipurpose prevention technologies.” There is understandably significant interest by non-profit and humanitarian organizations due to the enormous potential to impact global health, especially in areas that are challenged by access to healthcare.

Lastly, we’re working on sustained delivery solutions for neurodegenerative and neurological disorders, where patient non-compliance to their medication regimen is inherent to the disease, creating target end applications for diseases like Alzheimer’s, Parkinson’s, and schizophrenia. Compliance is one of our strongest drivers. Many studies report that, in the United States, non-adherence to medication is a $100 billion problem annually and a huge burden on the healthcare system, which ends up falling on the payers. Having solutions that can advance and promote greater public health overall is incredibly meaningful.

DA: What disciplines have to converge to facilitate development and manufacturing of such advanced biomaterials, and how challenging is it to assemble a team with the expertise needed to handle and advance these materials?

SR: Considering that the work we do is highly focused on biomaterial-tissue interactions, our people largely have deep expertise in polymer chemistry — but we need experts across disciplines, including expertise in analytical chemistry, formulation, pharmaceutics, process scale-up, immunology, biocompatibility, and hemodynamics. We’re seeking to onboard as much experience as possible within our strategic sectors and have been bringing on individuals with a diverse acumen, allowing us to take on a wider variety of projects.

DA: Beyond the evolving technology, have new offerings or services recently emerged at Secant?

SR: We’re moving fast here at Secant. We’ve recently brought in the capability to handle highly potent active pharmaceutical ingredients (HPAPIs), which require special safety equipment, such as the right glove boxes, a cleanroom environment, validated cleaning protocols, respiratory protection, and gowning.

Similarly, we’ve implemented pilot-scale equipment to translate what we’ve been doing on the bench with small-scale tools to a higher throughput system that demonstrates line-of-site to clinical and commercial scale manufacture. Our reaction injection molding system allows us to formulate and then fabricate 100 implants from a single shot of formulated material. With a well-designed setup, we can make up to 10,000 implants an hour. The reaction injection molding equipment works with many kilograms of material. We also have different molds that we can hook up to it so we can mold different sizes and shapes of drug-loaded Hydralese components.

We are also doubling the footprint of our headquarters in Telford, Pennsylvania, and adding in more clean rooms for medical device customers, a larger-capability cell culture lab, and more suites for compounding drug delivery products for pharma customers.

DA: How strong is the awareness in the pharma industry of the applications of this kind of technology?

SR: We have very strong interest from pharma right now and have been fortunate to have been speaking with a high volume of customers. It’s important to us to spend time exploring partnership opportunities, sharing data, discussing potential collaborations, and trying to see where a customer’s pipeline of APIs might fit in with our PGSU platform. Pharma customers that we engage with run the gamut from ophthalmology to neurology, oncology to diabetes, HIV/contraception to malaria/tuberculosis, and animal health. The interest is there, and we’ve been working on this platform for a few years. Our next step is to make those connections and anticipate where the partnerships will happen.

There is a lot of curiosity about implants, especially micro-scale implants and microspheres, as well as gastroretention devices. Though we’ve been delivering a lot of different small molecules, we’re constantly asked if Hydralese can deliver proteins, monoclonal antibodies, or smaller payloads like peptides. That’s the future of growth for us, to show biologic delivery beyond what we’ve demonstrated with small molecule delivery.

DA: Is the work you do with clients structured around longer-term strategic partnerships?

SR: Yes, although we do work within a variety of frameworks with clients. At the most fundamental level, we’ll take a client’s API and formulate it within our Hydralese polymer. We create implants, micro-implants, microspheres, gastroretentive rings, coatings, standalone devices, and fiber prototypes. Our clients come to us with their desired target product profiles, which we design against to meet all requirements. We basically create a whole data package, inclusive of physiochemical characterization and dissolution release kinetics around a variety of formulations, and share drug-loaded Hydralese prototypes with our customers before moving on to animal studies. We do a lot of heavy lifting early on to prove feasibility and offer the possibility to ultimately transfer the tech to our customers for later-stage clinical development and commercialization. We also provide technical, regulatory, and CMO support as desired.

DA: How is Secant positioned within the biomaterials landscape, and what are the true differentiators both in technology and as a broader business?

