What’s next for targeted protein degradation
As the technology goes mainstream, next-gen molecules will use new enzymes, tap new pathways, and address PK/PD challenges
As the technology goes mainstream, next-gen molecules will use new enzymes, tap new pathways, and address PK/PD challenges.
As targeted protein degradation grows up, the field is going after harder targets and new mechanisms of action.
Over the last year, a series of Phase I/II readouts from front-runner Arvinas Inc. (NASDAQ:ARVN), including the May 13 unveiling of the technology’s first efficacy signal, have taken targeted protein degradation from preclinical white space to clinically viable modality. More efficacy data are expected by year-end.
The company has shown its two lead candidates are well-tolerated and orally bioavailable, and that its androgen receptor degrader ARV-110 induced confirmed PSA declines of >50% in two out of eight castration-resistant prostate cancer (CRPC) patients previously treated with multiple lines of therapy; one of the patients showed a confirmed RECIST partial response. As of May 29, follow-up data had not found responses in four additional patients.
“It was a big de-risking event for the entire field,” Arvinas CSO Ian Taylor told BioCentury. Arvinas raised $238 million through its Sept. 2018 IPO and Nov. 2019 follow-on.
Almost all the major pharmas and big biotechs have entered the field via deals or through internal research programs, and at least ten newcos have been created in the last three years. At least eight other biotechs that were founded without an explicit focus on targeted protein degradation have disclosed they too are building programs in the space.
Targeted degraders work by bringing together a target protein and an enzyme that can trigger its degradation.
Unlike small molecule inhibitors and blocking mAbs, targeted degraders stop all of a protein’s functions, instead of only those carried out at a specific site. And unlike antisense, RNAi and CRISPR, which gradually reduce the amount of a target protein by preventing new copies from being made, targeted degraders rapidly deplete the existing protein pool as well as counter new protein synthesis.
“It’s the ultimate conditional gene knockout.”
The technology frees drug developers from having to hit a specific functional site on a target, which opens up targets historically considered “undruggable” because of their hard-to-reach or lack of active sites.
But targeted degraders can still only go after what they can bind. “The challenge is, and will continue to be, finding ligands for the proteins you want to eliminate,” said Arvinas founder and Yale University professor Craig Crews.
Advances in ligand discovery technologies are paving the way for companies to chase a wider range of therapeutic targets. The same platforms are also giving rise new degradation mechanisms.
The field’s first candidates work via a handful of well-characterized E3 ubiquitin ligases, which mark targets for proteasomal degradation by tagging them with a ubiquitin group. In the next wave, several companies are tapping lesser-known E3 ligases, or engaging entirely different protein degradation pathways such as endolysosomal trafficking or autophagy.
A challenge remains how to predict PK/PD relationships for targeted degraders across different cellular systems in the body, where drug exposure and protein expression differences could have an impact on their biological activity.
“That’s where companies will succeed or fail,” Kymera CEO Nello Mainolfi told BioCentury.