Buckle Therapeutics Reimagines Naloxone Delivery for Opioid Overdoses

Naloxone nasal sprays have revolutionized the response to opioid overdoses, turning bystanders into first responders. But in practice, positioning patients, clearing nasal passages and making close contact — can slow or complicate or naloxone delivery when every second counts.

Buckle Therapeutics Inc., a Cure Collaboration Residency company, believes it has a better way with potential well beyond naloxone. The company created a novel buccal drug-delivery platform that applies medication to the inside of the recipient's cheek, enabling naloxone to reach the bloodstream in seconds.

"With our device, which Buckle invented ourselves, the responder can be three or four inches away from the recipient's face. They push a plunger containing a drug-loaded swab inside the mouth and rub it inside the cheek. The naloxone works within 30 seconds," explained Nicole McKnight, PhD, President and COO of Buckle Therapeutics. "And it doesn't matter what position the recipient is in, which is helpful because often, they are sitting and hunched over."

The technology is currently in early-stage testing, with Buckle raising Series A funding to launch its first human study: a bioequivalence trial in healthy volunteers to assess how effectively the drug is absorbed into the bloodstream.

Pending FDA approval, Buckle aims to expand the platform to deliver other fast-acting medications for populations where pills or injections may be impractical, including children, older adults, people who have trouble swallowing pills, and those who are afraid of needles.

Recognizing a Need for Better Drug Delivery

For more than a century, investigators have known that some drugs applied to the buccal membrane enter the bloodstream quickly. Buckle's founders, however, feel this route has been under appreciated. Their platform offers a number of advantages when compared with other forms of drug administration.

"Not only do we bypass the need for the drug to be swallowed, inhaled or injected, but the medication does not go into the gut and pass through the liver," McKnight maintained. "It works straight away."

The Buckle team began thinking about drugs used in the emergency care setting, and naloxone was the first to come to mind.

"It's the safest drug we know. There's no known toxic dose and no side effects," said McKnight.

The medication is encased in a pod inside the applicator, which is small enough to be carried in a purse, pocket or backpack. The drug solution is ethanol-based, which acts as a natural preservative and temperature stabilizer and also enhances permeation through the buccal membrane. The solution contains a natural tree sap to enhance its ability to stick to the inside of the cheek and protect it from saliva so it can do its job.

Next Steps for Buckle’s Development

Through preclinical studies in dogs, whose buccal membranes are similar to humans, the Buckle team showed that its investigational device enables the drug to be absorbed into the bloodstream very well. They met with the FDA for a pre-Investigational New Drug (IND) meeting, and the FDA granted an accelerated pathway for approval called a 505(b)(2).

Next for Buckle will be an IND filing followed by the bioequivalence study, which will include about 30 volunteers. Because the drug is related to opioid use, the FDA will perform an accelerated approval process. Buckle will also conduct a usability study to demonstrate that people can read the directions and administer the drug, using a mannequin during the study.

McKnight noted that the buccal delivery platform could also be used to deliver epinephrine for people having severe allergic reactions — essentially any healthcare situation that requires a patient to receive a quick-acting medication in an efficient and convenient way.

Once buccal naloxone is approved by the FDA, McKnight expects the development of these drugs to follow the same 505(b)(2) pathway.

Catching the Startup Bug

McKnight's work with startup biotech organizations extends back to her teens, when she worked a summer job with a startup in Cambridge, MA, at age 18. After majoring in biology at the University of Chicago, she worked in lab and then as "employee #7" for another startup in Cambridge, where she did everything from cloning drug metabolizing enzymes to checking in packages in the reception area and building a tissue culture room.

"That's when it solidified for me that an early-stage startup is where I wanted to be," said McKnight. After getting a PhD in molecular and cellular biology at University College London, she moved to New York City in 2011 to start a postdoc, with the goal of eventually commercializing her own science or joining a startup.

"But when I got here, I realized there was no biotech in New York City!" McKnight recalled. "There was amazing academic research at world-renowned institutions with tons of labs, but nothing for a company that wanted to spin out and stay in New York City."

She co-founded a nonprofit called KiiLN, which set out to provide fully equipped wet labs designed to help emerging companies establish themselves and grow. She also spearheaded what is now known as BioLabs@NYULangone, raising funds from New York City and New York State and partnering with New York University.

"Recruiting those first companies and building a community was my job. I am an original believer about the importance of these sorts of spaces for bringing people together so they can learn from each other and catalyze collaborations," McKnight asserted. "Being an entrepreneur, a co-founder or employee number 2 or 3 can be very lonely. Having other people around for support is really important."

Making Connections

A few opportunities later, she joined Buckle in 2023. One requirement was that the company be based in New York City. So, the team set up shop at Cure.

"It's a great central location and a great place to meet with potential partners and investors. Walking into the lobby at Cure and seeing our name up on the wall is really special," said McKnight. "Being part of this community is very important to us as well."

She encourages other entrepreneurs to reach out and make connections, go to networking events and demo days and learn from other people.

"Mentally, it's very, very challenging. Having a community of other people going through the same thing at the same time is important," McKnight noted. "Just knowing that people are going through the same thing you're going through can give you comfort and confidence."