On September 9, 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 positive interim data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα (Press release, Relay Therapeutics, SEP 9, 2024, View Source [SID1234646442]). The data showed that despite heavy pre-treatment, patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer who received RLY-2608 600mg BID + fulvestrant demonstrated clinically meaningful progression free survival (PFS).

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"These interim data suggest that by selectively targeting mutant PI3Kα, RLY-2608 has the potential to offer a level of benefit to patients that has not previously been possible with existing non-selective medicines, while also having significantly less toxicity," said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. "We are very encouraged to see that RLY-2608 + fulvestrant led to clinically meaningful progression free survival in heavily pre-treated patients with PI3Kα-mutated, HR+, HER2- metastatic breast cancer. We will move quickly to share these data with regulators and align on the design of a pivotal study, which we anticipate starting in 2025."

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 alone, in combination with fulvestrant, and in combination with fulvestrant and ribociclib or atirmociclib (Pfizer’s selective CDK4 inhibitor). As of the August 12, 2024 interim data cut-off, the RLY-2608 + fulvestrant arm of the study 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 (17 in dose escalation and 47 in dose expansion). 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 currently proposed pivotal population. An abstract has been submitted for presentation at the San Antonio Breast Cancer Symposium, taking place December 10-13, 2024.

Patients were Heavily Pre-Treated

All 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:

•
45% of patients (n=29) had received two or more prior lines of therapy
•
52% of patients (n=33) had received a prior selective estrogen-receptor degrader (SERD), such as fulvestrant or a novel SERD
•
25% of patients (n=16) had received chemotherapy or an ADC
•
59% percent of patients (n=38) had visceral metastases
•
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 patients who received the RP2D and did not have a PTEN or AKT co-mutation:

•
Median PFS was 9.2 months across all mutations and 10.3 months among patients with kinase mutations
•
Clinical benefit rate (CBR) was 57% across all patients (20 of 35 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 30 patients with measurable disease, one third achieved a partial response (PR) (33% objective response rate, ORR; n=10; 8 confirmed, 1 confirmed post data cut-off date, 1 unconfirmed in an ongoing patient)
o
Nearly three quarters of patients experienced tumor reductions (73%; n=22)
•
Among the 15 patients with measurable disease who had a kinase mutation, more than half achieved a PR (53% ORR; n=8; 7 confirmed, 1 confirmed post data cut-off date)
•
Median follow-up was 7.5 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:

•
The low rate of TRAE-related dose modifications allowed for 95% 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 one patient experienced Grade 3 hyperglycemia; no Grade 4-5 hyperglycemia
•
Only 25% 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 portion of the ReDiscover study is currently testing biologically active doses of RLY-2608
o
On track to identify a dose of RLY-2608 that is combinable with full-dose ribociclib
o
Initial safety data expected in the fourth quarter of 2024
o
Expect to initiate dose expansion cohort(s) in first half of 2025
•
RLY-2608 + atirmociclib + fulvestrant triplet on track for initiation by the end of 2024

Anticipated RLY-2608 Next Steps

•
Doublet – Breast Cancer:
o
Initiate 2L pivotal study of RLY-2608 + fulvestrant in 2025, pending regulatory discussions
•
Triplets – Breast Cancer:
o
Report initial safety data for RLY-2608 + ribociclib + fulvestrant in the fourth quarter of 2024
o
Initiate RLY-2608 + ribociclib + fulvestrant triplet dose expansion cohort(s) in the first half of 2025
o
Initiate RLY-2608 + atirmociclib (CDK4) + fulvestrant triplet by the end of 2024
•
Monotherapy – Solid Tumors:
o
Initiate RLY-2608 monotherapy solid tumor dose expansion cohort(s) by the end of 2024
•
Monotherapy – Vascular Malformations:
o
Initiate vascular malformations study in the first quarter of 2025