SR: When you look across the market of commercialized products that use different biomaterials, they fall into two main buckets. The first category is called bio-durables, which are non-degradable materials, such as polyurethane, thermoplastic polyurethane, silicone, and EVA. In the biodegradable space at the other end of the spectrum, natural biomaterials such as fibrin, collagen, and gelatin don’t last long enough for most long-acting pharmaceutical formulations and suffer from animal sourcing issues that impact medical devices. Synthetic biodegradables like PLGA and PCL are widely used in tissue engineering, medical device, and pharma, but there has been no new polymer offering in a couple decades.

While we’re not naïve and we understand the legacy of these materials, our offering comes with unique advantages. Those other materials are best likened to generics because they’re all non-proprietary and have existed for decades. Our PGSU polymer can give our partners a competitive advantage, a compelling marketing angle, and a patent life-cycle extension strategy, especially by having a novel, proprietary material like ours in their product offering.

DA: What other areas is Secant likely to move into, and how do you predict customer needs changing?

SR: I believe the industry is at an inflection point in that there’s a lot of new therapy areas and indications in which a long-acting solution can be transformative for the end-use of the patient. There are a lot of innovations going on in oncology, immunoinflammation, and diabetes management that need a platform or a carrier that could provide better release kinetics.

There aren’t any biodegradable long-acting implants on the market beyond micro-scale ocular products, so this appears to be a gap likely driven by current polymer choices being inadequate. We envision biodegradable Hydralese devices at a range of micro- to macro-sizes that can be administered through subcutaneous, intramuscular, intravascular, ocular, intravaginal, intrauterine, and gastrointestinal routes. Additionally, Hydralese broadens drug candidates considered for long-acting formulations beyond potent molecules into less potent molecules as well, by being able to load larger amounts of a drug into an implant yet still deliver the payload in a sustained manner. Another trend is the move from small to large molecules. There are new advances in orally bioavailable large molecule biologics, and gastrointestinal delivery using a gastroretentive Hydralese device is going to open a lot of doors.

DA: How do you think the market for these materials, both in devices and pharma, is going to change over the next decade? How do you envision Secant evolving, and what is the future vision for the company?

SR: Our goal is for the PGSU platform to be in human trials within the next few years and to be commercialized in 10 years. We know that the path to commercialization is long and that there’s a lot of attrition along the way, which is why we value the many partnerships in our pipeline. We’re hoping to move through clinical development with the intention that two or three winners will emerge. At present, we’re doing preclinical work, but we’re looking to support up through phase IIA clinical trials in the next several years. The market for long-acting offerings is growing into new therapy areas, and we want to be prepared to support it.

DA: Are there any regulatory challenges facing this technology?

SR: There are usable guidelines from the FDA and IPEC about novel excipients for the pharmaceutical industry. We are submitting a Type IV Drug Master File (DMF) for Hydralese as a novel excipient at the end of this year. Our DMF will be beneficial to reduce the regulatory hurdles our partners may face.

The typical approval pathway that we would most likely be seeking is the 505(b)(2) pathway, where a drug substance has already been commercialized in an oral solid dose and the safety and efficacy profiles are known. When the FDA reviews an IND submission or an NDA/BLA submission for a drug/biological product, they’re going to be looking at the drug-polymer interaction and referencing the polymer data package contained in the DMF, including the stability and toxicity. Similarly, for medical devices, the DMF can be referenced for its data contents regarding shelf-life and biocompatibility.

DA: When you look forward at the future of medicine, what do you think is going to be the next big thing?

SR: COVID-19 thrust mRNA vaccines into the limelight. Two big questions come into play. What else can mRNA medicines solve? And what polymer carriers can advance and accelerate those mRNA technologies? Beyond that, there’s a prevailing hope that allogenic and autologous cell therapy will gain traction and accelerate. While the cost and the manufacturing challenges associated with those cell therapies are quite big, I’m hoping that new advancements will reduce expenses and make those cell therapies more accessible to broader patient populations.

There are many techniques to make the processing of ex vivo cells more uniform, reliable, and efficient. Our research team is doing some work with PGS in that space to try to improve things like ex vivo cell selection, cell activation, and transfection, as steps in the CAR-T cell therapy process.

