Bexson Biomedical is developing a version of ketamine that would offer an alternative to opiates for postoperative pain management.
In September, the company won patent protection for its SeValent novel formulation technology that would enable at-home therapy with a wearable device instead of in-hospital IV delivery.
The on-body delivery system, developed jointly with Stevanato Group, includes a prefilled sterilized subcutaneous pump. While Bexson is first exploring ketamine, the system could be used with numerous drug types, including antibiotics, psychedelics and new chemical entities with poor oral bioavailability.
Tight Control of Ketamine Levels
Bexson’s Chief Scientific Officer Dr. Jeffrey Becker said the inspiration for the technology after observing few doctors, apart from anesthesiologists, could precisely control blood levels of ketamine.
“If you are a maverick doctor or a doctor willing to learn procedural stuff, you can figure out how [accurately control ketamine levels] with injections and IVs,” Becker said. “But many psychiatrists just don’t want to even deal with a needle.”
Precise dosing of ketamine maximizes its effectiveness in pain management, anesthesia and breaking patterning in mental health disorders like depression. “But you have to be able to control those levels,” Becker said.
Getting that tight control is difficult using oral or intranasal dosing.
When mulling new strategies to ensure precise control of ketamine levels in the blood, Bexons co-founders had an aha moment when looking at insulin pumps. “Insulin pumps are this incredible Ferrari-level tech,” Becker said.
The Basis for Bexson’s Patent
The company decided to repurpose insulin pumps for the job.
As it turns out, they also needed to contend with the fact that ketamine solutions are formulated to be slightly acidic. “The problem with ketamine is that it is like salty orange juice,” Becker said. Ketamine’s pH can be as low as 3.5, while orange juice has a pH of about 3.9. “And the solute content in the solution is almost like ocean water,” Becker added.
As a result of its properties, ketamine injected into subcutaneous tissue can cause tissue site irritation and lead to the development of a sterile abscess.
To avoid that issue, Becker, Bexson’s CEO Gregg Peterson and the medicinal chemist Jason Wallach turned to the excipient captisol, a modified cyclodextrin. “Normally, it’s a sodium salt, but we turned it back into its acid, which we use to titrate freebase ketamine down to the desired pH,” Becker said. They ended up with a solution with a pH of 5.5, which is 100 times less acidic than standard ketamine.
The company was also able to maintain the stability of the ketamine solutions. “Normally, if you raise the pH to a certain point, all of a sudden, you have freebase crashing out, and you don’t have a solution anymore,” Becker said. “You have a bunch of powder at the bottom of a vial and liquid above it.”
Drugs with a similar acid-base dissociation constant (pKa) to ketamine can behave similarly. “There’s a reason why there are not very many subcutaneous formulations,” Becker said. “It’s just a handful compared to all the other routes of administration that we use for drugs.”
Priming the Pump
Pumps provide an opportunity to innovate pharmacokinetics to enable IV drugs to be used outside of a clinic. “So we hacked ketamine and were able to create a stable solution,” Becker said. The company ended up with a heptavalent salt — a captisol-ketamine salt. “That removes all this extra solute to get it down to isotonic.”
After the group successfully hacked ketamine, Becker recalls waking up one morning and thinking, “Oh man, there are all kinds of drugs we could do this with.”
After checking the fit for the technology across different molecules that could also be ionized to form a salt, the company identified multiple scaffolds it could tune in terms of osmolality and pH. “We could get 70 to even 120 milligrams of active pharmaceutical ingredients into a milliliter,” Becker said.
Bexson believes the patent it would win for the drug formulation could also apply to an array of other small molecules. The company is also exploring licensing deals related to a range of antibiotics, antifungals, psychedelics, empathogens, local anesthetics as well as antimigraine drugs.
Other therapies the company is pursuing include Flumazenil for benzodiazepine addiction and continuous-delivery naloxone for opioid overdose.
Ketamine remains the first focus of the company, however. “Ketamine has been kind of a hot drug in the mental health space for the past couple of years for good reason,” said the company’s CEO Gregg Peterson. For an initial indication, the company is positioning its ketamine therapy for non-opioid pain management for a couple of reasons. “One to be where everyone else is not,” Peterson said. “And also because there is an opioid crisis. We are mission-driven to address that critical need.”
“The reason pain makes so much sense for us is that it’s the tip of the spear,” Becker said. With tens of millions of surgeries annually in the U.S. alone, postoperative pain management is a big market.
It is also an acute indication, meaning the company doesn’t need to do a lengthy study to win approval.
“It’s also a low dose indication,” Becker said. “It is a lower threshold for getting through the FDA. “And it helps address the opioid crisis, which is the biggest crisis the world has seen besides maybe the Black Death.”
Opioid deaths surpassed 75,000 in 2021. “And one of the main entrées into opioid addiction is standard-of-care pain management in the postoperative setting,” Becker said. “People get a taste for opioids, and some of those patients develop an addiction. It’s just a numbers game.”