Chk2

The largest study to date of most common form of testicular cancer has uncovered a possible link between disease risk and variations in the genes controlling cell shape and movement. By investigating the fundamental risk factors that may influence certain men inheriting testicular cancer, the study reveals new insights into how rare genetic variants may contribute to susceptibility – laying the groundwork for improved risk prediction and a better understanding of potential targets for future treatments. The study, led by researchers at The Institute of Cancer Research, London, compared the genetic data of men with and without testicular germ cell tumours (TGCTs). TGCTs are tumours formed in germ cells, which are the cells that develop into sperm in the testes and eggs in the ovaries. They represent the most common form of testicular cancer, accounting for more than 90 per cent of cases. This study, published in the journal European Urology Open Science, built on previous studies led by or involving scientists at The Institute of Cancer Research (ICR), analysed 1,435 TGCT cases and 18,284 cancer-free controls. The researchers used whole-exome sequencing – a technique for sequencing all the protein-coding regions of genes – to identify rare genetic variants that disrupt protein sequences and ultimately cause diseases, such as TGCTs. While previous genome-wide association (GWAS) studies have linked 78 fixed chromosome positions to TGCT risk – explaining more than 44 per cent of the disease’s heritability – much of the genetic basis remains unknown. To uncover additional genetic factors, the research team aimed to evaluate rare and disruptive mutations using models that explain how certain inherited characteristics, such as eye colour or health problems, are passed down in families. The study, which was primarily funded by the Movember Foundation and the ICR, which is both a research institute and a charity, pooled data from three TGCT case series, incorporating previous analyses conducted by the ICR and The Cancer Genome Atlas programme, as well as newly analysed cases from the UK Biobank. It also greatly benefitted from a newer and much larger dataset of cancer-free controls compared with prior studies, significantly improving its statistical prominence and reliability. This study reaffirms the understanding that TGCTs have a strong heritable basis (37–49 per cent), with immediate family members being four to six times more likely to develop the disease. While testicular cancer is highly treatable – with cure rates exceeding 95 per cent –better understanding how and why the disease runs in families could support earlier diagnosis and more targeted monitoring. Despite the team using the largest UK Biobank dataset to date, no individual genes were found to be significantly associated with TGCTs, highlighting the complexity of its genetic foundations and the need for continued research. This study emphasises the challenge of pinpointing rare genetic variants in driving TGCTs. While past research has pointed to possible genes such as DNAAF1 and CHEK2 playing a role in TGCT susceptibility, these associations have not been consistently confirmed in larger studies. The researchers did, however, through analysing groups of related genes, find that rare genetic variants potentially linked to TGCTs were found in genes associated with microtubular and ciliary pathways – the tiny structural and movement systems of cells that play a vital role in their function and development. These findings hint at multiple biological mechanisms that may contribute to TGCT development and warrant further investigation. First author Zeid Kuzbari, a PhD student in the Translational Genomics Group at the ICR, said: “While this study didn’t pinpoint a single causative gene, it has significantly advanced our understanding of TGCT genetics. The results suggest that testicular cancer risk is likely influenced by a complex interaction between multiple low-effect genetic variants rather than a single high-risk gene. “From a patient perspective, these findings reinforce the importance of genetic research and analysis in the early detection and risk assessment of testicular cancer in those patients at higher risk. Although we have yet to identify a definitive genetic marker for TGCTs, studies like this pave the way for more personalised approaches to cancer prevention and treatment.” The lack of replication in larger studies emphasises a key barrier in genetic research, termed the ‘Winner’s curse’, where initial findings are often difficult to confirm in larger studies performed later. With ongoing advancements in next-generation sequencing and data-sharing initiatives, future studies will continue to refine our understanding of TGCT genetics, ultimately leading to improved risk prediction and targeted interventions for those at a higher genetic risk. Senior author Professor Clare Turnbull, Professor of Translational Cancer Genetics in the Division of Genetics and Epidemiology and Group Leader of the Translational Genetics Group, said: “We are continuing our research efforts and are currently in the process of a much larger analysis involving samples from 8,000 men with TGCTs. Larger datasets and novel analytical approaches are crucial in driving both our understanding and identification of the factors contributing to TGCT susceptibility to ultimately improve patient outcomes in the years ahead.”

