Bruce Beutel, PhD, who has worked in the drug development industry for over thirty years is ready for a change. He wants to move beyond the single target paradigm, in which a single molecule has a highly targeted effect on the function of one protein.
“The issue with [the single target paradigm] is that when you try to treat complex diseases, particularly diseases of aging or things like diabetes and autoimmune diseases, they’re multi-factorial,” Beutel said to Inside Precision Medicine. “Biology works through the interplay of different proteins affecting each other, doing work together, and compensating for each other—it’s very complicated circuitry. Since I started working in this industry, we’ve known we would eventually have to get more sophisticated in our approach… because the system’s work makes it difficult to achieve good efficacy when you are only modulating one protein and its activity. We knew that we had to get to multifunctional drugs.”
Also, due to regulatory requirements, clinical trials of drug combinations are usually conducted sequentially. Instead of testing two unapproved therapeutics in the same clinical trial, one is approved and may be paired with another in a subsequent trial. Thus, drugging multiple targets with multiple molecules provides little, if any, financial or temporal benefit—it’s additive in cost and time to approval.
“It’s a huge order developing multiple pharmaceutical products and then trying to combine them,” said Beutel. “That’s what happens in cancer research—doing trial and error of combinations after having something safe and proved in the clinic.”
According to Beutel, the answer lies in creating a single drug that can hit multiple targets, similar to creating a single key that can open multiple types of locks. But there’s a reason why there aren’t multifunctional drugs on the market. For starters, there has not been an effective method for screening protein combinations, which Beutel calls multilogs, that, when modulated, could significantly impact the condition. Determining how to construct a compound that can fit all of the “locks” to control the activity of a multilog is a different issue.
To solve these two problems, Beutel launched the startup Passkey Therapeutics, which today emerged from stealth and announced $20 million in seed funding. Passkey will use the funding to support the development of synergistic multifunctional therapeutics (SMThs, pronounced “smiths”), a new class of single-drug therapies that modulate protein combinations that work together with the company’s proprietary computational and experimental platform for SMTh discovery called Locksmith.
Beutel explained, “In the past when you wanted to hit more than one thing, you would just layer two drugs on top of each other or link two drugs together. We are not trying to do that; we are attempting to have two distinct functional effects on biology at the same time and with the same molecule.”
Breakout Ventures led Passkey’s seed funding, along with founding investors Innovation Endeavors and Bison Ventures. Additional participants include Wireframe Ventures, Alexandria Venture Investments, and GRIDS Capital.
The tools have arrived
About a century ago, the first modern therapeutics were found empirically. When Alexander Fleming returned from vacation and found a Petri dish of Streptococcus bacteria contaminated by mold, he recognized that the mold was stopping the bacteria’s growth and isolated it, identifying it as Penicillium. The discovery of the anticoagulant dicoumarol (also known as warfarin) came about as a result of the identification of a fungal hay spoilage that was killing cattle in North Dakota and Alberta because of bleeding disorders. Many of the drugs discovered during that era are still used today.
According to Beutel, neither the single target paradigm, which was founded on the foundations of molecular biology, nor the empirical approach of the past have permitted an efficient and effective way to drug multilogs.
“I have seen this tension throughout my career where you can go for complexity but only in very blind, empirical ways… or you can go for the modern approach but are stuck with single targets,” said Beutel. “I have struggled with this [problem] for decades because neither is good! The empirical approach is [crude and slow]. The [single target paradigm] is very good for rational, forward, computationally driven approaches where you know exactly what you will get. Still, because it is a single target, you are aiming at something with a [limited] impact. I could never find the solution.”
The bottleneck to developing multifunctional drugs can be conceptually broken down into several components: creating protein interaction maps, identifying the combination of proteins that drive a desired change in biology and, ultimately, disease state, and determining how to design a molecule that can independently target all of the proteins in the multilog.
With the creation of massive amounts of genomic data and recent developments in computational analysis and physics-based modeling, Beutel realized he now had a chance to address the multifunctional drug problem.
“You probably could not have done this even five years ago; fundamental genetic data and computational technology now exist, both for biology and chemistry, such that I can… finally solve the problem,” said Beutel.
A lead start
Passkey has developed the platform but is still in the early stages of drug discovery. Beutel declined to disclose the name or timeline of the drug programs Passkey is working on, but he did say that it will be “the typical number of years in the future that we will get to candidates in clinical trials.”
In response to a question about how Passkey will prioritize target multilogs drug programs, Beutel described the circumstance as an abundant opportunity.
“[Drug developers] are used to being in a very target poor environment—there’s tens of thousands of genes, but there’s only a handful of good targets for a given disease,” said Beutel. “For a complex disease, a huge number of combinations can work, and that means you can be really choosy. I can say things like, ‘Pick the [targets] that have the modality of properties that I like from a pragmatic standpoint, and I think I can drug that looks safe,’ and so on. “The number is massive that you’re starting with, but you can actually intelligently prioritize these and know which ones to go after.”
Even though Passkey’s platform extensively uses cutting-edge computational technology, it is also heavily reliant on experimental data. According to Beutel, Passkey is buzzing with excitement because a whole new generation of therapeutics could soon be on the horizon. Despite Beutel’s pride in potentially being an early adopter of multifunctional drug companies, he is cognizant that Passkey is not likely to be the sole firm working on such drugs.
“I know I’m not the only one who knew,” said Beutel. “We always said this is the inevitable next step… Everyone knows this is coming.”