My background is in 3D printing. This technology raises a lot of curiosity about how it can be explored for a wide host of applications, given the geometric complexity and multi-material designs achievable using additive manufacturing. While I don’t believe the printer hardware and throughput is at the level needed to enact sweeping, cost-effective disruption yet, there is some great research and product development in the works to help remove those barriers.

Perhaps one of the most promising innovations for the industry is in dark data dives, in which AI is utilized to mine information on industry failures gathered by a plethora of companies over decades to see what can be learned.

In the same realm as data-driven approaches, patient-centric medicine and personalized medicine require greater focus. Diversity and representation are often lacking in clinical trials, as is having more of the patient’s own data driving the medicine and the doses that they receive. I think there’s a lot that can be done to achieve more inclusive and tailored public health approaches in that space.

Originally published on PharmasAlmanac.com on October 21, 2021.

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.

Originally published on PharmasAlmanac.com on December 20, 2022.

The transition toward decentralized clinical trials marks a paradigm shift in medical research, propelled by a commitment to innovation and patient accessibility. These models, emerging from a need to diversify participant demographics and enhance engagement, have faced challenges like industry conservatism and technology integration. Innovative blood collection solutions have emerged as a pivotal component, enabling frequent and less invasive data capture, pivotal to the success of DCTs. The future promises an increase in these patient-focused trials, driven by regulatory guidance and technological advancement, including increasingly transformative contributions from artificial intelligence (AI).

Introduction

The recent and ongoing evolution of clinical trial models over the past few decades — particularly in the last few years — has been a testament to the commitments to innovation and adaptability on the part of the pharmaceutical industry and the medical community. While the premise of clinical research has remained consistent — to evaluate the safety and efficacy of new treatments — its execution has undergone significant optimization as new technologies and approaches have emerged and been embraced. The most notable recent paradigm shift to transform the conduct of clinical trials was the arrival of decentralized clinical trials (DCTs). Although DCTs have received far greater attention and wider adoption of late, the underlying concept is not new, having emerged from the need to make clinical studies more patient-centric and accessible, thus improving participation rates and the diversity of patient populations, as well as reducing patient dropouts and trial failures.

In traditional clinical trial models, participants are required to frequently travel to central sites, a process that can disrupt their schedules and presents accessibility challenges. This is especially cumbersome for trials investigating rare diseases with geographically dispersed patient populations. In addition, such barriers can lead to a lack of diversity among study participants, potentially affecting the understanding of a therapy’s varied impacts across different population groups. DCTs, by contrast, harness patient-centric methods like direct-to-patient (DTP) supply of drugs and ancillary supplies and direct-from-patient (DFP) delivery of samples, home healthcare services, and digital technologies, such as mobile health apps, wearable devices, telemedicine, and remote monitoring tools, to bring the trial directly to participants, irrespective of their location. This methodology is not just a patient-centric advancement that can reduce the burdens of clinical trial participation; it is transforming how clinical data is collected, with real-time data offering a more dynamic and accurate reflection of a treatment’s performance in diverse, real-world settings.

The roots of DCTs lie in earlier efforts to incorporate electronic data capture and telehealth components into trial design. However, the widespread adoption of DCTs, as well as hybrid clinical trials, which combine aspects of centralized and decentralized models, was propelled by the exigencies of the COVID-19 pandemic, which drove a rapid reimagining of clinical research methodologies. During this period, even industry stakeholders who previously had reservations about the shift witnessed the resilience of decentralized approaches, which allowed for the continuation of trials that would have otherwise been paused or canceled during the global crisis. The learning curve was steep, but the eventual success stories have made a compelling case for the broader adoption of DCTs.