Generative Phosphoproteomics AP3 platform designed to enable streamlined, rational drug discovery, with proprietary, proteome-wide SAR delivering desirable pathway effects R&D event highlighted positive ACR-368 endometrial cancer data in OncoSignature-positive (BM+) patients with heavily pretreated aggressive tumors, and who had all progressed on prior anti-PD-1 and chemotherapy, with 35% confirmed overall response rate (cORR), which is >2-fold higher than last prior line of therapy (15%) In the BM+ patients who had relapsed after prior anti-PD-1 and chemotherapy, the cORR was 50% with the median duration of response (mDOR) not yet reached (>10 months), while in BM+ patients who were refractory to their last prior line of therapy, the cORR was 33% and mDOR was ~3.4 months Endometrial cancer prioritized given limited treatment options and compelling commercial opportunity; represents first potential regulatory approval opportunity for ACR-368 Phase 1 trial of ACR-2316 ahead of schedule with enrollment in first three dose-escalation cohorts completed; initial clinical activity with tumor shrinkage already observed at dose level three Cash runway extended into 2027 WATERTOWN, Mass., March 27, 2025 (GLOBE NEWSWIRE) -- Acrivon Therapeutics, Inc. (“Acrivon” or “Acrivon Therapeutics”) (Nasdaq: ACRV), a clinical stage precision medicine company utilizing its Acrivon Predictive Precision Proteomics (AP3) platform for the discovery, design, and development of drug candidates through a mechanistic match to patients whose disease is predicted sensitive to the specific treatment, today reported financial results for the fourth quarter and full year ended December 31, 2024 and reviewed recent business highlights. “We continue executing our highly differentiated Generative Phosphoproteomics AP3-enabled strategy, delivering rapid progress towards key milestones across all programs, including our clinical assets, ACR-368 and ACR-2316,” said Peter Blume-Jensen, M.D., Ph.D., chief executive officer, president, and founder of Acrivon. “We previously identified endometrial cancer as a sensitive tumor type with our AP3 platform prior to clinical entry. At our recent R&D event, we shared positive data for ACR-368 in patients with stage III/IV endometrial cancer who had all progressed after prior anti-PD-1 and chemotherapy. Despite patients presenting with large, heavily pretreated tumors (including 65% treated with prior pembrolizumab and lenvatinib) with aggressive histopathologies (75% serous or carcinosarcomas), pMMR, and p53 mutations, we observed strong anti-tumor activity, both among refractory and relapsed patients. Interestingly, amongst the patients that had relapsed after their last prior line, we observed 50% cORR and mDOR (not yet reached) of greater than 10 months, and 33% cORR in refractory patients who did not respond at all to their last prior line of therapy. In our ACR-2316 Phase 1 trial, we have completed enrollment in the first three dose-escalation cohorts, and have observed approximate dose proportionality, target engagement, and initial clinical activity with significant tumor shrinkage already at dose level three. Finally, we continue to expand the actionable capabilities of our Generative Phosphoproteomics AP3 platform to enable us to optimize therapeutic compounds for desired pathway effects, which drives our streamlined drug discovery, design and development.” Program Updates Presented at Corporate R&D Event on March 25, 2025 Reviewed continued expansion of the differentiated capabilities of the Generative Phosphoproteomics AP3 platform, highlighting the growing suite of powerful, internally-developed tools, including the AP3 Interactome, the AP3 Kinase Substrate Relationship Predictor, the AP3 Data Portal and the AP3 Chatbot. Together, these proprietary tools have enabled the company to go beyond the limitations of traditional drug discovery to rapidly design and advance innovative agents into clinical development. Presented data (from February 25, 2025) from the ongoing Phase 2b registrational-intent trial of ACR-368 that included 20 BM+ endometrial cancer patients treated with ACR-368 monotherapy and 38 BM- patients treated with ACR-368 plus ultra-low dose gemcitabine (LDG) that were efficacy-evaluable by RECIST (2 BM- had treatment discontinued without scan) All BM+ patients had progressed after prior platinum-based chemotherapy and prior anti-PD-1, and the median and mean prior lines of therapy for these patients were 2 and 2.6, respectively. A majority of these BM+ patients were refractory to the last prior line of therapy, with aggressive, generally heavily pre-treated tumors: 12 had refractory disease (best overall response of PD in last prior line of therapy), 6 had relapsed disease, and 2 were unknown. Among the 20 BM+ patients, 15 were either serous or carcinosarcomas, 13 were pMMR (2 deficient DNA mismatch repair, 5 not tested), and 11 had p53 mutations (3 wild-type; 6 unknown) The ACR-368 OncoSignature assay accurately identified patients whose tumors are sensitive to ACR-368, with 80% of BM+ patients demonstrating tumor shrinkage. Among all 20 BM+ patients, the