Lirafugratinib Update

•
Updated FGFR2 fusion tumor agnostic data, which have generally stayed consistent with the October 2023 disclosure, will be presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place October 23-25, 2024
•
The company met with the FDA regarding the lirafugratinib regulatory path. The FDA suggested that the company first file a new drug application (NDA) in cholangiocarcinoma, followed by a tumor agnostic supplemental NDA for FGFR2 fusions with data from more patients and more follow up
•
The company plans to seek a global commercialization partner for lirafugratinib in order to maintain focus on the remainder of the portfolio

Portfolio Prioritization is a Continued Focus

•
The company continues to advance high-value next-generation programs:
o
Fabry disease: clinical start anticipated in the second half of 2025
o
NRAS: clinical start anticipated in the second half of 2025
•
Ongoing streamlining of the research organization

Wholly-Owned Portfolio Provides Strategic Flexibility for Cash Runway

As of the end of the second quarter of 2024, cash, cash equivalents and investments were approximately $688 million, which the company expects to be sufficient to fund its current operating plan into the second half of 2026, assuming all current programs remain wholly owned and are fully prosecuted.

Conference Call Information

Relay Therapeutics will host a conference call and live webcast today, Monday, September 9, 2024, at 8:00 a.m. ET. Registration and dial-in for the conference call may be accessed on 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.

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 trial designed to treat patients with advanced solid tumors with a PIK3CA (PI3Kα) mutation. For more information on RLY-2608, please visit here.

On September 9, 2024 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported the presentation of data from its oncology portfolio at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer (September 7-10) and the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting (September 13-17) (Press release, Regeneron, SEP 9, 2024, View Source [SID1234646441]). A combined 11 presentations across both congresses highlight Regeneron’s commitment to transforming care for people living with difficult-to-treat cancers, including advanced melanoma, advanced non-melanoma skin cancer, and different types of lung cancer.

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"The breadth of our presentations at ESMO (Free ESMO Whitepaper) and WCLC underscore our progress in advancing treatment approaches for cancer that have the potential to be among the best in their class," said Israel Lowy, MD, PhD, Clinical Development Unit Head, Oncology, at Regeneron. "At WCLC, five-year outcomes for Libtayo monotherapy in advanced NSCLC reinforce its position as the anti-PD-1 backbone of our oncology portfolio. At ESMO (Free ESMO Whitepaper), the latest two-year data for our LAG-3 inhibitor fianlimab combined with Libtayo show persistent and high clinical activity in advanced melanoma patients. As our portfolio and pipeline mature, the insights from these data are helping us advance our differentiated and novel combination approaches – all with the goal of transforming care for those living with cancer."

Notably, at ESMO (Free ESMO Whitepaper), Regeneron will present new, two-year results evaluating the investigational combination of LAG-3 inhibitor fianlimab and Libtayo (cemiplimab) in adults with advanced melanoma across three independent expansion cohorts of a first-in-human, multi-cohort trial. The combination is being further studied in an ongoing, randomized, placebo-controlled, blinded Phase 3 trial of fianlimab and Libtayo versus pembrolizumab in previously untreated unresectable locally advanced or metastatic melanoma. Additional trials are underway in the adjuvant and perioperative settings, as well as against other first-line, standard-of-care LAG3 and PD-1 combinations.

The longer-term analysis of 98 patients from the initial trial builds on results presented at ASCO (Free ASCO Whitepaper) 2023, with data assessed per blinded independent central review presented for the first time. With a median follow-up of 23 months and median treatment duration of 35 weeks, the results show persistent and deepening tumor responses across all three independent cohorts. Results were as follows:

In MM1, the initial cohort (n=40), there was a 23% complete response (CR) rate and a 60% objective response rate (ORR).
In MM2, the confirmatory cohort (n=40), there was a 25% CR rate and a 63% ORR.
In MM3, the cohort of patients with prior neoadjuvant or adjuvant systemic therapy (n=18; including 13 patients who had progressed despite prior anti-PD-1 treatments, and thus might be expected to have lower response rates to the combination), there was a 28% CR rate and a 39% ORR.
In a post-hoc analysis of the three cohorts combined, there was a 25% CR rate (24 of 98 patients) and a 57% ORR (56 of 98 patients).
Initial progression-free survival (PFS) and overall survival (OS) assessments from this single arm trial, which support the ongoing Phase 3 trial designed to evaluate these survival endpoints for the Libtayo and fianlimab combination, were as follows:

PFS for the MM1, MM2, and MM3 cohorts, respectively: Not reached (95% CI: 8 months to not evaluable [NE]), 19 months (95% CI: 8 months to NE), and 12 months (95% CI: 1 month to NE).
In a post-hoc analysis of the three cohorts combined, median PFS was 24 months (85% CI: 12 months to NE) and median OS was not reached (95% CI: 42 months to NE). Median OS was also not reached for any individual cohort.
Additional analyses on difficult-to-treat subgroups, including patients who had received prior adjuvant anti-PD-1 therapy, will be presented.

The safety profile of the fianlimab and Libtayo combination was generally consistent with the safety profile of Libtayo monotherapy and other anti-PD-(L)1 agents, except for higher rates of treatment-related adrenal insufficiency (12% of patients; 5% were ≥Grade 3). Adverse events (AEs) of any grade occurred in 95% of patients. Grade 3 or greater AEs, serious AEs, and immune-mediated AEs (IMAEs) occurred in 47%, 36%, and 13% of patients, respectively. AEs leading to death occurred in seven patients; two were considered treatment related.

An overview of all data presentations at both congresses is summarized below:

Regeneron presentations at WCLC:

Medicine Abstract title Abstract Presenter Presentation date/time
(all PDT)
Libtayo

Cemiplimab monotherapy for first line advanced NSCLC patients with PD-L1 expression ≥50%: 5-year outcomes of EMPOWER-Lung 1 #OA11.06
Oral Session: Shifting the Bar in the Front Line Immunotherapy Setting
Ana Baramidze Monday, September 9
2:32 p.m. – 2:42 p.m.
Prognostic utility of peripheral myeloid cells for clinical outcomes in patients with NSCLC treated with cemiplimab # P2.11A.26
Poster Presentation
Session: Metastatic Non-small Cell Lung Cancer—Immunotherapy—Immunobiology
Rolando J. Acosta Sunday, September 8
6:15 p.m. – 7:45 p.m
Real-world comparative effectiveness in advanced NSCLC and high PD-L1 with 1L immune checkpoint inhibitors ± chemotherapy
#EP.11A.08
e-Poster Presentation Melinda L. Hsu N/A
Fianlimab

Fianlimab-based combination therapies in patients with advanced non-small cell lung cancer: Trials in progress updates # P4.11D.09
Poster Presentation
Session: Metastatic Non-small Cell Lung Cancer—Immunotherapy—Clinical Trials in Progress
Ana Baramidze Monday, September 9
6:30 p.m. – 8:00 p.m.
Phase 2 peri-operative study of fianlimab + cemiplimab + chemotherapy vs cemiplimab + chemotherapy in resectable early-stage NSCLC #P4.07D.03
Poster Presentation
Session: Early-Stage Non-small Cell Lung Cancer —Clinical Trials in Progress
Luis Paz-Ares Monday, September 9
6:30 p.m. – 8:00 p.m.
REGN7075, Libtayo A Phase 1/2 Study of REGN7075 (EGFR×CD28) Combined with Cemiplimab (anti–PD-1) in NSCLC: Trial in Progress Update #P4.11D.04
Poster Presentation
Session: Metastatic Non-Small Cell Lung Cancer—Immunotherapy—Clinical Trials in Progress
Melissa Johnson Monday, September 9
6:30 p.m. – 8:00 p.m.

