On December 11, 2024 Prelude Therapeutics Incorporated (Nasdaq: PRLD) ("Prelude" or the "Company"), a clinical-stage precision oncology company, reported the presentation of the first interim clinical data from its ongoing open-label, dose-escalation trial of PRT2527, a potent and highly selective CDK9 inhibitor, as monotherapy and in combination with zanubrutinib in patients with relapsed/refractory lymphoid malignancies (Press release, Prelude Therapeutics, DEC 11, 2024, View Source [SID1234649051]). The data were presented at a poster session of the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California.

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The study investigators reported on the 46 patients that were enrolled, treated, and safety evaluable as of September 17, 2024. PRT2527 was generally well-tolerated through 4 dosing cohorts as monotherapy and 3 dosing cohorts in combination with zanubrutinib. PRT2527 monotherapy and in combination with zanubrutinib demonstrated an acceptable safety profile with evidence of preliminary activity in patients with relapsed/refractory lymphoid malignancies, including patients who received prior CAR-T therapy.

"CDK9 has long been considered a potential therapeutic approach for treating hematologic malignancies and a highly selective CDK9 inhibitor was sought to minimize off target toxicity," stated Jane Huang, M.D., President and Chief Medical Officer of Prelude. "We are encouraged by the results demonstrated to date by PRT2527 both as a monotherapy and particularly in combination with zanubrutinib resulting in an overall response rate of 38.5% including two patients with aggressive lymphomas who had received prior CAR-T therapy. These results represent a positive step for CDK9 inhibition as a possible future therapeutic approach for patients with aggressive hematologic cancers with limited treatment options."

PRT2527 Interim Phase 1 Results

PRT2527 is an investigational, potent and highly selective CDK9 inhibitor being evaluated in select relapsed/refractory (R/R) hematologic malignancies as monotherapy and in combination with zanubrutinib.

As of the cutoff date, 46 patients with relapsed/refractory lymphoid malignancies were treated with PRT2527. 29 patients were treated once weekly via intravenous infusion at four dose levels of PRT2527 monotherapy (9 mg/m2, 15 mg/m2, 18 mg/m2, 24 mg/m2) and 17 patients were treated once weekly at three dose levels of PRT2527 (9 mg/m2, 15 mg/m2, 18 mg/m2) in combination with zanubrutinib administered orally starting on C1D1 at 320 mg daily or 160 mg BID.

Initial Safety Data

The most frequent treatment emergent adverse events (TEAEs) observed in ≥20% of patients were neutropenia (48%) and nausea (33%), and the most frequent grade ≥3 TEAEs (≥10% of patients) were neutropenia (46%) and anemia (11%). Five patients discontinued treatment due to TEAEs in the monotherapy cohort; 3 TEAEs in 1 patient were treatment related: grade 3 hypotension, grade 3 diarrhea, and grade 4 neutropenia (n=1 each). No TEAEs led to treatment discontinuation in the combination therapy cohort.

PRT2527 dose interruptions due to TEAEs occurred in 17 patients (11 monotherapy; 6 combination therapy). Most dose interruptions were due to neutropenia and were managed with growth factor support. One DLT of grade 3 tumor lysis syndrome (TLS) occurred in a patient with primary cutaneous peripheral T cell lymphoma who had extensive disease at the 24 mg/m2 monotherapy dose level and did not receive ramp-up dosing. TLS was managed with rasburicase and IV fluids and resolved. The patient was able to resume study treatment as planned. No DLTs were observed in the combination therapy cohort.

Dose level 3 (18 mg/m2) was selected for dose confirmation for monotherapy and in combination with zanubrutinib due to higher rates of grade 3/4 neutropenia and of dose interruptions and reductions in the 24 mg/m2 dose level.