The advantages of DCTs extend beyond mere convenience. They embody a more inclusive approach to clinical research by enabling individuals from a variety of demographic backgrounds, including those from remote or underserved regions who have traditionally been underrepresented in clinical research, to participate. Additionally, DCTs can lead to more efficient enrollment and higher retention rates and may contribute to cost reductions associated with site infrastructure and participant travel reimbursements.¹ The rich, diverse data sets derived from these trials can enhance the understanding of a treatment’s effectiveness across different populations, leading to more robust and generalized findings. This panoply of benefits has led to enthusiasm for DCTs among regulators like the U.S. Food and Drug Administration (FDA). In May 2023, the FDA’s guidance on decentralized clinical trials became a beacon for the industry, signaling a clear commitment to support this innovative approach.²

Despite the promise and potential of DCTs, their adoption has not come without challenges. Industry conservatism, coupled with a learning curve associated with new digital tools and methodologies, still tempers wider implementation, as do challenges associated with remote sampling and monitoring for which novel solutions have yet to emerge. However, continued encouragement from regulatory authorities, concerted educational efforts from clinical research organizations and digital solution providers, and the growing evidence of successful DCT outcomes are collectively driving the clinical trial landscape toward a more decentralized future.

Challenges of Decentralization

The first roadblock in the transition from traditional trials to DCTs — which is still a work in progress — was overcoming the inertia associated with a well-established model in a traditionally conservative sector. Concerns over data integrity, patient safety, and aligning with regulators posed significant barriers. The validation of remote monitoring tools and the development of robust electronic data capture systems have driven significant progress in alleviating some of these early concerns. These tools have become integral in ensuring that remote data collection adheres to regulatory standards for clinical practice and in navigating the complex web of international regulations for trials spanning regions and regulatory agencies.

The emergence of electronic consent (eConsent) has significantly streamlined the enrollment process, and telehealth services have expanded the potential patient base, allowing participants from remote locations to contribute valuable data. Mobile healthcare and home visits, along with improvements in DTP/DFP infrastructure and the optimization of remote clinical trials kits, have addressed logistical hurdles by reducing the necessity for in-person visits at trial sites. However, these solutions come with a fresh set of challenges that require persistent attention and innovation.

Ensuring data quality and integrity remains a core focus for all stakeholders. The technology underpinning DCTs must not only be reliable but must also produce clinically meaningful outcomes that are accepted by the medical community and regulatory authorities. As clinical trials incorporate increasingly sophisticated technology, such as wearable devices and electronic clinical outcome assessments (eCOAs) and patient-reported outcomes (ePROs), the imperative to validate these tools becomes even more critical.

Artificial intelligence (AI) has emerged as a potentially transformative solution to address the new challenges resulting from increasingly decentralized and digitalized clinical trials. AI can enhance data management through sophisticated algorithms capable of analyzing complex data sets from wearables and other remote monitoring tools, ensuring data integrity and regulatory compliance. Furthermore, AI can significantly improve participant monitoring by predicting potential compliance issues or health risks, enabling preemptive interventions. Such capabilities not only streamline trial operations but also foster a proactive approach to patient safety. As AI continues to evolve, its integration into decentralized trials could greatly enhance operational efficiency and patient engagement, thereby reinforcing the foundations of patient-centric clinical research.

Ultimately, patient centricity is at the heart of DCTs. Tailoring trial designs to meet the needs and preferences of patients — whether that means the choice between the convenience of decentralization and the focused care of physician visits or different cohorts’ comfort levels with digital technologies — plays a crucial role in enhancing patient engagement and compliance. As clinical trials transition to a more virtual nature, maintaining patient engagement and providing adequate support become paramount. The experience of participating in a trial must be as intuitive and reassuring as the more familiar traditional methods, if not more so.

Amid these technological and patient-focused innovations, the industry continues to grapple with the need for sophisticated logistical solutions, particularly those involving cold-chain management for the transport of sensitive materials and samples. The increased burden on clinical research professionals, who are expected to adapt to these new technologies and methodologies, also calls for comprehensive training and support systems.

