NeoImmuneTech’s Lead Asset NT-I7 (efineptakin alfa) Shows Preliminary Anticancer Activity in Combination with Check-Point Inhibitors

On June 6, 2022 NeoImmuneTech, Inc. (NIT or "NeoImmuneTech"), a clinical-stage T cell-focused biopharmaceutical company, reported that new data from two on-going clinical studies at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, 3-7 June 2022 (Press release, NeoImmuneTech, JUN 6, 2022, View Source [SID1234615676]). The data, presented in poster discussion and poster display sessions, combine its lead asset NT-I7 (efineptakin alfa), a long-acting human IL-7, with check-point inhibitors (CPI) pembrolizumab and atezolizumab, and showed that anti-cancer and safety results associated with NT-I7 were consistent with previously communicated results.

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In the phase 2a study NIT-11o, NT-I7 combined with pembrolizumab showed preliminary anticancer activity and a manageable toxicity profile in heavily pretreated patients with immunologically cold microsatellite stable tumors (MSS), colorectal cancers (CRC), and pancreatic ductal adenocarcinoma cancers (PDAC) not previously treated with CPIs, as well as in CPI-treated patients with triple negative breast cancers (TNBC), non-small cell lung cancers (NSCLC), and small-cell lung cancers (SCLC). CPIs are usually ineffective in patients with immunologically cold tumors, such as MSS-CRC or PDAC, and in patients progressing despite prior PD-1/PD-L1 inhibition. ORR for the MSS-CRC cohort was 11.1% with 40.7% DCR; and the PDAC cohort had an ORR of 7.7% with 34.6% DCR (per iRECIST). Two patients out of 26 in the PDAC cohort showed significant target lesion reduction (- 100% and -72% respectively). In all cohorts, including CPI-treated and CPI-naïve subjects, NT-I7 plus pembrolizumab led to an increase in change of mean absolute lymphocyte count from baseline.

In the phase 1b/2a study NIT-106, the combination of NT-I7 with atezolizumab showed favorable safety and anticancer activity in CPI-relapsed/refractory high-risk skin cancer patients. The recommended phase 2 dose (RP2D) was determined so that phase 2a dose expansion is now enrolling. The combination increased by 30-fold the stem-cell memory T cells (Tscm), which may be associated to better anti-tumor activity.

Dr. Se Hwan Yang, Ph.D., President and Chief Executive Officer of NeoImmuneTech said: "We are pleased to gather additional evidence of the efficacy and safety of NT-I7 in combination with check-point inhibitors. Encouraging preliminary results from study NIT-110 led us to expand patient recruitment in the MSS-CRC and PDAC cohorts in order to enhance statistical significance. While study NIT-110 is still on-going, we look forward to more mature data by Q4 2022 that could confirm the benefit of combining our T cell amplifier NT-I7 with a checkpoint inhibitor (CPI) in patients with immune-cold microsatellite stable colorectal cancer or pancreatic cancer and in those who progressed on previous CPI treatment."

As part of the ASCO (Free ASCO Whitepaper) 2022 poster program, a Trial-in-Progress poster was also presented on the design of Phase 1b study NIT-112, indicating progress of NT-I7 plus CAR-T development.

The links to the posters are as follows:

Primary Author

Poster Title

Poster link

Naing, A

Efficacy and Safety of NT-I7, Long-Acting Interleukin-7, plus
Pembrolizumab in patients with advanced solid tumors: results
from the Phase 2a study

Poster #170

Gastman, B

A phase 1b/2a study of safety and efficacy of NT-I7 in
combination with anti-PD-L1 (atezolizumab) in patients with
anti-PD-1/PD-L1 naïve or relapsed/refractory (R/R) high-risk
skin cancers: The phase 1b report.