Analysis of Initial Clinical Activity

Of the 23 efficacy evaluable patients in the monotherapy cohort, complete responses (CRs) were observed in 1 patient (DLBCL) and 3 partial responses observed (TCL), with an overall response rate (ORR) of 17.4% (4 of 23). Of the 13 patients in the combination cohort who were evaluable for efficacy, complete responses (CRs) were observed in 3 patients (2 DLBCL, 1 MCL) and 2 partial responses (PRs) observed (DLBCL and CLL) with an overall response rate (ORR) of 38.5% (5 of 13).

The above-noted presentation can be found at Publications – Prelude Therapeutics (preludetx.com).

"We believe the clinical data presented today with PRT2527 confirm our hypothesis that a highly selective and potent inhibitor of CDK9 has the potential to offer meaningful clinical activity for patients with hematologic malignancies, while avoiding the off-target toxicities observed with less selective agents," stated Kris Vaddi, Ph.D., Chief Executive Officer of Prelude. "However, given the significant progress and potential of our SMARCA degrader programs that are currently advancing in the clinic, along with our productive discovery organization, we plan to focus our resources towards the continued advancement of those programs. As a result, we will only advance the CDK9 program with a partner beyond completion of the current ongoing Phase 1 study."

On December 11, 2024 Alpha Tau Medical Ltd. ("Alpha Tau", or the "Company") (NASDAQ: DRTS, DRTSW), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, reported that CEO Uzi Sofer and CFO Raphi Levy will present a corporate overview and update at the J.P. Morgan 43rd Annual Healthcare Conference on Thursday, January 16, 2025 at 9:45am PT / 12:45pm ET, in San Francisco, CA, and will host institutional investor meetings at the event (Press release, Alpha Tau Medical, DEC 11, 2024, View Source [SID1234649037]).

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Event: J.P. Morgan 43rd Annual Healthcare Conference
Format: Presentation and 1-on-1 Meetings
Date: January 16, 2025
Time: 9:45AM PT – 10:25AM PT
Location: Westin St. Francis, San Francisco, CA

Webcast: Link located on the "Events & Presentations" page in the Investor Relations section on the Company’s website at View Source

Please reach out to your J.P. Morgan representative to schedule 1-on-1 meetings with Mr. Sofer and Mr. Levy.

On December 11, 2024 Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, reported updated interim clinical data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα (Press release, Relay Therapeutics, DEC 11, 2024, View Source [SID1234649052]). The updated data show a median progression free survival (PFS) of 11.4 months in second line (2L) patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer who received RLY-2608 600mg twice daily (BID) + fulvestrant. These data are being presented today at the San Antonio Breast Cancer Symposium (SABCS) 2024.

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"These updated data help build on previously reported results that show a level of benefit that had not previously been seen with non-selective PI3Kα inhibitors," said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. "We are particularly encouraged to see even greater benefit observed in the patients in which we are working to start a pivotal study next year; in these 2L patients, RLY-2608 + fulvestrant demonstrated a median progression free survival that is more than twice that of the existing standards-of-care."

ReDiscover – RLY-2608 First-in-Human Study

RLY-2608 is currently being evaluated in ReDiscover, an ongoing first-in-human study, which was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of RLY-2608 in combination with fulvestrant, and in combination with fulvestrant and ribociclib or atirmociclib (Pfizer’s selective CDK4 inhibitor).

The RLY-2608 + fulvestrant arm of the study, as of the November 4, 2024 interim data cut-off for this arm, had enrolled 118 patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer across all doses in both the dose escalation and dose expansion portions of the study, including 64 patients at the company’s recommended Phase 2 dose (RP2D) of 600mg BID. Among these 64 patients, 31 had a kinase mutation and 33 had a non-kinase mutation. Twelve patients also had a PTEN or AKT co-mutation and were therefore excluded from the efficacy analysis, consistent with the planned pivotal population.

The RLY-2608 + ribociclib + fulvestrant arm of the study continues to enroll patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer in dose escalation. The RLY-2608 + atirmociclib + fulvestrant arm of the study has recently been initiated.

