On March 26, 2024 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported financial results for the fourth quarter and full year ended December 31, 2023, and provided a business update (Press release, Aprea, MAR 26, 2024, View Source [SID1234641435]).

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"Aprea had a very productive 2023 with significant progress across our diversified pipeline of synthetic lethality-based cancer therapeutics. We are pleased to continue this positive momentum in 2024 and focus on the execution on our programs towards successfully delivering potentially safer and more effective therapies for cancer patients," said Oren Gilad, Ph.D., President and Chief Executive Officer of Aprea. "We continue to enroll and treat patients in the ongoing Phase 1/2a study of our novel macrocyclic ATR inhibitor, ATRN-119. ATRN-119 appears to be well tolerated with a manageable toxicity profile. Dose escalation will proceed throughout 2024 with potential for human efficacy data in the second half of the year. We are preparing to enter the clinic with our next generation inhibitor of WEE1 kinase, APR-1051, having received clearance from the FDA on our IND. Based on the unique characteristics of APR-1051 we believe it will be best in class."

Dr. Gilad continued "the closing of our recent private placement financing provides us with the capital to fund both of these lead programs through meaningful clinical milestones. I would like to thank our dedicated team, our academic collaborators, as well as existing and new investors who have supported our recent advancements. Our mission is to be a global leader in synthetic lethality and we see a great opportunity to help cancer patients in need and create value for our shareholders."

Key Business Updates and Potential Upcoming Key Milestones

ATR inhibitor, ATRN-119, on track to complete monotherapy dose escalation end of the year; initial efficacy data expected in second half of 2024

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 mutation in DDR-related genes represent a high unmet medical need. Patients with DDR-related gene mutations have poor prognosis and, currently, have no effective therapies.
In January 2023, enrollment commenced in an open-label Phase 1/2a clinical trial of ATRN-119 (study AR-276-010) as monotherapy in patients with advanced solid tumors having at least one mutation in a defined panel of DDR-related genes. In the ongoing monotherapy dose escalation phase (Part 1) of the trial, the primary endpoint is evaluating the tolerability and pharmacokinetics of continuous daily oral dosing of ATRN-119 using a 3+3 trial design in up to approximately 30 patients. A secondary endpoint is evaluating potential initial efficacy.
An update from Part 1 of the trial was featured in a poster presentation at the AACR (Free AACR Whitepaper)-NCI-EORTC International Conference in October 2023.
As of January 2, 2024, 12 patients were enrolled to the first four cohorts of the Phase 1 escalation stage (50mg/day, 100mg/daily, 200mg/daily and 350mg/daily). ATRN-119 was found to be safe and well tolerated in all four cohorts, with no related adverse effects > grade 2. The most recent efficacy analysis conducted at that date shows that two patients achieved stable disease – one each in the 50 mg and 200 mg cohorts. Both these patients’ tumors have mutations that have been predicted to confer sensitivity to ATR inhibition.
As of March 26, 2024 four clinical sites have been activated in the US. At completion of Part 1 of the study, the company anticipates identification of a recommended Phase 2 dose (RP2D) that will be used in a Phase 2a cohort expansion (Part 2) to test the tolerability and potential efficacy of ATRN-119 monotherapy in approximately 30 additional patients. The Phase 1 dose escalation is expected to be completed in 4Q 2024, and RP2D is to be determined in 1Q 2025. Enrollment in the Phase 2a cohort is expected to begin in 1Q 2025 with additional efficacy data expected in 3Q 2025.
A more comprehensive dataset from Part 1 of the study has been accepted for presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in April 2024.
For more information, please refer to clinicaltrials.gov NCT04905914.

Oral WEE1 inhibitor, APR-1051, expected to enter Phase 1 clinical trial in the first half of 2024

APR-1051 is a potent and selective small molecule that has the potential to avoid off target toxicity and achieve greater clinical activity than other WEE1 programs currently in development. Aprea is advancing APR-1051 as monotherapy in ovarian cancer with Cyclin E over expression. Cancers over expressing Cyclin E represent a high unmet medical need. Patients with Cyclin E over expression have poor prognosis and, currently, have no effective therapies.
In March 2024, the U.S. FDA cleared the Investigational New Drug (IND) application (IND 169359) for APR-1051. Clearance of this IND will allow Aprea to initiate the Phase 1 ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) trial. This dose escalation trial will evaluate the safety, tolerability, and preliminary efficacy of APR-1051. Enrollment of the first patient is expected in H1 2024 with an update expected in the Q4 2024.
Preclinical data on APR-1051 were presented in a poster at the AACR (Free AACR Whitepaper)-NCI-EORTC International Conference in October 2023. The data highlighted the selectivity of APR-1051 with low off-target activity against PLK1, PLK2 and PLK3, a family of kinases that promote M phase entry, a critical phase in the cell cycle. APR-1051 showed potentially favorable PK properties and appears to cause lower inhibition of hERG, a potential indication of low cardiotoxicity. At doses and scheduling that suppress tumor growth, APR-1051 causes little anemia. The selectivity of APR-1051 may solve a long-standing problem with other WEE1 inhibitors. Recent studies indicate that PLK1 off-targeting partially counters the intracellular effects of WEE1 inhibition and could potentially contribute to the myelosuppression observed with other WEE1 inhibitors.