Poster #154

Ghobadi, A

Trial in Progress: A phase 1b study evaluating the safety,
tolerability and preliminary anti-tumor activity of NT-I7
(efineptakin alfa), a long-acting human IL-7, post-
tisagenlecleucel in subjects with relapsed/refractory large B-cell
lymphoma

Poster #239b

About NT-I7 (efineptakin alfa) (rhIL-7-hyFc)

NT-I7 (efineptakin alfa) is the only clinical-stage long-acting human IL-7, and is being developed in oncologic and immunologic indications, where T cell amplification and increased functionality may provide clinical benefit. IL-7 is a fundamental cytokine for naïve and memory T cell development and for sustaining immune response to chronic antigens (as in cancer) or foreign antigens (as in infectious diseases). NT-I7 exhibits favorable PK/PD and safety profiles, making it an ideal combination partner. NT-I7 is being studied in multiple clinical trials in solid tumors and as vaccine adjuvant. Studies are being planned for testing in hematologic malignancies, additional solid tumors and other immunology-focused indications.

OriCell Reports OriCAR-017 Phase I POLARIS study Data in Oral Presentation at American Society of Clinical Oncology(ASCO) Annual Meeting 2022

On June 6, 2022 OriCell Therapeutics Co., Ltd (OriCell), a leading innovative biopharmaceutical company pioneering novel oncology cell therapies for the unmet medical needs in in hematology and oncology, reported the positive results from Phase I POLARIS study, an investigator-sponsored study evaluating Ori-CAR017, an autologous GPRC5D-directed CAR-T cell, in patients with relapsed/refractory multiple myeloma at American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, OriCell Therapeutics, JUN 6, 2022, View Source [SID1234615675]).

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Single Infusion of OriCAR-017 Demonstrates an Early, Deep and Durable Responses at All Dose Levels in Heavily Pretreated RRMM Patients, including Patients Who Relapsed from BCMA CAR-T Therapy.
Overall Response Rate(ORR) was 100% with Complete Response (CR)/ stringent Complete Response (sCR) rate of 60%,including Five patients with prior BCMA CART therapy achieved 2 sCR, 2 VGPR and 1PR. Patient medium follow up time 175 days (range 35-281). All patients were progression free without additional therapy at data cutoff. Results Highlights a Major Advance for OriCAR-017 Future Potential in RRMM Setting, regardless prior BCMA Targeted Therapy.
No Dose Limiting Toxicities (DLTs) or Serious Adverse Events (SAE) was observed. No Immune effector Cell Associated Neurotoxicity Syndrome(ICANS). Only Grade 1/2 Cytokine Release Syndrome(CRS). Most common Grade 3/4 AE was cytopenia, mainly due to lymphodepleting chemotherapy.
"We are delighted to share the FIH data from our Phase I POLARIS study, we strongly believe these data has demonstrated our advantages from the proprietary platforms for CAR-T optimization structure. Next step, we will be focusing on filling an IND with the NMPA and FDA for Ori-CAR017." said Dr. Helen Yang, Chairman and CEO of OriCell. "We look forward to continue developing novel cell therapies, to provide patient with better treatment option in the future."

Prof. He Huang, M.D., Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University said: "Multiple Myeloma (MM) remains incurable with extremely low overall survival for relapsed/refractory patients. Therapies using newer targets are urgently needed. The data presented at ASCO (Free ASCO Whitepaper) 2022 demonstrated that OriCAR-017 is a safe and effective treatment for patients with RRMM who received multiple lines of therapy, especially those who relapsed after BCMA-targeted therapy. I look forward to advancing the research of Ori-CAR017, a first-in-class autologous GPRC5D-directed CAR-T cell, with OriCell, so that patients can benefit from clinical results as soon as possible."

Ryvu Therapeutics to Host Key Opinion Leader Webinar on RVU120 for the Treatment of Hematological Malignancies and Solid Tumors

On June 6, 2022 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported that it will host a key opinion leader (KOL) webinar on RVU120, a first-in-class CDK8/19 inhibitor, the Company’s lead asset currently in Phase I studies for hematological malignancies and solid tumors on Monday, June 13, 2022, at 2:30 pm Eastern Time (Press release, Ryvu Therapeutics, JUN 6, 2022, View Source [SID1234615674]).

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The webinar will feature a presentation by KOL Dr. Michael Savona, MD, from Vanderbilt University School of Medicine, who will discuss the current treatment landscape and unmet medical need in treating patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS).