Patients were Heavily Pre-Treated

All RLY-2608 + fulvestrant patients across doses had received a significant level of prior therapy in the advanced setting, including at least one prior endocrine therapy and at least one prior CDK4/6 inhibitor. Among the 64 patients who received the RP2D:

•
41% of patients (n=26) had received two or more prior lines of therapy
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52% of patients (n=33) had received a prior selective estrogen-receptor degrader (SERD), such as fulvestrant or a novel SERD
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25% of patients (n=16) had received chemotherapy or an ADC
•
59% of patients (n=38) had visceral metastases
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34% of patients (n=22) had a BMI of at least 30 and/or HbA1c of at least 5.7%

Promising Efficacy Data in Proposed Pivotal Population

Among the 52 RLY-2608 + fulvestrant patients who received the RP2D and did not have a PTEN or AKT co-mutation:

•
The median PFS was 9.2 months for all patients and 11.4 months for 2L patients
o
Median PFS was 11.4 months for patients with kinase mutations
•
Clinical benefit rate (CBR) was 67% across all patients (32 of 48 CBR-evaluable patients; CBR defined as the proportion of patients with complete response, partial response or stable disease for at least 24 weeks)
•
Among the 31 patients with measurable disease, 12 achieved a partial response (PR) (39% confirmed objective response rate, ORR)
o
Nearly three quarters of patients experienced tumor reductions (74%; n=23)
•
Among the 15 patients with measurable disease who had a kinase mutation, two thirds achieved a PR (67% confirmed ORR; n=10)
•
Median follow-up was 9.5 months

Maintained Meaningfully Differentiated Tolerability Profile

RLY-2608 + fulvestrant was generally well tolerated in the 118 patients treated across all doses as of the data cut-off date. The overall tolerability profile consisted of mostly low-grade treatment-related adverse events (TRAEs) that were manageable and reversible. Safety outcomes were generally as expected across dose levels based on exposure and consistent with mutant-selective PI3Kα inhibition. Among the 64 patients who received the RP2D:

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The low rate of TRAE-related dose modifications allowed for 94% median dose intensity
•
Only two patients discontinued treatment due to TRAEs (Grade 1 pruritis; Grade 1 nausea, loss of appetite)
•
The majority of hyperglycemia was Grade 1; only two patients (3%) experienced Grade 3 hyperglycemia; no Grade 4-5 hyperglycemia
•
Only 31% of patients experienced a Grade 3 TRAE; no Grade 4-5 TRAEs

Continued Progression of Front-Line Breast Cancer Regimens

Two front-line triplet regimens are being progressed – one with the existing CDK4/6 standard-of-care ribociclib and one with Pfizer’s investigative selective-CDK4 inhibitor atirmociclib. RLY-2608 + ribociclib + fulvestrant dose escalation is ongoing with biologically active doses of RLY-2608. The RLY-2608 + atirmociclib + fulvestrant arm of the ReDiscover study has been initiated.

Anticipated RLY-2608 Next Steps

•
Breast Cancer:
o
Initiate 2L pivotal study of RLY-2608 + fulvestrant in 2025
o
Disclose complete Phase 1/2 data in 2025
•
Vascular Malformations:
o
Initiate vascular malformations study in the first quarter of 2025

Cash balance will be operationalized to preserve ability to complete 2L pivotal study

As of the end of the third quarter of 2024, cash, cash equivalents and investments were approximately $840 million.

Conference Call Information

Relay Therapeutics will host a conference call and live webcast today, December 11, 2024, at 7:00 a.m. ET (6:00 a.m. CT). Registration and dial-in for the conference call may be accessed through Relay Therapeutics’ website under Events in the News & Events section through the following link: View Source An archived replay of the webcast will be available following the event.

