Advanced Microbubbles: Drug delivery across tumor and brain barriers

 

Getting drugs through the tumor barrier and across the blood-brain barrier is a well-known, major challenge for medicine. Many clinical trials are underway using chemotherapy co-administered with diagnostic microbubbles, energized by ultrasound at the site of the tumor — but these are performing poorly, with inconsistent acoustics, because the bubbles are highly-varied in size.

Today, I sat down with Dr Jameel Feshitan, CEO and Connor Slagle, CTO of Advanced Microbubbles from our current class to learn more about not only the field but also how their product compares to the existing solutions out there. The conversation below is a paraphrased version of our interview.

How did you get into this field of microbubbles?

Jameel: In college, in my final year, I took an elective class on medicinal chemistry which proved to be among my favorite classes. I was fascinated by the design of drugs. The different ways we can engineer poisons into life-saving drugs and how entire drug classes such as, say,statens are found. That started a fire that stayed with me all the way till grad school, at Columbia University. There I had a chance encounter with Dr Mark Borden, he was the first person I met during orientation and he introduced me to the use of microbubbles in medicine. The rest is history.

I learned while there are many applications of bubbles in medical imaging, producing uniform sized bubbles in a reproducible manner was a big problem for the field. You cannot control bubbles of varied sizes. For bubbles to realize their potential for drug delivery they had to be uniform. Uniformity leads to consistency, an essential feature to control the dosage of the drugs our bubbles would enable. My first big project — to make bubbles uniform for their use to deliver drugs — turned into Advanced Microbubbles over time, the only company in the world currently offering uniform size-controlled microbubbles. It was also during my time at Columbia University, that I got to translate this work to that of other labs at Columbia University working on the use of microbubbles to deliver drugs across biological barriers and tumors.

Connor: Similar to Jameel, I had a chance encounter with bubbles. Got introduced to the company via a job-board posting for a chemical engineer to scale microbubble production. Dr Mark Borden, who at that time, was an Assistant Professor at my alma mater at Colorado University Boulder, where I studied Chemical and Environmental engineering, acted as the glue. He provided me with supplemental materials and some of the research on the field; that got me hooked. After going through the research and work done by the company thoroughly, uniform microbubbles emerged as a strangely commonsensical solution. Uniform bubbles and the use of ultrasound to trigger them was such an elegant solution not just for medical imaging but also for drug discovery, where controllable as well as localized response is key.

For you, it might seem commonsensical, but for the readers who are new to the product, injecting bubbles into the body is somewhat terrifying, no?

Jameel: When we talk about injecting bubbles people start thinking about embolisms and clots. It is, in reality, a very well characterized, commonly used and sophisticated engineered product similar to other prevalent delivery methods such as liposomes — which are spherical vesicles with lipid layers — used to deliver a range of drugs into the body. Our proprietary microbubbles are similar to liposomes, engineered on a microscale, except with a gas core. The gas core makes them reactive to ultrasound and they are precisely engineered to last for 30 minutes in the body.

Connor: And to give a bit more context, our bubbles can be easily co-administered with existing clinical protocols for the most part. They are injected systemically, using IV, which is already used in chemotherapy clinics and for most indications they can be triggered in a highly localized manner using conventional ultrasound machines. Our bubbles are designed with the clinic and the patient in mind. It is only for specialized indications of the brain that we look to R&D and partnerships with specialized ultrasound machines.

Now that we understand the concept, how will Advanced Microbubbles impact the space?

Connor: Delivering precise amounts of drugs in a precise space is the holy grail for oncology — really motivates me to work towards this goal. Our lofty goal is to pair our size-isolated microbubbles with promising drugs that can’t get to cancer or are injected at such high doses that cause debilitating side effects to the patient.

One example that comes to mind is glioblastoma, a notorious cancer of the brain that can’t be challenged well today, and a lot of it is due to the blood-brain barrier making it hard to deliver drugs with consistency and safety. With our technology, we have preliminary mice data showing that we can temporarily disrupt the blood-brain barrier. This data is published in a study Advanced Microbubbles did with NIH- NIDA, that showed dramatic improvement in delivery to the brain compared to non-uniform bubbles. And off that study, a dozen partners have interest in using AMB’s bubbles instead of conventional bubbles. Of course, the data is not in-human / clinical data, but offers promise to one day deliver the payload across the barrier and then the barrier heals for normal biological purposes.