The Ryvu Therapeutics leadership team will discuss the underlying mechanism of action of RVU120, which targets hematological malignancies and solid tumors characterized by deregulated transcription. Additionally, an update on the Phase I data for RVU120 will be provided.

A live question and answer session will follow the formal presentations. To register for the event, please click here.

Michael Savona, MD is the Head of Hematology, Cellular Therapy, and Stem Cell Transplant, the Beverly and George Rawlings Director of Hematologic Malignancies Research, and Professor of Internal Medicine and Cancer Biology at Vanderbilt University.

Dr. Savona led the development and approval of several novel therapies for myeloid malignancies. He has been involved in medical research for over 20 years and has published over 100 manuscripts in major academic journals.

Dr. Savona is board certified in medical oncology and hematology, an elected fellow of the American College of Physicians, and a Leukemia and Lymphoma Society Clinical Scholar. Dr. Savona obtained his bachelor’s degree in philosophy from Davidson College and medical degree at Wake Forest University School of Medicine in Winston-Salem, North Carolina. He did post-graduate clinical and research training at the University of California Davis, and the University of Michigan. He also served as a physician in the United States Air Force and is a veteran of Operation Enduring Freedom/Operation Iraqi Freedom.

About RVU120 (SEL120)

RVU120 (SEL120) is a clinical-stage, highly specific, and orally bioavailable dual inhibitor of CDK8/CDK19 kinases, which has demonstrated efficacy in a number of solid tumor in vitro and in vivo models as well as in hematologic malignancies.

At present, Ryvu is conducting two clinical studies with RVU120: (i) Phase Ib in patients with AML/HR-MDS (NCT04021368) and (ii) Phase I/II in relapsed/refractory metastatic or advanced solid tumors (NCT05052255). Additionally, multiple translational research activities are underway.

On March 25, 2020, the U.S. Food and Drug Administration (FDA) granted an orphan drug designation (ODD) to RVU120, for the treatment of patients with AML.

RVU120 has been internally discovered by Ryvu and has received support from the Leukemia & Lymphoma Society Therapy Acceleration Program (TAP).

CARsgen Therapeutics Presents Updated Data for CT041 Claudin18.2 CAR T-cells in Solid Tumors at ASCO 2022

On June 6, 2022 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, reported that at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, the Company presented two posters with study results for CT041, an autologous CAR T-cell product candidate against protein Claudin18.2 (CLDN18.2) (Press release, Carsgen Therapeutics, JUN 6, 2022, View Source;301561407.html [SID1234615673]). The two posters included (1) results from the multicenter Phase 1b CT041 trial in the U.S. for patients with advanced gastric and pancreatic adenocarcinoma and (2) the safety and preliminary efficacy results from the Phase Ib/II CT041 study in China for patients with advanced gastric/gastroesophageal junction adenocarcinoma.

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The abstracts of the posters are listed below:

Abstract #2538: Multicenter Phase 1b Trial of Salvage CT041 CLDN18.2 – specific Chimeric Antigen Receptor T Cell Therapy for Patients with Advanced Gastric and Pancreatic Adenocarcinoma

A single-arm, open-label, Phase 1b trial (NCT04404595) was conducted in six centers in the U.S. CLDN18.2 positive patients who had gastric cancer or gastroesophageal junction cancer (GC/GEJ) with ≥ 2 prior lines of systemic therapy or pancreatic cancer (PC) with ≥ 1 prior line were eligible for the study. A preconditioning regimen with fludarabine, cyclophosphamide, and nab-paclitaxel (100 mg or 100 mg/m2; FNC) was given prior to CT041 infusion. Adverse events (AEs) were graded per CTCAE v5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASTCT criteria. Tumor response was assessed per RECIST 1.1.

As of May 6, 2022, 14 patients had enrolled (5 GC/GEJ, 9 PC) with a median of 3 prior lines of therapy (range 1-5) and had received 18 total cycles of CT041. Fourteen patients were given by three dose levels (DL) including DL1 of 2.5-3.0×108 cells (n=6), DL2 of 3.75-4.0×108 cells (n=6) and DL3 of 6.0×108 cells (n=2).