Regeneron presentations at ESMO (Free ESMO Whitepaper):

Medicine Abstract title Abstract Presenter Presentation date/time
(all CDT)
Skin Cancer
Libtayo

Neoadjuvant Cemiplimab for Stage II–IV Cutaneous Squamous Cell Carcinoma (CSCC): 2-year Follow-up and Biomarker Analyses
#1091
Poster
Session
Danny Rischin Saturday, September 14
9:00 a.m. – 5:00 p.m.

Fianlimab Long-term follow-up of advanced melanoma (unresectable/metastatic – aMel) patients (pts) treated with fianlimab (FIAN) + cemiplimab (CEMI): Results from blinded independent central review (BICR) efficacy assessment
#1097
Poster
Session
Meredith McKean Saturday, September 14
9:00 a.m. – 5:00 p.m.

Lung Cancer

Libtayo

Efficacy of Cemiplimab as Monotherapy or in Combination with Chemotherapy in Japanese Patients with Advanced Non-Small Cell Lung Cancer (aNSCLC)
#1384PPoster
Session
Yuki Sato Saturday, September 14
9:00 a.m. – 5:00 p.m.

Risk model for overall survival (OS) based on composite patient-reported outcomes (PROs) in aNSCLC patients treated with first-line (1L) cemiplimab-based therapy
#1853P
Poster
Session
David Gandara Sunday, September 15
9:00 a.m. – 5:00 p.m.
METxMET

MET×MET bispecific antibody davutamig (REGN5093) for MET-altered advanced non-small cell lung cancer (aNSCLC): Update from a first-in-human (FIH) study
#1302P
Poster
Session
Byoung Chul Cho Saturday, September 14
9:00 a.m. – 5:00 p.m.

The potential uses of Libtayo in neoadjuvant CSCC, fianlimab and Libtayo, davutamig, and REGN7075 described above are investigational, and their safety and efficacy have not been fully evaluated by any regulatory authority. Fianlimab, davutamig, and REGN7075 are not currently approved for use in any indication.

On September 9, 2024 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported five-year results from the final pre-specified overall survival (OS) analysis of the Phase 3 EMPOWER-Lung 1 trial, which evaluated Libtayo (cemiplimab) monotherapy versus chemotherapy as a first-line treatment for adults with advanced non-small cell lung cancer (NSCLC) with ≥50% PD-L1 expression and no EGFR, ALK or ROS1 aberrations (Press release, Regeneron, SEP 9, 2024, View Source [SID1234646440]). The late-breaking results will be presented in an oral session at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer.

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"The five-year results from EMPOWER-Lung 1 showcase the durable survival benefit and impressive efficacy of first-line Libtayo monotherapy compared to chemotherapy in patients with PD-L1 high, advanced NSCLC, including a direct correlation between survival benefits and PD-L1 expression level," says Ana Baramidze, MD, PhD, Head of Clinical Research Department at Todua Clinic, Tbilisi, Georgia. "Furthermore, EMPOWER-Lung 1 continues to offer important new data to help doctors increase their understanding of investigational treatment strategies for patients who progress on PD-1 inhibitor monotherapy. For instance, EMPOWER-Lung 1 was one of the few trials to evaluate survival when adding chemotherapy to a PD-1 inhibitor following progression."

At the five-year follow-up, Libtayo remained superior to chemotherapy in the population of patients confirmed to have ≥50% PD-L1 expression (using an FDA approved assay), demonstrating continued and clinically meaningful benefits consistent with the prior 1-year analysis in this study population (as previously published in The Lancet and also as previously provided in the approved label for the FDA-approved assay):