The data presentation from the San Antonio Breast Cancer Symposium is also available on the Relay Therapeutics website in the "Publications/Presentations" section through the following link: View Source

About RLY-2608

RLY-2608 is the lead program in Relay Therapeutics’ efforts to discover and develop mutant selective inhibitors of PI3Kα, the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 14% of patients with solid tumors. RLY-2608 has the potential, if approved, to address more than 300,000 patients per year in the United States, one of the largest patient populations for a precision oncology medicine.

Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. The Dynamo platform enabled the discovery of RLY-2608, the first known allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor, designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608. RLY-2608 is currently being evaluated in a first-in-human study designed to treat patients with advanced solid tumors with a PIK3CA (PI3Kα) mutation. For more information on RLY-2608, please visit here.

On December 11, 2024 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage precision oncology company developing innovative therapies for cancers with specific genetic alterations to potentially minimize damage to healthy cells, reported that the first patient has been dosed at Dose Level 7, evaluating ATRN-119 550 mg twice daily, in the ongoing ABOYA-119 Phase 1/2a clinical trial (Press release, Aprea, DEC 11, 2024, View Source [SID1234649038]).

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The ABOYA-119 trial is evaluating ATRN-119 as monotherapy in patients with advanced solid tumors having at least one mutation in a defined panel of DNA damage response (DDR)-related genes. The study was initially designed to dose patients with ATRN-119 once daily and has tested doses of 50 to 800 mg to date. A protocol amendment allows for twice daily dosing, beginning with 550 mg twice daily (for a total daily dose of 1,100 mg). This strategic dose adjustment is driven by robust scientific evidence suggesting that more frequent dosing of ATRN-119 will maintain optimal therapeutic levels and potentially enhance the drug’s efficacy.

Twice daily dosing is expected to optimize ATRN-119’s activity across a 24-hour cycle thereby providing better target coverage and maximal benefit. This will increase the likelihood of achieving superior clinical outcomes and may potentially accelerate the path to regulatory approval and commercialization. It could also strengthen Aprea’s competitive positioning by addressing key pharmacokinetic and pharmacodynamic factors.

"The addition of twice daily dosing in the ABOYA-119 trial underscores Aprea’s commitment to delivering innovative treatments while continuously refining our approach based on the latest data and insights," said Oren Gilad, Ph.D., President and Chief Executive Officer of Aprea. "Twice daily dosing represents a proactive step to de-risk the trial, potentially increasing the probability of success. Importantly, it reflects our commitment to scientific excellence and we believe it positions the ATRN-119 program as a high-value asset that may be differentiated from other ATR inhibitors. To our knowledge, we believe ATRN-119 is the only ATR inhibitor in clinical development that is currently being tested as monotherapy on a continuous twice daily schedule. We believe this adjustment will further enhance shareholder value and support the long-term success of our mission."

Dr. Gilad added, "This approach not only enhances our development strategy but also creates new opportunities for partnership that could accelerate commercialization of ATRN-119 and expand patient access globally."

Anthony Tolcher, M.D., FRCPC, FACP, CEO of NEXT Oncology and Investigator in the ABOYA-119 trial commented, "Inhibition of ATR has emerged as a promising strategy for cancer treatment that exploits synthetic lethal interactions with proteins that are involved in DNA damage repair. This mechanism holds considerable promise for patients with difficult-to-treat cancers. We are pleased to continue to enroll our patients in this important study and recognize that a twice daily dosing regimen of ATRN-119 may allow us to maximize the therapeutic potential of the drug."

Dose escalation in the ABOYA-119 trial is expected to continue with both once-daily and the twice-daily dosing schedules, to be studied independently. The primary endpoint of the trial is the tolerability and pharmacokinetics of ATRN-119. Under the current updated protocol, Aprea anticipates the Phase 1 readout in the second half of 2025. For more information, please refer to clinicaltrials.gov NCT04905914.

About ATRN-119

ATRN-119 is a potent and highly selective first-in-class macrocyclic ATR inhibitor, designed to be used in patients with mutations in DDR-related genes. Cancers with mutations in DDR-related genes represent a high unmet medical need. Patients with DDR-related gene mutations have a poor prognosis and, currently, there are no effective therapies available for them.