Safety

No dose-limiting toxicities or treatment-related deaths were observed. No ≥ Grade 3 CRS or ICANS was observed. No gastrointestinal bleeding or acute gastric mucosal injury were reported. One patient did not have CRS. Among the 13 patients with CRS, 11 patients had Grade 1 and 2 patients had Grade 2.

Efficacy

In a subgroup of patients with GC/GEJ, an objective response rate (ORR) of 60% was reported, and one patient achieved complete response (CR). Additionally, tumor shrinkage was observed in 80% (4 of 5) of patients with stable disease (4 patients with PC). Median duration of response (mDOR) and progression-free survival (mPFS) have not been reached. Two patients who received DL3 did not have tumor response assessments by the data cutoff date. Dose-dependent responses were observed in DL1 and DL2. An ORR of 16.7% and a disease control rate (DCR) of 50% was observed in DL1. An ORR of 33.3% and a DCR of 83.3% were observed in DL2. Tumor response details are listed in the table below.

Tumor response by tumor type

GC/GEJ (n=5)

n (%)

PC (n=7)

n (%)

Complete response

1 (20)

0 (0)

Partial response

2 (40)

0 (0)

Stable disease

1 (20)

4 (57.1)

Progressive disease

1 (20)

3 (42.9)

Note: GC/GEJ= gastric cancer or gastroesophageal junction cancer; PC=pancreatic cancer.

Conclusion

In heavily pre-treated gastric cancer, CT041 CLDN18.2 CAR T cells may have significantly improved antitumor activity compared to historical treatment regimens.

Abstract #4017 Safety, Tolerability and Preliminary Efficacy Results in Patients with Advanced Gastric/Gastroesophageal Junction Adenocarcinoma from a Phase Ib/II Study of CLDN18.2 CAR T-cell Therapy (CT041)

This multicenter, open-label, Phase Ib/II study (NCT04581473) was conducted to evaluate the safety and efficacy in Chinese patients with GC/GEJ. In Phase Ib, CT041 dose levels of 2.5×108 and 3.75×108 cells were investigated using a 3 + 3 design.

Key eligibility criteria for the Phase Ib study: patients with CLDN18.2-positive expression confirmed by immunohistochemistry (IHC) staining (2+/3+ in ≥40% tumor cells), advanced GC/GEJ adenocarcinoma who were refractory to or intolerant of at least 2 prior treatments are eligible for this study. HER2–positive patients should have received standard anti–HER2 therapy.

As of December 22, 2021, 14 eligible patients with GC/GEJ were enrolled in Phase Ib, among which 57.1% had ≥ 3 metastatic organs and 92.9% had peritoneal dissemination. Most of the patients (85.7%) had received 2 prior treatments or a triple combination of fluoropyrimidine, oxaliplatin and paclitaxel. 35.7% of the patients had been exposed to PD-1/PD-L1 inhibitor. The baseline characteristics are shown in the table below.

Demographics and baseline characteristics

Total (N = 14)

Median age (range), year

44.5 (23–71)

Male, n (%)

6 (42.9%)

Eastern Cooperative Oncology Group performance status=1, n (%)

12 (85.7%)

Lauren classification, n (%)

Intestinal type

3 (21.4%)

Diffuse type

9 (64.3%)

Mixed type

2 (14.3%)

Signet ring cell carcinoma, n (%)

9 (64.3%)

Claudin18.2 staining, n (%)

2+

2 (14.3%)

3+

12 (85.7%)

HER2 expression, n (%)

Positive

1 (7.1%)

Negative

12 (85.7%)

Unknown

1 (7.1%)

Numbers of metastatic organs, n (%)

< 3

6 (42.9%)

≥ 3

8 (57.1%)

Peritoneal metastasis, n (%)

13 (92.9%)

Liver metastasis, n (%)

3 (21.4%)

Numbers of prior lines, n (%)

2*

12 (85.7%)

≥ 3

2 (14.3%)

Prior systemic therapies, n (%)

Fluorouracil

14 (100%)

Platinum

14 (100%)

Paclitaxel / nab–paclitaxel

13 (92.9%)

PD–1/PD-L1 inhibitor

5 (35.7%)

Tyrosine–kinase inhibitor

2 (14.3%)

* Five patients received a triple combination of fluoropyrimidine, oxaliplatin and paclitaxel as first line treatment.