Jameel: Couldn’t agree more. I see the potential of Advanced Microbubbles to enable a new standard of care in the field. The standard of care for chemotherapy hasn’t changed in hundreds of years.

With chemo, we have to poison the patient to hope to cure them. Advanced microbubbles can really impact the life of a lot of patients by making chemo less toxic and more efficacious.

Where are you currently in this process?

Jameel: We have been hard at work to get preliminary in-vivo data during IndieBio. Despite the pandemic and limitations of being a pre-seed startup, we were able to work with an excellent partner lab at the University of Texas. Led by company co-founder Dr Shashank Sirisi. Dr Sirsi has been with the company since it’s origins at Columbia University. There he was the key liaison between laboratories for the execution of microbubble development and therapy experiments.

Thanks to his support the team was able to get preliminary results in animal data. In “n of three”, small cohorts of neuroblastoma mice models — a tumor and rare disease that develops in adrenal glands. We are excited to showcase the data this demo day where we demonstrate not only proof of delivery, relative to control, with a commonly used chemo-drug. But more importantly, we show efficacy, a 1mg/Kg effect at significantly lower doses. Sending a strong signal in support of our thesis of low-dose efficacy without chemo-like side effects.

Excited to see this data this demo day. Looking beyond demo day, what does the next phase look like for Advanced Microbubbles?

Jameel: Work in mice models can always go wrong. Demonstrating reproducible and consistent results in-vivo, and in outcompeting non-uniform bubbles is where we are going next. This would mean running larger cohorts. We plan to show the efficacy of the platform in Neuroblastoma and pancreatic cancer animal models by the end of next year.

Looking beyond next year we want to show the versatility of this platform in more than one indication. Extending in-vivo proof of concept in a wide range of chemo toxic drugs expanding the market to other cancers such as breast cancer, prostate, and lung cancer. Showing we can take existing chemo toxic drugs and achieve higher efficacy at hopefully lower doses also plays into our business model to partner with Pharma to enable the efficacy and safety of their old and new drug classes.

With clinical trials coming next, should we be preparing for a long wait to see your product commercialized? Curious to learn more about your regulatory strategy and some learnings in this process?

Connor: At a very high level this data helps us gather more safety data points, setting us on a trajectory to get to IND and therefore, into the clinic in two year’s time. We do realize that there are many indications and potential drugs we can partner with.

Bubbles can go so many places, but at IndieBio, we learned that focus will set you free.

Jameel: Totally. To piggyback off that comment, focus is key. Bubbles have been used in ultrasound imaging, tumor ablation and other medical uses as an approved product for many years. IndieBio emphasized the value of tying key scientific milestones and data to a good go to market strategy. Starting with hard and rare diseases to drug tumors and then opening up to broader markets as we gather more performance and safety data.

Delving into regulatory strategy, early-on, was also a big learning that came out of the program. We didn’t wait instead the regulatory strategy helped us focus on our experiments. We learned how we can leverage the existing safety profile of bubbles and use an accelerated FDA pathway, the 505 (b) 2 to speed up going to market. An eye-opening experience to learn the role of the regulatory process in go-to-market decisions. Furthermore, based on advice from industry experts, we plan on combining this pathway with the orphan drug pathway can cut our time to market to 3 to 4 years.

Connor: When I come to think of it went from the mode of optimizing the best bubble and researching methods to do so in the lab to operationalizing the company to scale and sell the best bubble coming out of that research. In doing so we learned there is a new set of skills one has to code-switch to. Acknowledging this mindset shift is important as there is a stigma of moving too slowly in the lab. It is also exciting as we face a new set of challenges.

Jameel: In all this, I must say, IndieBio network really helped get a sense of the bigger picture and conveying that to a different set of audiences. We are gaining a sense of pitching the company to a rare disease investor versus a platform investor. How to engage different stakeholders and get people excited about what we are doing. We will continue to advance our relationship with regulatory experts and mentors we gained through the program. Look forward to keeping the momentum going around demo day and recruiting post-doc scientists to help speed up our preclinical data package.

IndieBio’s Demo Day is October 27–28, with the New York batch on Tuesday the 27th at 10 am, and the San Francisco batch on October 28th at 10 am. Please follow this link to Eventbrite to RSVP. A single registration will grant you access to both days’ events.

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