On December 11, 2024 Amplia Therapeutics Limited (ASX: ATX), ("Amplia" or the "Company"), reported updated data from Company’s ongoing Phase 2a clinical trial. This trial is investigating the Company’s FAK inhibitor narmafotinib in combination with standard-of-care chemotherapy of gemcitabine and Abraxane in the treatment of advanced pancreatic cancer (the ACCENT trial) (Press release, Amplia Therapeutics, DEC 11, 2024, View Source [SID1234649053]). This latest data analysis was conducted up to 6 December 2024 and expands on the previous interim data release1 which covered data up to 27 September 2024.

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Nine (9) confirmed partial responses (PRs) have now been recorded from the initial 26 patient cohort of the Phase 2a trial. This represents an objective response rate of ~35%, significantly better than the 23% reported for the historical trial2 being used as the benchmark for this study. A confirmed PR is recorded when there is at least a 30% decrease in the overall size of tumour lesions sustained for two or more months, with no new tumour lesions apparent.

Importantly, the median duration on trial for the 26 patients is currently 172 days which is a 47% improvement over the historical data of 117 days. The duration on trial is a measure of how effective the treatment is in inhibiting disease progression, as patients with progressive disease must leave the trial. Currently 11 patients from the initial 26 enrolled remain on trial.

Narmafotinib continues to be generally well tolerated by patients and no patients have withdrawn from study due to issues from narmafotinib.

The Company is now recruiting the second cohort of patients for the Phase 2a study to bring the total number of evaluable patients for the trial to 50. At this time 12 new patients have enrolled on the trial since reopening recruitment in October.

Amplia CEO and MD Dr Chris Burns commented: "Adding narmafotinib to the standard-of-care treatment continues to show promise in comparison to the historical data for standard-of-care alone. We’ve recruited over 75% of the trial at this time, and with ongoing positive support from clinicians involved in the study, we are well on track to fully recruit the trial by end of Q1 2025. In addition, we have been reassured by our clinical team in Korea that the recent political situation in the country is not impacting the trial sites located there in terms of recruitment and ongoing support of patients."

This ASX announcement was approved and authorised for release by the Board of Amplia Therapeutics.

About Narmafotinib

Narmafotinib (AMP945) is the company’s best-in-class inhibitor of the protein FAK, a protein overexpressed in pancreatic and other cancers, and a drug target gaining increasing attention for its role in solid tumours. The drug, which is a highly potent and selective inhibitor of FAK, has shown promising data in a range of preclinical cancer studies. The drug has successfully completed a healthy volunteer study, and is currently in an open-label Phase 2a trial in pancreatic cancer where a combination of narmafotinib and the chemotherapies gemcitabine and Abraxane is being assessed for safety, tolerability and efficacy.

About the ACCENT Trial

The ACCENT trial is entitled ‘A Phase 1b/2a, Multicentre, Open Label Study of the Pharmacokinetics, Safety and Efficacy of AMP945 in Combination with Nab-paclitaxel and Gemcitabine in Pancreatic Cancer Patients’.

The ACCENT trial explores the use of narmafotinib in combination with standard-of-care chemotherapy of gemcitabine and Abraxane in first-line patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. The firststage (Phase 1b), completed in November 2023, identified a 400 mg oral daily dose of narmafotinib, given in the days preceding regular chemotherapy infusion, as safe and well tolerated.

This second stage (Phase 2a), of the trial is designed to assess drug efficacy in combination with gemcitabine and Abraxane. The primary endpoints are Objective Response Rate (ORR) and Duration on Trial (DOT) with secondary endpoints being Progression Free Survival (PFS) and Overall Survival (OS). Safety and tolerability will continue to be assessed.

More information about the ACCENT trial, including a list of participating sites can be found via the ACCENT website, the Amplia Therapeutics website, and at ClinicalTrials.gov under the identifier NCT05355298.