All 14 patients received 1 cycle of bridging chemotherapy determined by the investigators, including 13 patients (92.9%) received FOLFIRI, and only 1 received 5–FU plus intraperitoneal nab–paclitaxel. All patients received preconditioning treatment (fludarabine 25 mg/m2 on d1–2, cyclophosphamide 250 mg/m2 on d1–3 and nab–paclitaxel 100 mg on d2) before CT041 infusion. All patients received at least one infusion (11 received 2.5×108 cells and 3 received 3.75×108 cells) of CT041 and 7 patients received two infusions. For the 7 patients who received two infusions, the median interval between infusions was 132 days (range 49–252 days).

Safety

No patients had dose–limiting toxicities or AEs leading to death. Thirteen patients had Grade 2 CRS, and only one patient had Grade 4 CRS, which was related to the patient’s disease burden, who fully recovered after corticosteroid treatment. No ICANS or gastrointestinal mucosal injury were reported.

Efficacy

Thirteen patients were evaluable and one patient withdrew from the study before any tumor assessment was performed. Eight of 14 (57.1%) patients achieved partial response at the first tumor assessment after the first CT041 infusion. Based on the investigators’ assessment, the ORR and DCR were 57.1% and 78.6% respectively.

While the median follow-up time was 8.8 months, the mPFS and median overall survival were 5.6 months and 10.8 months respectively. Seven patients were still alive by the cutoff date.

Conclusion

These preliminary results suggest that CT041 had manageable safety/tolerability profile and promising efficacy in patients with previously treated advanced GC/GEJ adenocarcinoma. This study is ongoing with further investigation of CT041 in confirmatory Phase II underway.

Dr. Raffaele Baffa, Chief Medical Officer of CARsgen Therapeutics Holdings Limited, said, "Solid tumors, including gastric cancer, are of high incidence globally. As treatment options for gastric cancer are still limited, there is a strong need for more innovative therapies. The updated clinical data of CT041 at ASCO (Free ASCO Whitepaper) 2022 are very encouraging in pre-treated GC/GEJ and PC patients, demonstrating significant efficacy and excellent tolerability, including the impressive ORR of 60% and a case of CR. We look forward to the continuing development of CT041 and we believe it can help more patients."

Dr. Zonghai Li, Founder, Chairman of the Board, Chief Executive Officer, and Chief Scientific Officer of CARsgen Therapeutics Holdings Limited, said, "It is the first time that we presented the data for CT041 from registrational trials in China and the U.S. Following the publication of the results of an investigator-initiated trial of CT041 in Nature Medicine earlier in May, the updated results announced at ASCO (Free ASCO Whitepaper) 2022 further demonstrated the promising therapeutic efficacy and favorable safety of CT041. CT041 is currently the only CAR T-cell product candidate entering a confirmatory Phase II clinical trial for the treatment of solid tumors. We will spare no efforts to continue driving the global clinical development of CT041 to benefit more cancer patients worldwide."

About CT041

CT041 is an autologous CAR T-cell product candidate against the protein CLDN18.2 that has the potential to be the first-in-class globally. CT041 targets the treatment of CLDN18.2 positive solid tumors with a primary focus on GC/GEJ and PC. CT041 has demonstrated promising therapeutic efficacy and favorable safety in ongoing clinical trials. CARsgen believes that CT041 has the potential to become a backbone therapy for GC/GEJ and PC in the future and benefit a large population of patients worldwide.

As of the date of the announcement, CT041 is the only CLDN18.2-targeted CAR T-cell product candidate globally that is being studied in clinical trials with IND/CTA approvals from the FDA, the NMPA and Health Canada.