1-year Analysis 5-year Analysis
Libtayo
(n=283) Chemotherapy
(n=280) Libtayo
(n=284) Chemotherapy
(n=281)
Overall survival (OS)
Mediana not reached 14 months 26 months 13 months
Hazard ratio (HR)
(95% confidence
interval [CI]; p-value)b 0.57
(0.42 to 0.77; p=0.0002) 0.59
(0.48 to 0.72; p<0.0001)
Progression-free survival (PFS)
Mediana 8 months 6 months 8 months 5 months
HR (95% CI; p-value)b 0.54
(0.43 to 0.68; p<0.0001) 0.50
(0.41 to 0.61; p<0.0001)
Objective response
rate (ORR) 39% 20% 46.5% 21%
Median duration of
response (DoR) 17 months 6 months 24 months 6 months
NOTE: The analysis was conducted in a subset of the randomized population that excluded 147 patients whose tumors could not be retested or were later found to have <50% PD-L1 expression.
a Based on Kaplan-Meier method
b Based on stratified proportional hazards model

Continued and clinically meaningful benefits were also observed at this five-year follow-up of the overall trial population (in which not all patients were confirmed to have ≥50% PD-L1 expression), as compared to the prior 1-year analysis in this population.

1-year Analysis 5-year Analysis
Libtayo
(n=356) Chemotherapy
(n=354) Libtayo
(n=357) Chemotherapy
(n=355)
OS
Mediana 22 months 14 months 23 months 14 months
HR (95% CI; p-value)b 0.68
(0.53 to 0.87; p=0.0022) 0.64
(0.54 to 0.77; p<0.0001)
PFS
Mediana 6 months 6 months 6 months 5 months
HR (95% CI; p-value)b 0.59
(0.49 to 0.72; p<0.0001) 0.55
(0.46 to 0.66; p<0.0001)
ORR 37% 21% 42% 21%
Median DoR 21 months 6 months 24 months 6 months
a Based on Kaplan-Meier method
b Based on stratified proportional hazards model

Importantly, EMPOWER-Lung 1 allowed patients who experienced disease progression to change their therapy, with those assigned to Libtayo having the option to add four cycles of chemotherapy. Among these patients (n=75), the addition of chemotherapy was associated with a 15-month median OS (95% CI: 11 to 18 months), 7-month median PFS (95% CI: 6 to 8 months) and 28% ORR (95% CI: 18% to 40%).

The exploratory subgroup analysis of EMPOWER-Lung 1 also showed direct correlations between survival and disease progression benefits and PD-L1 expression level among Libtayo patients, supporting the direct correlation between tumor response and PD-L1 expression level previously observed. At five years, those with tumor PD-L1 expression of ≥90% (n=99) derived the greatest benefit with a median OS of 39 months (95% CI: 23 months to not evaluable) and a 15-month median PFS (95% CI: 10 to 21 months). These correlations with PD-L1 expression level were not observed with chemotherapy.

No new safety signals were observed at five years among evaluable patients (Libtayo=356; chemotherapy=343), following a median duration of exposure of 36 weeks to Libtayo and 18 weeks to chemotherapy. Adverse events (AEs) of any grade occurred in 93% of Libtayo patients (46% ≥Grade 3) and 96% of chemotherapy patients (52% ≥Grade 3). The most common AEs occurring in at least 10% of Libtayo patients included anemia (20%), decreased appetite (14%), fatigue (14%), pneumonia (12%), arthralgia (12%), back pain (12%), dyspnea (11%), cough (10%) and pruritus (10%). Among Libtayo patients, AEs were serious in 36% and led to permanent discontinuation in 9% and death in 10%, compared to 29%, 5% and 10% in the chemotherapy arm, respectively.

Among the 75 Libtayo patients who received additive chemotherapy after disease progression, AEs of any grade occurred in 89% (36% ≥Grade 3), following a median duration of exposure of 27 weeks to Libtayo. The most common AEs included anemia (35%), alopecia (24%), diarrhea (21%), nausea (20%), neutropenia (15%) and asthenia (11%). AEs were serious in 27% of patients and led to discontinuation of treatment in 5% of patients and death in 4% of patients.

