On September 11, 2023 Bicycle Therapeutics (Nasdaq: BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported that the company will proceed with its plan to expedite development of BT8009 for metastatic bladder (urothelial) cancer following recent discussions with the U.S. Food and Drug Administration (FDA) (Press release, Bicycle Therapeutics, SEP 11, 2023, View Source [SID1234635056]). The company has aligned with the FDA on a Phase 2/3 registrational trial, called Duravelo-2, that has an innovative design allowing for potential accelerated approval in untreated (first-line) and previously treated (second-line plus) metastatic bladder cancer. The company plans to initiate the Duravelo-2 trial in the first quarter of 2024.

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"We prepared a robust and innovative clinical development plan for BT8009, with the goal of getting this much-needed therapy to patients as quickly as possible. We are pleased to have reached alignment with the FDA on the registrational trial design, dose selection and clinical trial endpoints that could support potential accelerated approval in a broad metastatic bladder cancer population," said Santiago Arroyo, M.D., Ph.D., chief development officer at Bicycle Therapeutics. "In preparation for this positive outcome, we have put in place the clinical infrastructure that will allow us to start the registrational trial early next year."

The Phase 2/3 Duravelo-2 trial will assess BT8009 in untreated metastatic bladder cancer (Cohort 1) and previously treated metastatic bladder cancer (Cohort 2). In Cohort 1, two doses of BT8009 plus standard pembrolizumab regimen will be initially assessed. Following selection of the optimal dose, BT8009 plus pembrolizumab will be evaluated against chemotherapy. Potential accelerated approval will be determined by objective response rate (ORR), and progression-free survival (PFS) will be used to confirm clinical benefit.

In Cohort 2, two doses of BT8009 as monotherapy will be initially studied. Following selection of the optimal dose, an additional arm of BT8009 plus standard pembrolizumab regimen will be added. Potential accelerated approval for BT8009 monotherapy and in combination with pembrolizumab will be determined by ORR compared to historical control data. Discussions with the FDA about the design of the confirmatory trial for previously treated metastatic bladder cancer are ongoing.

"At Bicycle Therapeutics, we are committed to using our novel platform to develop precision targeted therapeutics and improve the lives of patients who are battling devastating diseases. This is why, in line with the philosophy of the FDA’s Project FrontRunner and following the agency’s recent draft guidance on accelerated approval of oncology therapeutics, we have initially focused on defining the regulatory path for BT8009 in untreated patients. We believe today’s announcement is good news for patients, and we are greatly appreciative of the FDA for their collaboration and guidance," said Kevin Lee, Ph.D., chief executive officer of Bicycle Therapeutics. "As we look to the rest of 2023, we continue to make progress in our research and development programs and look forward to providing updates on BT8009, BT5528 and BT7480 later this year."

Conference Call and Webcast Information
Bicycle Therapeutics will host a conference call and webcast today, September 11, 2023, at 8 a.m. ET to review the BT8009 regulatory update. To access the call, please dial 1-833-816-1408 (U.S.) or +1 412-317-0501 (international) and ask to be joined into the Bicycle Therapeutics call. A live webcast and replay of the conference call will be available in the Investor section of the Bicycle website, bicycletherapeutics.com.

About BT8009
BT8009 is an investigational Bicycle Toxin Conjugate (BTC) targeting Nectin-4, a well-validated tumor antigen with elevated levels of expression in multiple tumor types, including bladder (urothelial) cancer. It is currently being evaluated in a Phase 1/2 clinical trial enrolling patients with Nectin-4 expressing advanced solid tumors. BT8009 will be evaluated in the Phase 2/3 Duravelo-2 trial, a global, multi-center, adaptive study designed to assess the safety and efficacy of the therapy for metastatic bladder cancer.

On September 11, 2023 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported updated preclinical data supporting development of the Company’s WEE1 inhibitor candidate, ATRN-1051, for the treatment of ovarian cancer (Press release, Aprea, SEP 11, 2023, View Source [SID1234635055]).

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The preclinical and in vitro data suggest that the selective properties of ATRN-1051 may make it a more efficacious cancer therapy than the other WEE1 inhibitors in development. Importantly, ATRN-1051 is a highly potent and selective inhibitor of WEE1 that does not significantly affect off-target PLK1, PLK2 and PLK3, a family of kinases that promote M phase entry, a critical phase in the cell cycle. Such off-targeting of the PLK family has been a challenge to other WEE1 inhibitors in the class. Evidence generated by Aprea suggests that off-target inhibition of PLK1 substantially limits the ability of WEE1 inhibitors to cause genotoxicity, the proposed mechanism by which WEE1 inhibitors act as cancer therapeutics.

The preclinical research of ATRN-1051 in ovarian cancer also shows an increased expression of cyclin E1, or CCNE1. CCNE1 amplification, which is associated with platinum resistance and poor survival, has been shown to be a reliable predictive biomarker of response to WEE1 inhibition. As part of the preclinical studies with ATRN-1051, the Company conducted cell culture and CDX mouse model studies using the CCNE1-normal and CCNE1-amplified ovarian cancer cell lines to show that low doses of ATRN-1051 completely suppress the growth of CCNE1-amplified ovarian cancer cells and tumors. In addition to the anti-tumor activity, the preclinical studies of ATRN-1051 indicate improved AUC pharmacokinetic properties compared to other WEE1 inhibitors, with the low dose of ATRN-1051 showing a similar AUC as higher doses of other WEE1 inhibitors.

