Targeted protein degraders (TPDs) are found in the lighter weight divisions of therapetuic development. But even though these therapeutic contenders qualify as small-molecule agents, they pack a big punch. Indeed, they can selectively remove disease-causing proteins inside cells, delivering knockout-like pharmacology.
Like many small-molecule agents, TPDs have well-understood properties and development paths. TPDs also offer oral availability and several other advantages over gene therapies. According to Nicola (Nicki) Thompson, PhD, the CEO of Amphista Therapeutics, TPDs engineer protein levels “by piggybacking on what cells do naturally to remove or recycle proteins.”
First-generation TPDs entered clinical trials relatively recently. They are dominated by proteolysis-targeting chimera (PROTAC) molecules that use the ubiquitin-proteasome system (UPS) to degrade their targets. These TPDs are effective at reducing target-based resistance, but they may result in mechanistic resistance that limits duration of response.
Second-generation TPDs may possess greater scope and degradation efficiency, offer superior drug-like properties, and reduce the risk of acquired resistance. In early studies—for example, those employing Amphista’s second-generation platform, Eclipsys—TPDs have been produced that appear to be longer acting and more effective against tumor cells than first-generation PROTAC solutions.
Novel approach
Amphista is developing bivalent degraders. Each binds a target protein and a novel component of the cell’s UPS machinery. “We engage a mechanism that’s very broadly expressed across a wide range of cells,” Thompson says. “The recycling mechanism we target also is essential for tumor cells’ function.” Consequently, a tumor cell cannot bypass it as a way to become drug resistant.
Amphista has not yet disclosed its precise mechanism, but Thompson notes that the chemistry used in the company’s degraders “is very different, is more flexible, and has good drug-like properties.” Basically, the Eclipsys platform is made up of a target-binding ligand that attaches to the protein you want to degrade. “The other end is the novel degrader ‘warhead’ that engages the cell’s natural machinery to degrade that protein,” Thompson points out. She adds that Amphista’s TPDs have been showing high selectivity.
Within the industry, first-generation products generally are focused on oncology. Amphista shares that focus. It also is starting to target neurodegeneration, which is considered difficult to address with current TPD approaches.
The promise of targeting the central nervous system led the Dementia Discovery Fund to invest in Amphista last December as part of a Series B extension. “[This investment] means that we can start to turn our focus to areas that are largely untouched by those who employ the TPD modality,” Thomson declares. “We have the ability to reach all cells and tissues.”
Founded on a hypothesis
At the end of 2017, with no data in hand, Alessio Ciulli, PhD, professor of chemical and structural biology, University of Dundee, Scotland, formed Amphista. He did so by leveraging the strength of a novel idea—and by winning the support of Advent Life Sciences, Amphista’s founding investor.
“The hypothesis was that you didn’t have to engage a specific E3 ligase,” Thompson relates. Instead, Ciulli and his team thought it might be possible to drive target degradation by engaging different components of the UPS machinery based upon proximity. “Of the three initial approaches, two proved very effective,” Thompson recalls. “That was very different.”
At that time, the prevailing thought among researchers was to look for new degraders by recruiting specific E3 ligases from among more than 600. That approach required identifying the E3 ligase of choice and then finding a binding partner for it. These steps made for a slow and difficult process.
Thompson tells GEN that Amphista decided to “step back and look at the whole process and all of the [protein degradation] machinery.” When Amphista identified chemistry that could engage different parts of the UPS machinery, the company used that as a starting point to design and test small molecules as protein degraders. Amphista’s findings led to the development of what the company says are novel, potent bifunctional protein degradation molecules.
Amphista’s approach uses a completely different mechanism than first-generation TPDs. And when Amphista assessed its TPDs against first-generation PROTAC molecules, the company, Thompson asserts, found that its agents “were as effective and as potent” in terms of driving degradation.
By early 2019, the company received Series A funding that allowed it to move out of Ciulli’s laboratory and to begin recruiting the founding team.
Defined by differentiation
One of the challenges in those early days was competing with U.S. companies, which received much of investors’ attention. “There was,” Thompson says, “a hurdle to overcome just to stand alongside those we viewed as our peers.” She adds that Amphista’s team surmounted that hurdle with science: “We had an advantage in oncology in terms of a lower probability of the emergence of resistance, and we had strong intellectual property. We knew we had something novel.”
What the company didn’t know was the extent of its differentiation. “It’s important not only to have something novel, but also to be solving an actual problem for the field,” Thompson stresses. Amphista, as it turned out, was well differentiated.
Amphista had another benefit, too. The company’s founder, Ciulli, and its incoming chief science officer, Ian Churcher, PhD, were pioneers in the TPD space, which helped give the company the gravitas to attract investors. Ciulli, as noted earlier, was a University of Dundee professor when he founded the company. (He later became the founder and director of the University of Dundee’s Centre for Targeted Protein Degradation.) Churcher set up and led GlaxoSmithKline’s TPD group.
Near-term goals
Early funding was used to exploit the differences of Amphista’s approach and determine how those differences could resolve some of the challenges associated with the first-generation degraders. On the strength of those learnings, in 2021, the company’s Series B round was oversubscribed.
Now, Thompson says, “We’re developing our technology and progressing our own drug discovery pipeline.” She adds that in the coming year, Amphista will select the first development candidate molecule and begin IND-enabling studies. Afterward, the challenge will be to move the molecule into the clinic.
Amphista plans to develop its own clinical programs. The company also is working with partners, namely, Merck and Bristol Myers Squibb. “We wanted to build our internal value, so didn’t partner with anyone on any of our early projects,” Thompson explains. “But we all realized there is so much more you can do with the technology.
“Partnerships on newly launched projects will enable Amphista to explore other areas and targets in which our TPD technology may be effective, such as immunology. We’re working very hard to progress those through the discovery process.”
The role of TPDs in therapeutics will continue to evolve for many years. “TPDs unlock a new era in small-molecule research,” Thompson observes. “It’s clear that no one approach will always unlock everything, so I think we’ll see many different flavors of TPDs.”