Additional presentations on data from Regeneron’s oncology portfolio and pipeline are being shared at WCLC.

The potential use of adding chemotherapy to Libtayo following disease progression as described above is investigational, and the safety and efficacy of this regimen have not been fully evaluated by any regulatory authority.

On September 9, 2024 Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, reported completion of the first cohort of the Phase 2 STARBORN-1 trial evaluating TARA-002, an investigational cell-based immunopotentiator, for the treatment of pediatric patients with lymphatic malformations (LMs) (Press release, Protara Therapeutics, SEP 9, 2024, https://ir.protaratx.com/news-releases/news-release-details/protara-therapeutics-announces-completion-first-cohort-phase-2 [SID1234646439]). Enrollment is now underway in additional cohorts.

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"The initial data is compelling and reflective of the significant benefit observed in previous studies with OK-432, the predecessor of TARA-002," said Nancy Bauman, MD, Children’s National Medical Center: Children’s Research Institute, Washington DC, and investigator for the STARBORN-1 trial. "There is a pressing need for an effective therapeutic option for LMs, a rare condition mainly affecting children for which there are currently no U.S. FDA approved agents. I remain excited about the potential for TARA-002 to play a meaningful role in the treatment of these patients and look forward to future learnings from this important study."

Of three patients treated in the first cohort, which enrolled individuals six years to less than 18 years of age, two patients treated with TARA-002 achieved a complete response after receiving one dose of TARA-002; the responses were seen in a patient with a macrocystic lymphatic malformation and a patient with a ranula. The safety and tolerability seen in this cohort was consistent with that of the historical experience with OK-432 and included treatment emergent adverse events (TEAEs) of pain, swelling, fatigue, and body temperature increases. All TEAEs were mild to moderate and resolved.

"We are pleased with the progress of our Phase 2 STARBORN-1 trial and the encouraging results we have seen thus far," said Jesse Shefferman, Chief Executive Officer of Protara Therapeutics. "We have received positive feedback from our investigators and already have a number of patients on waiting lists for our subsequent cohorts, and expect to share initial results from our next cohort in the first half of 2025."

STARBORN-1 is a Phase 2 single-arm, open-label, prospective clinical trial evaluating the safety and efficacy of intracystic injection of TARA-002 for the treatment of macrocystic and mixed cystic LMs (≥ 50% macrocystic disease) in participants six months to less than 18 years of age. The trial will enroll approximately 30 patients including age de-escalation safety lead-in cohorts of children ages six years to less than18 years, two years to less than six years, and six months to less than two years, who will receive up to four injections of TARA-002 spaced approximately six weeks apart.

The primary endpoint of the trial is the proportion of participants with macrocystic and mixed cystic LMs who demonstrate clinical success, defined as having either a complete response (90% to 100% reduction from baseline in total LM volume) or substantial response (60% to less than 90% reduction in total LM volume) as measured by axial imaging.

About TARA-002 in LMs

TARA-002 is an investigational cell therapy based on the broad immunopotentiator, OK-432, which was originally granted marketing approval by the Japanese Ministry of Health and Welfare as an immunopotentiating cancer therapeutic agent. This cell therapy is currently approved in Japan and Taiwan for LMs and has been used to successfully treat thousands of pediatric patients with this rare condition. In addition, OK-432 was studied in the largest ever conducted Phase 2 trials in LMs, in which the therapy was administered via a now-closed compassionate use program led by the University of Iowa.

TARA-002 has been granted Rare Pediatric Disease designation by the U.S. Food and Drug Administration (FDA) for the treatment of LMs.