cORR was 35%, more than double than in the prior line of therapy, and the disease control rate (DCR) was 80%. In patients that had relapsed after the prior line of therapy (N=6), the cORR was 50%, mDOR was not yet reached (>10 months), and DCR was 100%. In the 12 patients with tumors refractory to last prior line of therapy (ORR = 0%), significant clinical activity was observed with a cORR of 33% and DCR of 75%. In BM- patients treated with the ACR-368 + LDG combination, cORR was ~13%, which is comparable to the best overall response rate in the last prior line of therapy (median = 3), which was 17%. The totality of the preclinical and observed clinical data support significant LDG sensitization to ACR-368 in BM- patients. The company expects that a similar sensitization would occur in BM+ patients, which could be explored in a future all-comer study of ACR-368 + LDG. Several case studies were presented with imaging showing clinically significant, powerful tumor shrinkage in endometrial cancer patients treated with ACR-368 Given encouraging, maturing data in endometrial cancer, combined with limited treatment options for second-line therapy (standard of care ORR of 10-12% and mPFS of ~3 months, based on estimates from key opinion leaders and derived from control arms of past Phase 2 trials), and potential market opportunity, the company is prioritizing endometrial cancer, reallocating all clinical resources to ACR-368 in endometrial cancer and ACR-2316 Due to increased competition and a smaller market opportunity, the company set a high internal clinical bar for ovarian cancer, which preliminary data suggests is unlikely to be met Bladder cancer is also being deprioritized due to lower than preclinically predicted BM+ rate, leading to enrollment challenges Continued dosing of patients with a certain advanced solid tumors in the ongoing Phase 1 monotherapy clinical trial of ACR-2316 (initiated 2 quarters ahead of original timelines). ACR-2316 was uniquely designed by AP3 to overcome the limitations of current WEE1 and PKMYT1 inhibitors, for superior therapeutic index, and for potent single-agent activity. Dose levels 1 and 2 were cleared without safety concerns or dose-limiting toxicities (DLTs) by the safety review committee; dose level 3 is fully enrolled and the safety observation period is anticipated to be completed by April 1 Encouraging early observations include: evidence of approximate dose proportionality, based on pharmacokinetic analyses of the first two DLs; drug target engagement, identified using the company’s mass spectrometry-based AP3 profiling capabilities; and initial clinical activity in a DL3 patient, with significant decrease in size of metastatic lesions throughout the chest, abdomen and pelvis. This patient (who had received 3 prior lines of therapy including chemotherapy and anti-PD-1) remains on therapy. Using AP3-based Indication Finding and AP3-based analyses of in-house and publicly available data, the company is enrolling selected, high unmet need solid tumor types predicted sensitive to ACR-2316 in the clinical trial All BM+ patients had progressed after prior platinum-based chemotherapy and prior anti-PD-1, and the median and mean prior lines of therapy for these patients were 2 and 2.6, respectively. A majority of these BM+ patients were refractory to the last prior line of therapy, with aggressive, generally heavily pre-treated tumors: 12 had refractory disease (best overall response of PD in last prior line of therapy), 6 had relapsed disease, and 2 were unknown. Among the 20 BM+ patients, 15 were either serous or carcinosarcomas, 13 were pMMR (2 deficient DNA mismatch repair, 5 not tested), and 11 had p53 mutations (3 wild-type; 6 unknown) The ACR-368 OncoSignature assay accurately identified patients whose tumors are sensitive to ACR-368, with 80% of BM+ patients demonstrating tumor shrinkage. Among all 20 BM+ patients, the cORR was 35%, more than double than in the prior line of therapy, and the disease control rate (DCR) was 80%. In patients that had relapsed after the prior line of therapy (N=6), the cORR was 50%, mDOR was not yet reached (>10 months), and DCR was 100%. In the 12 patients with tumors refractory to last prior line of therapy (ORR = 0%), significant clinical activity was observed with a cORR of 33% and DCR of 75%. In BM- patients treated with the ACR-368 + LDG combination, cORR was ~13%, which is comparable to the best overall response rate in the last prior line of therapy (median = 3), which was 17%. The totality of the preclinical and observed clinical data support significant LDG sensitization to ACR-368 in BM- patients. The company expects that a similar sensitization would occur in BM+ patients, which could be explored in a future all-comer study of ACR-368 + LDG. Several case studies were presented with imaging showing clinically significant, powerful tumor shrinkage in endometrial cancer patients treated with ACR-368 Given encouraging, maturing data in endometrial cancer, combined with limited treatment options for second-line therapy (standard of care ORR of 10-12% and mPFS of ~3 months, based on estimates from key