NEW YORK – Acrivon Therapeutics is developing precision oncology drugs with a proteomics lens and working to prove that protein biomarker signatures can identify best responders to treatments that couldn't be personalized using genomic biomarkers.
The firm is investigating its lead candidate, the CHK1/CHK2 inhibitor ACR-368, in ovarian, endometrial, and bladder cancer with the help of a protein biomarker signature, dubbed OncoSignature. The Cambridge, Massachusetts-based firm is assessing pretreatment tumor biopsies using the drug-specific protein multiplex imaging test to select patients most likely to benefit from the drug.
Acrivon licensed ACR-368, previously called prexasertib, from Eli Lilly in 2021. Lilly, in turn, had acquired prexasertib from Array Biopharma, but decided to out-license the drug after seeing modest activity in Phase II ovarian cancer trials. In one Phase II study involving patients with BRCA1/2-mutant and wild-type recurrent platinum-resistant high-grade serous ovarian cancer, researchers found that 12.1 percent of platinum-resistant patients responded to prexasertib. In another study that included only BRCA1/2 wild-type high-grade serous ovarian cancer patients, the response rate was 29 percent across platinum-resistant, platinum-refractory, and platinum-sensitive patients.
That's when Acrivon picked up the rights to develop the CHK1/2 inhibitor, aiming to use its Acrivon Predictive Precision Proteomics (AP3) platform to develop a protein biomarker signature that could further refine the patient population for the drug. The AP3 approach uses unbiased mass spectrometry-based phosphoproteomics to generate the OncoSignature test.
"Through [the AP3 platform], we are identifying with very high resolution, in a quantitative manner, all the drug-regulated biomarkers and phosphorylation sites," Acrivon CEO Peter Blume-Jensen explained. "Phosphoproteomics is a way to assess the activity states of what drives the disease. We are able to identify three biomarkers from all these drug-regulated sites through a functional definition and these are assembled into a clinically actionable, drug-tailored OncoSignature test."
The end result is the OncoSignature test, which Acrivon developed to run on Akoya Biosciences' spatial phenotyping technology, called PhenoImager. The test quantifies the expression of a signature comprising clinically relevant protein biomarkers within the tumor. While Acrivon has not disclosed the specific protein biomarkers that make up the signature, generally, the multiplex protein imaging-based test is designed to factor in the phosphoproteomic profile of the drug and tumor cells, according to the firm.
If studies are successful, Acrivon and Akoya hope to seek regulatory approval of OncoSignature as a companion diagnostic alongside ACR-368.
According to Blume-Jensen, the company is using its AP3 platform to focus on drugs that have shown some single-agent activity across tumor types in clinical studies, but where genetics-based methods have not identified the subset of patients that will respond best to treatment. Since genetic mutations implicated in cancer often cause dysregulated protein activity, Acrivon's strategy is to measure these dysregulated proteins in patient biopsies using OncoSignature.
"As far as we can tell, the reason that Lilly divested this asset after trying to develop it for 10 years was that despite [conducting] full genomic analysis and next-generation sequencing in all their studies, they concluded that there is need for an alternative biomarker method," he explained. "That's why they found us an attractive partner because we had already developed an OncoSignature very early on for ACR-368 and we could share initial predictive data with licensors, in this case Lilly, and convince them that we know how to develop it."
About a year after acquiring rights to ACR-368, the company began a Phase Ib/II master protocol trial, in which investigators are using OncoSignature to select advanced platinum-resistant ovarian, endometrial, and urothelial cancer patients for treatment. The trial has two arms: one for OncoSignature-positive patients who will receive ACR-368 monotherapy and one for OncoSignature-negative patients who will receive ACR-368 plus an ultra-low dose of gemcitabine.
Acrivon expects to report patients' initial treatment outcomes in the trial in the second half of this year. However, the firm has so far found that about 30 percent to 40 percent of ovarian, endometrial, and bladder cancer patients will be OncoSignature-positive, and therefore, predicted to be sensitive to ACR-368, Blume-Jensen said.
"The OncoSignature-negative patients will get the treatment with low-dose gemcitabine, and that's because we used our AP3 platform to uncover the major resistance mechanism to ACR-368 and showed that [resistance] could be overcome with very low doses of gemcitabine in a proportion of patients," Blume-Jensen said. The firm hopes that the addition of gemcitabine will allow ACR-368 to also be used in patients who are OncoSignature-negative.
The firm is also enrolling ovarian cancer patients regardless of BRCA1/2 mutation status and regardless of prior PARP inhibitor treatment, based on a study conducted by Lilly that showed similar response rates to ACR-368 between these subgroups. That study found that a group of patients with a variety of clinical characteristics responded to the drug, including those with and without a BRCA1/2 mutation and prior PARP treatment. The authors concluded that there may be an "underlying molecular mechanism" driving responses in this clinically diverse group.
"We treat both BRCA-mutant and BRCA wild-type, prior PARP and no PARP, and we are evaluating ACR-368 in many lines and settings of therapy," Blume-Jensen said. "It's a broader approach compared to many companies trying to treat platinum-resistant ovarian cancer where they have more defined genetic backgrounds and primarily focused on earlier lines of therapy."
In May, the US Food and Drug Administration granted fast-track designation to ACR-368 as a potential treatment for locally advanced or metastatic, recurrent platinumresistant ovarian cancer patients who are OncoSignature-positive and have received at least one prior systemic treatment, and for OncoSignature-positive, recurrent high-grade endometrial cancer patients who have received at least two prior systemic treatments. Fast-track designation opens up the accelerated approval pathway for Acrivon, and if the master protocol trial underway for ACR-368 is successful, Blume-Jensen said the firm is hoping to secure the first approval for the drug through that pathway.
Beyond ovarian cancer, Acrivon disclosed an option to investigate ACR-368's activity in human papillomavirus (HPV)-positive squamous cell carcinomas, such as anal, head and neck, and cervical cancers. In 2015, prior to Acrivon licensing the drug from Lilly, ACR-368 was granted orphan drug designation by the FDA for treating anal cancer.
The firm also has in its drug development pipeline therapeutic candidates targeting DNA damage response and cell cycle regulation pathways, including a WEE1 inhibitor and a PKMYT1 inhibitor, and is optimistic that either one or both of these agents will advance into investigational new drug (IND) application-enabling studies this year. Acrivon is hoping to generate single-agent activity within these programs, Blume-Jensen said.
Acrivon is currently using its AP3 platform to uncover mechanisms of resistance, develop new compounds with optimal target selectivity and potency profile, and determine other tumors that may be sensitive to drugs already in its pipeline, just like it is doing for ACR-368.
"We cannot use simple genetics-based precision medicine approaches [in many cancers], typically for advanced solid tumors where you have very complex underlying genetic alterations," Blume-Jensen said, underscoring that this is where Acrivon is hoping to make a difference with its proteomics-based approach. "We are not aware of any other company that has the ability to go from that unbiased protein biomarker indication all the way up to a clinically actionable test."