About Lymphatic Malformations

Lymphatic malformations (LMs) are rare, congenital malformations of lymphatic vessels resulting in the failure of these structures to connect or drain into the venous system. Most LMs are present in the head and neck region and are diagnosed in early childhood during the period of active lymphatic growth, with more than 50% detected at birth and 90% diagnosed before the age of three years. The most common morbidities and serious manifestations of the disease include compression of the upper aerodigestive tract, including airway obstruction requiring intubation and possible tracheostomy dependence; intralesional bleeding; impingement on critical structures, including nerves, vessels, lymphatics; recurrent infection; and cosmetic and other functional disabilities.

On September 9, 2024 Prelude Therapeutics Incorporated (Nasdaq: PRLD) ("Prelude" or the "Company"), a clinical-stage precision oncology company, reported the publication of an abstract regarding PRT3789 at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 taking place in Barcelona, Spain September 13-17, 2024 (Press release, Prelude Therapeutics, SEP 9, 2024, View Source [SID1234646438]). The abstract can be found on the ESMO (Free ESMO Whitepaper) 2024 website Registration | ESMO (Free ESMO Whitepaper) Congress 2024

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"We are excited for the opportunity to share the first ever clinical data of a novel, highly-selective SMARCA2 degrader," stated Jane Huang, M.D., President and Chief Medical Officer of Prelude. "Patients whose cancer has a SMARCA4 mutation have limited treatment options and generally very aggressive disease. Although PRT3789 as a first-in-class molecule targeting a novel mechanism is early in its development, we are highly encouraged by the safety profile, target engagement and clinical activity we have seen to date."

PRT3789 is a potent and highly selective, first-in-class SMARCA2 degrader, in Phase 1 clinical development in biomarker selected SMARCA4 mutant patients. Enrollment remains on track, and the Company expects to conclude monotherapy dose escalation by year end 2024 and identify a recommended Phase 2 dose. In addition, enrollment of patients into back-fill cohorts enriched for NSCLC and SMARCA4 loss-of-function mutations is ongoing. Objectives for this first Phase 1 clinical study are to establish the safety and tolerability profile of PRT3789 as both monotherapy and in combination with docetaxel, evaluate activity, pharmacokinetics and pharmacodynamics and determine a dose and potential indications for advancement into a registrational clinical trial.

Oral presentation title: First Clinical Results from a Phase 1 Trial of PRT3789, a First-in-Class Intravenous SMARCA2 Degrader, in Patients with Advanced Solid Tumors with a SMARCA4 Mutation.

Observations in the abstract include:

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As of the March 7, 2024 data cutoff date, 40 pts had been enrolled (NSCLC [18], pancreatic [5], breast [3], esophageal [2], other [12]; 55% have loss-of-function mutations;

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Dose escalation had proceeded through 6 levels, from 24-212 mg, with 2 backfill cohorts opened;
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No DLTs or study drug-related SAEs have been reported;
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The most common AEs reported, of any grade or relatedness, are nausea (25%), constipation and dyspnea (each 17.5%), decreased appetite and fatigue (each 15%), and anemia (12.5%);
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Dose-related increases in AUC were observed;
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Dose-dependent decreases in SMARCA2 levels were seen at all doses with a trend for increasing depth and duration with increasing doses;
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Minimal effects on SMARCA4 levels were seen;
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Clinical activity of PRT3789 therapy noted to date includes RECIST partial responses, tumor shrinkage and prolonged stable disease (longer than response to most recent therapy) in patients with advanced, heavily pretreated esophageal cancer and NSCLC.

Updated data will be presented at ESMO (Free ESMO Whitepaper).

Investor Conference Call and Webcast Information

Prelude Therapeutics will host a conference call, live webcast with slides and a Q&A on Friday, September 13, 2024 at 12:00 PM EST. A live webcast of the presentation will be available at Events & Presentations – Prelude Therapeutics (preludetx.com). A replay of the webcast will be available shortly after the conclusion of the call and archived on the Company’s website for 60 days following the call. The Company will be posting its updated corporate presentation shortly after 10:00 AM EST on its website at Events & Presentations – Prelude Therapeutics (preludetx.com).