opinion leaders and derived from control arms of past Phase 2 trials), and potential market opportunity, the company is prioritizing endometrial cancer, reallocating all clinical resources to ACR-368 in endometrial cancer and ACR-2316 Due to increased competition and a smaller market opportunity, the company set a high internal clinical bar for ovarian cancer, which preliminary data suggests is unlikely to be met Bladder cancer is also being deprioritized due to lower than preclinically predicted BM+ rate, leading to enrollment challenges Due to increased competition and a smaller market opportunity, the company set a high internal clinical bar for ovarian cancer, which preliminary data suggests is unlikely to be met Bladder cancer is also being deprioritized due to lower than preclinically predicted BM+ rate, leading to enrollment challenges Dose levels 1 and 2 were cleared without safety concerns or dose-limiting toxicities (DLTs) by the safety review committee; dose level 3 is fully enrolled and the safety observation period is anticipated to be completed by April 1 Encouraging early observations include: evidence of approximate dose proportionality, based on pharmacokinetic analyses of the first two DLs; drug target engagement, identified using the company’s mass spectrometry-based AP3 profiling capabilities; and initial clinical activity in a DL3 patient, with significant decrease in size of metastatic lesions throughout the chest, abdomen and pelvis. This patient (who had received 3 prior lines of therapy including chemotherapy and anti-PD-1) remains on therapy. Using AP3-based Indication Finding and AP3-based analyses of in-house and publicly available data, the company is enrolling selected, high unmet need solid tumor types predicted sensitive to ACR-2316 in the clinical trial Anticipated Upcoming Milestones Provide update on registrational intent trial and confirmatory trial design for ACR-368 Report initial clinical data from the Phase 1 clinical study of ACR-2316 in the second half of 2025 Advance a new potential first-in-class cell cycle drug discovery program for an undisclosed target towards development candidate nomination in 2025 Fourth Quarter and Full Year 2024 Financial Results Net loss for the quarter and full year ended December 31, 2024 was $22.8 million and $80.6 million, respectively. This compares to a net loss of $19.3 million and $60.4 million, respectively for the same periods in 2023. Research and development expenses were $18.6 million for the quarter ended December 31, 2024, and $64.0 million for the full year 2024, compared to $15.5 million and $46.0 million, respectively, for the same periods in 2023. The difference was primarily due to the continued development of ACR-368 - which included the progression of the ongoing clinical trial and the achievement of milestones for the companion diagnostic, the initiation of the ACR-2316 clinical trial in the third quarter of 2024, and increased personnel to support development activities. General and administrative expenses were $6.3 million for the quarter ended December 31, 2024, and $25.2 million for the full year 2024, compared to $5.6 million and $21.1 million, respectively, for the same periods in 2023. The difference was primarily due to increased personnel costs, inclusive of non-cash stock compensation expense. As of December 31, 2024, the company had cash, cash equivalents and investments of $184.6 million, which is expected to fund operating expenses and capital expenditure requirements into 2027. About Acrivon Therapeutics Acrivon is a clinical stage biopharmaceutical company discovering and developing precision oncology medicines for patients whose tumors are predicted to be sensitive to each specific medicine by utilizing its proprietary Generative Phosphoproteomics platform, Acrivon Predictive Precision Proteomics, or AP3. The AP3 platform is engineered to measure compound-specific effects on the entire tumor cell protein signaling network and drug-induced resistance mechanisms in an unbiased manner yielding terabytes of high resolution proprietary quantitative data for pathway-based drug design, indication finding, and response prediction. These distinctive capabilities enable AP3’s direct application for streamlined rational drug discovery for monotherapy activity, the identification of rational drug combinations, and the creation of drug-specific proprietary OncoSignature companion diagnostics that are used to identify the patients most likely to benefit from Acrivon’s drug candidates. Acrivon is currently advancing its lead candidate, ACR-368 (also known as prexasertib), a selective small molecule inhibitor targeting CHK1 and CHK2 in a potentially registrational Phase 2 trial, focusing on endometrial cancer. The company has received Fast Track designation from the Food and Drug Administration, or FDA, for the investigation of ACR-368 as monotherapy based on OncoSignature-predicted sensitivity in patients with endometrial cancer. Acrivon’s ACR-368 OncoSignature test, which has not yet obtained regulatory approval, has been extensively evaluated in preclinical studies, including in two