Table 1
ATRN 1051 (1) Zentalis AstraZeneca
ZN-c3 (2) AZD-1775 (2)
Dose (mg/kg/d) 10 20 40 80 20 40 80
Cmax ng/ml 1,460 1,167 1,997 5,100 635 2,460 4,703
Tmax hr 3 1 1 1 1 1 1
AUC0-24, ng*hr/ml 16,739 4,863 17,088 39,722 1,494 6,313 13,408

Note: Head-to-head studies have not been conducted
(1) Data from an exploratory formulation of ATRN-1051 administered to fasted Balb/c mice
(2) Data from study in A-427 NSCLC xenograft model as reported in Zentalis Corporate Overview, March 2022

"We are very excited and encouraged by these positive findings that demonstrate ATRN-1051’s promise as a clinical agent based on its preclinical in vivo activity and safety profile," said Dr. Oren Gilad, President and CEO of Aprea. "We look forward to presenting the full data set at an upcoming 2023 scientific conference and to filing an IND for ATRN-1051 by the end of 2023. We believe these findings support the further development of this potentially substantial and clinically important agent. We also look forward to hosting a key opinion leader (KOL) event this fall highlighting these exciting data and outlining our development plan."

WEE1 kinase is a key regulator of multiple phases of the cell cycle, most prominently in progression from G1 to S phase and S to M phase through inhibitory phosphorylation of CDK2 and CDK1, respectively. Thus, when WEE1 is inhibited, both G1-S and S-M checkpoints are abrogated, leading to premature S-phase and M-phase entry. Notably, the replication stress caused by CCNE1 overexpression is transformed into toxic levels of double stranded breaks and cancer cell death when WEE1 is inhibited. The Company believes that CCNE1 gene amplification or high CCNE1 protein expression is a potential predictive biomarker of ATRN-1051 efficacy.

About ATRN-1051
The Company is targeting the WEE1 kinase, a key regulator of multiple phases of the cell cycle, with its lead WEE1 inhibitor product candidate, ATRN-1051. ATRN-1051 is an orally bioavailable small molecule inhibitor of WEE1 that is highly potent and selective. ATRN-1051 is distinct from other WEE1 inhibitors based on its potentially superior pharmacokinetic properties and selectivity. The company anticipates filing an IND for ATRN-1051 by the end of 2023.

On September 11, 2023 Amgen (NASDAQ:AMGN) reported that it will present at the Bank of America Merrill Lynch Global Healthcare Conference at 11:40 a.m. BST on Thursday, Sept. 14, 2023 (Press release, Amgen, SEP 11, 2023, View Source [SID1234635054]). Peter H. Griffith, executive vice president and chief financial officer at Amgen will present at the conference. The webcast will be broadcast over the internet simultaneously and will be available to members of the news media, investors and the general public.

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The webcast, as with other selected presentations regarding developments in Amgen’s business given by management at certain investor and medical conferences, can be found on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

On September 11, 2023 AIM ImmunoTech Inc. (NYSE American: AIM) ("AIM" or the "Company") reported that Roswell Park Comprehensive Cancer Center has announced the complete topline data from its Phase 1 study evaluating Ampligen (rintatolimod) as a component of a CKM regimen for the treatment of early-stage triple negative breast cancer (TNBC) (Press release, AIM ImmunoTech, SEP 11, 2023, View Source [SID1234635053]). The complete topline results are now available on ClinicalTrials.gov: NCT04081389.

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The research was led by Roswell Park Comprehensive Cancer Center medical oncologist Shipra Gandhi, MD, a physician scientist who is Assistant Professor of Oncology at Roswell Park, in collaboration with senior investigator Pawel Kalinski, MD, PhD, Chair of Immunology and Senior Vice President for Team Science at Roswell Park.

The now completed topline results from the Phase 1 study confirm the positive findings that were previously presented at the 2022 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting in a poster presentation titled Safety and efficacy of de-escalated neoadjuvant chemoimmunotherapy of triple negative breast cancer (TNBC) using chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib)1.

"We are pleased to bolster our growing body of data from Ampligen and the results demonstrated in the Phase 1 study with the completed topline data report now in hand. We continue to be encouraged by Ampligen’s demonstrated potential to deliver promising clinical activity in an area where there remain significant immune-related toxicities with the current standard of care and look forward to its continued development," stated David Strayer, MD, AIM’s Chief Scientific and Medical Officer.

In the Phase 1 study, 9 patients with stage I-III TNBC, median age 47 (37-55) years, were treated with paclitaxel 80 mg/m2 IV weekly for 12 weeks and CKM for the first 3 weeks, days 1-3 (IV Ampligen 200 mg daily and oral celecoxib 200 mg twice daily). IFN-α2b was administered in an accelerated dose-escalation at 0 or 5 million units (MU)/m2 [dose levels (DL) 1,2 respectively] in the first 2 patients; 10 MU/m2 [DL 3] in 4 patients and 20 MU/m2 [DL 4] in 3 patients. CKM/paclitaxel was followed by standard dose-dense doxorubicin and cyclophosphamide (AC) and surgery.

The primary endpoint of the study was safety and tolerability. The results demonstrated that treatment was well-tolerated with mostly grade 1 or 2 treatment-related adverse events (TRAEs) without dose-limiting toxicities (DLTs) or delayed or immune-related toxicities. DLT was defined as grade 3 or higher toxicities within the first 3 weeks. Secondary endpoints included pCR rate where 5/9 (56%) of patients attained pCR and 1 more patient attained ypTmic. Tumor and blood biomarkers were also analyzed in exploratory studies.

For more information about the Phase 1 study, visit ClinicalTrials.gov: NCT04081389.

On September 11, 2023 ADC therapeutics presented its corporate presentation (Presentation, ADC Therapeutics, SEP 11, 2023, View Source [SID1234635052]).

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