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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On September 9, 2023 AstraZeneca reported that Positive results from the FLAURA2 Phase III trial showed Tagrisso (osimertinib) in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared to Tagrisso alone for patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC).

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These results were presented today in a Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC) (abstract #PL03).

Results showed Tagrisso plus chemotherapy reduced the risk of disease progression or death by 38% compared to Tagrisso alone (based on a hazard ratio [HR] of 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). By investigator assessment, the combination extended median PFS by 8.8 months versus Tagrisso alone. PFS results from blinded independent central review (BICR) were consistent, showing Tagrisso plus chemotherapy extended median PFS by 9.5 months (based on HR of 0.62; 95% CI 0.48-0.80; p=0.0002). Importantly, a clinically meaningful PFS benefit was observed across all prespecified subgroups, including sex, race, type of EGFR mutation, age at time of diagnosis, smoking history and central nervous system (CNS) metastases status at baseline.

At the time of this analysis, the overall survival (OS) data were immature however, a favourable trend was observed for Tagrisso plus chemotherapy.

Pasi A. Jänne, MD, PhD, medical oncologist at Dana-Farber Cancer Institute and principal investigator for the FLAURA2 trial, said: "Patients received nearly nine additional months before their EGFR-mutated non-small cell lung cancer progressed as a result of the addition of chemotherapy to standard-of-care osimertinib, building on the strong efficacy we have already seen with osimertinib monotherapy. With these convincing data, patients may soon have a choice of two highly effective osimertinib-based treatment options in this advanced disease setting."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "The compelling FLAURA2 results add to the extensive evidence supporting Tagrisso as the backbone therapy in EGFR-mutated non-small cell lung cancer and establish a new benchmark for progression-free survival in this setting. We look forward to bringing this potential treatment regimen to patients with advanced lung cancer to further delay disease progression, especially for patients with the greatest unmet need including those with central nervous system metastasis at diagnosis."

Summary of results: FLAURA2

PFS by INV

PFS by BICR

Tagrisso plus chemotherapy

(n=279)

Tagrisso monotherapy

(n=278)

Tagrisso plus chemotherapy

(n=279)

Tagrisso monotherapy

(n=278)

Median PFS (in months)i

25.5

(24.7, NCii)

16.7

(14.1, 21.3)

29.4

(25.1, NCii)

19.9

(16.6, 25.3)

Hazard ratio (95% CI)

0.62 (0.49-0.79)

0.62 (0.48-0.80)

p-value

<0.0001

0.0002

Data maturity

51%

43%

i. Data cut-off date was 3 April 2023.

ii. NC: Not calculable

Safety results and discontinuation rates due to adverse events (AEs) were consistent with the established profiles of each medicine and no new safety concerns were reported. Grade 3 or higher AEs from all causes occurred in 64% of patients in the Tagrisso plus chemotherapy arm versus 27% in the Tagrisso monotherapy arm.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer.2 Each year, there are an estimated 2.2 million people diagnosed with lung cancer globally with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.1-3 Approximately 70% of people are diagnosed with advanced NSCLC.4

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.5-7 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.8

FLAURA2
FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once daily oral tablets in combination with chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks.

The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. This is the analysis of the primary endpoint of PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 700,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

Tagrisso, the only targeted therapy to improve survival in both early- and late-stages of EGFRm NSCLC, is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. These include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC (FLAURA), locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage (IB, II and IIIA) EGFRm NSCLC (ADAURA), where Tagrisso recently demonstrated a statistically significant and clinically meaningful OS benefit.

AstraZeneca also has several ongoing Phase III trials focused on earlier stages of lung cancer including a trial in the Stage IA2-IA3 adjuvant resectable setting (ADAURA2), and in the Stage III locally advanced unresectable setting (LAURA).

The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.