separate, blinded, prospectively-designed studies on pretreatment tumor biopsies collected from past third-party Phase 2 trials in patients with ovarian cancer treated with ACR-368. The FDA has granted Breakthrough Device designations for the ACR-368 OncoSignature assay for the identification of patients with endometrial cancer who may benefit from ACR-368 treatment. In addition to ACR-368, Acrivon is also leveraging its proprietary AP3 precision medicine platform for developing its co-crystallography-driven, internally discovered pipeline programs. These include ACR-2316, the company’s second clinical stage asset, a novel, potent, selective WEE1/PKMYT1 inhibitor designed for superior single-agent activity through strong activation of not only CDK1 and CDK2, but also of PLK1 to drive pro-apoptotic cell death, as demonstrated in preclinical studies against benchmark inhibitors. In addition, the company has a preclinical cell cycle program with an undisclosed target. Acrivon has developed its AP3 Interactome, a proprietary, computational analytics platform driven by Generative Phosphoproteomics machine learning for integrated comprehensive analyses across all large, in-house AP3 phosphoproteomic drug profiling data sets to advance its in-house research programs. Forward-Looking Statements This press release includes certain disclosures that contain “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 about us and our industry that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this press release, including statements regarding our future results of operations or financial condition, preclinical and clinical results, business strategy and plans and objectives of management for future operations, are forward-looking statements. In some cases, you can identify forward-looking statements because they contain words such as “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” or “would” or the negative of these words or other similar terms or expressions. Forward-looking statements are based on Acrivon’s current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, risks and uncertainties that are described more fully in the section titled “Risk Factors” in our reports filed with the Securities and Exchange Commission. Forward-looking statements contained in this press release are made as of this date, and Acrivon undertakes no duty to update such information except as required under applicable law. Investor and Media Contacts: Adam D. Levy, Ph.D., M.B.A.alevy@acrivon.com Alexandra Santos asantos@wheelhouselsa.com

Acrivon Therapeutics\' OncoSignature test proved less useful when it came to recruiting bladder cancer patients for ACR-368.\n Acrivon Therapeutics is halting work on developing its lead drug for ovarian and bladder cancers, instead focusing the Eli Lilly castoff solely on endometrial cancer.The Watertown, Massachusetts-based biotech had been evaluating the CHK1/2 inhibitor, called prexasertib or ACR-368, in a phase 2b trial of patients with endometrial cancer. These patients were split between 20 individuals who had tested positive for Acrivon’s OncoSignature biomarker test and 38 who tested negative.Based on an interim data extract, Acrivon was able to show that the OncoSignature “accurately identified patients whose tumors are sensitive to ACR-368,” with 80% of these individuals seeing their tumor shrink to some extent, according to Acrivon. This cohort saw a confirmed overall response rate of 35%, the biotech said in a Securities and Exchange Commission filing March 25.“Overall, these results demonstrate significant anti-tumor activity and disease control in BM+ patients with aggressive, refractory tumors that did not respond at all to the last line of prior therapy, and with a confirmed ORR more than double the best ORR observed in the last prior line of therapy for all BM+ patients,” Acrivon said in the filing.The company had already made endometrial cancer its top priority but used yesterday\'s filing to announce that it had now “officially deprioritized ovarian and bladder cancers” as targets for ACR-368.“Due to increased competition and a smaller market opportunity, the company set a high internal clinical bar for ovarian cancer, which preliminary data suggests is unlikely to be met,” Acrivon explained. In addition, the OncoSignature had been less useful recruiting bladder cancer patients with a suitable biomarker for ACR-368, meaning less than 10 individuals had been enrolled for this indication, the company added.The clinical resources for these two indications will be redirected to testing ACR-368 in endometrial cancer as well as toward Acrivon’s other clinical-stage candidate, ACR-2316. The WEE1/PKMYT1 inhibitor is currently in a phase 1 trial for patients with advanced solid tumors.ACR-368’s story dates back to the late 1990s, when it was discovered by Array BioPharma. Lilly had later picked up the CHK1/2 inhibitor before discarding it in 2019 after phase 2 studies didn\'t show enough promise. In 2021, Acrivon launched with a mission to reignite development of the drug and touted the therapy’s potential when it organized a $99 million IPO the following year.