The ABCs of DCTs

The implementation of DCTs brings forth a multitude of benefits, which can be easily remembered using a ABCDE framework:

• Access: DCTs expand access to clinical trials by removing geographical barriers and logistical constraints associated with traditional centralized models. Participants can engage in trials from the comfort of their homes, regardless of their location, thereby broadening the reach of research studies and enabling a more diverse participant pool.
• Benefits for participants: By shifting the trial activities to the patient’s environment, DCTs alleviate the burden of frequent travel and site visits, enhancing the overall participant experience. Patients experience greater convenience and flexibility, leading to higher satisfaction levels and increased willingness to participate in future studies.
• Costs: DCTs offer potential cost savings by minimizing expenses related to site infrastructure, participant travel reimbursements, and on-site staffing. The elimination of the need for physical trial sites and centralized monitoring can result in more efficient resource utilization and overall cost reductions.
• Data: DCTs enable the collection of richer and more comprehensive data sets by leveraging digital technologies for real-time, real-world data capture. This approach results in a higher frequency of data points, providing researchers with a more nuanced understanding of treatment effects across diverse patient populations. Moreover, the ability to engage participants from various demographic backgrounds — with recruitment efforts supported by real-world data — enhances the representativeness of study findings, while the improved patient experience reduces the likelihood of study drop-outs that represent losses of data.
• Efficiency: The streamlined processes inherent in DCTs lead to increased operational efficiency and accelerated trial timelines. By leveraging digital platforms for patient recruitment, consent, and data collection, researchers can expedite study start-up and execution, ultimately bringing new therapies to market faster. As the adoption of DCTs continues to grow, stakeholders across the healthcare ecosystem stand to benefit from improved accessibility, efficiency, and data quality in clinical research endeavors.

Need for Novel Sample Collection Solutions

One notable challenge associated with the DFP side of DCTs is the need for novel sample collection solutions that are patient-friendly and can be used remotely. Traditional methods of blood collection typically involve venipuncture at a clinical site, which does not align with DCT models. Even with the expansion of local testing labs that can collect samples and distribute them to sites, venipuncture can cause anxiety and discomfort to patients, which can have consequences on enrollment and retention of certain types of patients, potentially preventing the trials from meeting the industry’s and regulators’ diversity and representation goals for such studies.

Novel patient-centric sampling methods can not only improve patient convenience and the sampling experience but also enable more frequent testing, which could enable the capture of data that was previously impossible and unlock new possibilities in clinical trial protocols. Moreover, there’s a financial aspect to consider: while some patient-centric technologies might present higher initial costs compared with traditional methods, the overall societal cost could be lower due to improved health outcomes and broader access​​.

When it comes to home-based blood collection, finger-stick methods for collecting dried blood spots are suitable for small sample volumes. For larger volumes, conventional phlebotomy had long been necessary, despite its associated challenges, including discomfort and the logistical complexity of transporting samples from remote locations. However, innovations in self-collection devices, like the Touch Activated Phlebotomy (TAP^®) Micro Select device, allow patients to collect their own samples with less discomfort and without the need for a trained professional. The challenge lies in ensuring that these devices are validated to deliver data that can be reliably used for clinical analysis, which has traditionally been based on venous blood.

The use of such devices in clinical trials requires careful consideration during protocol design, considering the regulatory status of these devices, the most appropriate applications, and the patient’s ability to use the device correctly. Assay development and validation is another significant aspect, as most laboratory tests approved by regulatory authorities are based on venous blood, not capillary blood, which may necessitate the development of specific reference ranges for capillary blood​​.

Logistical considerations are equally critical, from kit building to ensuring proper centrifugation of samples, which might be required before shipment. Direct-to-patient kit delivery and the logistics of sample pick-up and return are also key factors, with patient preferences for pick-up times and the need for expedited return of samples to ensure sample integrity. Supporting patients with these new sampling techniques will be essential and could include video training, live support, and rapid resupply if an adequate sample is not obtained on the first attempt.

However, any novel challenges associated with self-collection are a small price to pay for a solution that allows fully decentralized, remote sample collection that maximizes patient convenience and comfort, and the path toward optimization is clear.

The TAP^® Micro Select

The TAP^® Micro Select device from YourBio Health produces high-quality blood samples at high volumes, making it ideal for DCTs, wellness testing, and clinical-grade blood sampling. The device leverages YourBio Health’s HALO^™ technology, a bladeless microneedle array consisting of 30 microneedles thinner than eyelashes placed in a circle. The needles only pierce the skin to a depth of approximately 1 millimeter, remaining above where nerve endings are located and eliminating the major source of pain during blood draws. This microneedle technology is the primary differentiator of the TAP^® devices from other upper-arm blood collection devices because it has been specifically designed to address the pain-point component of blood collection.