Active trials in CARsgen include investigator-initiated trials, a Phase Ib clinical trial for advanced GC/GEJ and PC and a confirmatory Phase II clinical trial for advanced GC/GEJ in China (CT041-ST-01, NCT04581473), and a Phase 1b/2 clinical trial for advanced gastric or pancreatic adenocarcinoma in North America (CT041-ST-02, NCT04404595). CARsgen also intends to conduct a pivotal Phase 2 clinical trial in North America in 2022.

In May 2022, the phase I trial interim results of an investigator-initiated trial of CT041 have been published in Nature Medicine. In this largest clinical trial for solid tumors to date, the CAR T-cell therapy showed unprecedented efficacy against solid tumors.

In 2020 and 2021, CT041 received Orphan Drug designation from the U.S. FDA for the treatment of GC/GEJ and Orphan Medicinal Product designation from the EMA for the treatment of advanced gastric cancer. In November 2021, CT041 was granted PRIME Eligibility by the EMA for the treatment of advanced gastric cancer. In January 2022, CT041 was granted Regenerative Medicine Advanced Therapy (RMAT) Designation by U.S. FDA for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma with CLDN18.2 positive tumors.

Linnaeus Therapeutics Announces Presentation of Positive Clinical Data of LNS8801 at 2022 ASCO Annual Meeting

On June 6, 2022 Linnaeus Therapeutics, Inc. (Linnaeus), a privately held clinical-stage biopharmaceutical company focused on the development and commercialization of novel small-molecule oncology therapeutics, reported the presentation of clinical data from its phase 1/2 clinical trial of LNS8801 in combination with pembrolizumab in patients who have developed secondary resistance to anti–PD-1/L1 therapy at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Linnaeus Therapeutics, JUN 6, 2022, View Source [SID1234615672]).

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The poster is entitled, "Phase 1b study of the novel first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in combination with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-relapsed and refractory solid malignancies."

In the dose-escalation portion of the study, LNS8801 demonstrated exceptional safety and tolerability. With monotherapy, no dose-limiting toxicities (DLTs) or treatment-related serious adverse events were observed, and the combination of LNS8801 and pembrolizumab was confirmed to be safe and tolerable with no DLTs observed. The recommended phase 2 dose of LNS8801 was identified as 125 mg daily as a monotherapy and in combination with pembrolizumab (200 mg every 3 weeks). Predictive, prognostic, and confirmatory biomarkers have been shown to correlate well with anticancer activity and clinical benefit. These biomarkers are being further validated and will aid in the selection of patients in future clinical studies.

The combination of LNS8801 with pembrolizumab has demonstrated strong signals of activity in patients with metastatic cancer who had previously benefited from and then developed secondary resistance to ICI therapy. An objective response rate of 15.4% was achieved, with 2 of 13 evaluable patients achieving confirmed partial responses. A disease control rate of 69.2% was observed, with 9 of 13 evaluable patients achieving partial responses or stable disease. Four patients have already remained on study longer than 6 months with ongoing benefit for the duration of therapy. The combination of LNS8801 and pembrolizumab is tolerable without unanticipated toxicities.

"We are very pleased to showcase these data at ASCO (Free ASCO Whitepaper)," commented Patrick Mooney, MD, CEO of Linnaeus. "LNS8801 continues to be extremely safe and well tolerated and shows very promising activity in combination with pembrolizumab. It is important to note that the disease control rate of ICI therapy alone in this patient population is expected to be very low, so it is exciting to see that the addition of LNS8801 to pembrolizumab is stopping progression in almost 70% of patients without any additional toxicity. We look forward to further exploration of LNS8801 alone and in combination, and we are encouraged by the continuing data we are seeing from these open cohorts."

About LNS8801
LNS8801 is an orally bioavailable, highly specific, and potent agonist of GPER whose activity is dependent on the expression of GPER. GPER activation by LNS8801 rapidly and durably depletes c-Myc protein levels. In preclinical cancer models, LNS8801 displays potent antitumor activities across a wide range of tumor types, rapidly shrinking tumors and inducing immune memory.

In the ongoing phase 1/2a study in humans, LNS8801 monotherapy has been safe and well tolerated. Additionally, LNS8801 has demonstrated target engagement, c-Myc protein depletion, and clinical benefit in some patients with advanced cancer.