The needles are attached to a proprietary spring mechanism and can only be activated by pressing a plunger on the device, which actuates the needles at the right velocity and angle to pierce the skin. When ready to be used, the TAP^® Micro Select is placed against clean skin, and the plunger is pressed. The needles retract after about 3 milliseconds, creating a vacuum into which capillary blood is drawn. Over 90% of users can successfully draw 200 µL blood in under two minutes, while 75% will collect 500 µL.

Along with the device, YourBio Health offers customizable sample management services, including kitting, fulfillment, and sample tracking from the end user to any central lab. The standard kit contains items to produce whole capillary blood samples from any remote location, including the TAP^® Micro Select device, instructions for use, a warming pack, alcohol wipe, gauze, bandage, and return bag and box. The kit design can be customized to meet the specific needs of different clinical trial protocols, with varying imagery, layouts, and other components.

Use of the TAP^® Micro Select device helps to reduce barriers to blood collection and enables high success rates. The devices are end-user preferred, virtually painless, and yield a 99% collection success rate in several trials and commercial products. In clinical trials, a 200% increase in patient retention and completion rates has been observed when TAP^® technologies, rather than a fingerstick approach, have been employed. In addition, 98% of patients report they would repeat self-collection using TAP^® devices. By leveraging patient blood collection in the home with TAP^® technologies, it is possible to increase trial diversity, collect more representative data, and reduce DCT completion times and failures.

Enhancing Patient-Centricity in Clinical Trials

The TAP^® Micro Select device has proven to be an invaluable tool for patient-centric sample collection in decentralized and hybrid clinical trials, as exemplified by the studies below.

Assessment of immune responses post-booster during the Omicron wave: A decentralized, real-world study centered on evaluating the antibody response following COVID-19 boosters during the Omicron wave employed the TAP^® device to enable participants to self-collect blood samples. This approach facilitated a digitally supported DCT model, where individuals, without the need for professional medical assistance, could contribute data from any location, highlighting the device’s versatility in supporting public health research.

Antibody monitoring in COVID-19 vaccine trials: Researchers in a study investigating the longevity and efficacy of maternal antibodies against SARS-CoV-2 were able to conveniently collect blood samples from infants at key developmental stages using the TAP^® Micro Select device. The non-intrusive nature of the device facilitated adherence to the study protocol and ensured robust data collection, which was vital in reaching the conclusion that maternal antibodies provided protection, but that protection waned after six months.

Both trials underscore the TAP^® device’s contribution to streamlining the blood collection process, making it possible to reach a wider participant base, including diverse demographics and geographically dispersed individuals, with high participant retention and satisfaction rates. While both studies underscore the TAP device’s role in reducing patient burden (particularly for infants), enhancing participant compliance, and broadening the potential for diverse data collection, they also demonstrate its adaptability across different research contexts—be it monitoring long-term vaccine-induced immunity in adults or providing insights into maternal-fetal antibody transfer.

Conclusion and Outlook

Innovative solutions have been crucial in facilitating DCTs and further advancing patient centricity and accessibility. As new solutions are widely adopted, focus will shift to other pain points in an ongoing effort to decrease patient burden, maximize enrollment and retention, and enhance data security and robustness, which is likely to increasingly involve AI, machine learning, and related technologies. The development of novel, less invasive blood collection methods and devices is a representative example of a conceptually simple but technically challenging solution that resolves a significant challenge in remote sampling and patient compliance and comfort, with wider ramifications for the success and representation of clinical trials.

As these technologies and a range of digital health tools mature, they will continue to enhance the execution of DCTs. However, challenges persist, such as the high cost of logistics and the need for standardization in data collection. Looking forward, continuous improvement in these areas, coupled with growing regulatory support and technological adoption, suggests a promising trajectory for DCTs, aiming for a more inclusive and efficient future for clinical research.

References

1. Borfitz, Deborah. “Tufts Study Provides ‘First Hard Metrics’ Around Decentralized Clinical Trials.” 13 Jul. 2022.
2. Decentralized Clinical Trials for Drugs, Biological Products, and Devices. U.S. Food and Drug Administration. May 2023.

Originally published on PharmasAlmanac.com on June 18, 2024