Pipeline – lead candidate for a third synthetic lethality program to be selected in 2024

Aprea’s research and development team has identified a new target in synthetic lethality. Our discovery team is developing a series of molecules that are selective and potent against it.
A lead molecule is expected to be declared in 2Q 2024.
This program may provide clinically meaningful differences for cancer patients that currently have limited therapies.

KOL Event

Hosted a Key Opinion Leader (KOL) event on October 31, 2023, highlighting the Company’s portfolio of small molecules focused on Synthetic Lethality (SL) by targeting the DNA Damage Response (DDR) Pathways. The event featured Key Opinion Leaders Dr. Fiona Simpkins, Professor in the Division of Gynecology Oncology and Department of OB-GYN at the University of Pennsylvania, Dr. Timothy Yap, medical oncology physician-scientist and Professor at the University of Texas MD Anderson Cancer Center, Dr. Eric Brown, a consultant to Aprea and a Professor at the University of Pennsylvania and a member of the Abramson Family Cancer Research Institute, and Aprea’s Dr. Nadeem Mirza, Senior Medical Advisor. The speakers, along with the management team, provided an overview of the Company’s lead ATR inhibitor candidate, ATRN-119, and its WEE1 inhibitor candidate, APR-1051, and highlighted the addressable unmet clinical need and potential combination therapies using these programs. A replay of the event can be access on the Aprea corporate website here.

Select Financial Results for the Fourth Quarter ended December 31, 2023

As of December 31, 2023, Aprea reported cash and cash equivalents of $21.6 million.
For the quarter ended December 31, 2023, the Company reported an operating loss of $3.7 million, compared to an operating loss of $2.7 million in the fourth quarter of 2022.
Research and Development (R&D) expenses were $2.0 million for the quarter ended December 31, 2023, compared to $0.5 million for the fourth quarter of 2022. The increase in R&D expense was primarily related to the Phase 1/2a clinical trial evaluating ATRN-119 which enrolled its first subject in Q1 2023 and IND enabling studies for APR-1051, the Company’s small molecule WEE1 inhibitor.
General and Administrative (G&A) expenses were $1.6 million for the quarter ended December 31, 2023, compared to $2.1 million for the comparable period in 2022. The decrease in G&A expenses was primarily due to a decrease in personnel costs and insurance premiums.
The Company reported a net loss of $3.4 million ($0.92 per basic share) on approximately 3.7 million weighted-average common shares outstanding for the quarter ended December 31, 2023, compared to a net loss of $2.4 million ($0.92 per basic share) on approximately 2.6 million weighted average common shares outstanding for the comparable period in 2022.

Select Financial Results for the Year ended December 31, 2023

As of December 31, 2023, the Company reported cash and cash equivalents of $21.6 million compared to $28.8 million as of December 31, 2022. The Company believes its cash and cash equivalents as of December 31, 2023, combined with the upfront gross proceeds of approximately $16.0 million received from the Company’s private placement of common stock and warrants in March 2024, before deducting placement agent fees and offering costs of approximately $1.4 million, will be sufficient to meet its currently projected operating expenses and capital expenditure requirements into the third quarter of 2025.
For the year ended December 31, 2023, the Company reported an operating loss of $15.5 million, compared to an operating loss of $113.4 million, which include $76.0 million for acquired in-process research and development, for the year ended December 31, 2022.
Research and Development (R&D) expenses were $7.6 million for the year ended December 31, 2023, compared to $16.4 million for the year ended December 31, 2022. The decrease in R&D expense was primarily related to the close out of our clinical trials of eprenetapopt and APR-246, non-cash stock-based compensation from the acceleration of vesting of all outstanding stock options and restricted stock units in connection with the acquisition of Atrin Pharmaceuticals Inc. in 2022 and personnel costs primarily related to the close out of our research facility in Sweden during 2022.
General and Administrative (G&A) expenses were $8.4 million for the year ended December 31, 2023, compared to $21.0 million for the year ended December 31, 2022. The decrease in G&A expenses was primarily due to a decrease in non-cash stock-based compensation from the acceleration of vesting of all outstanding stock options and restricted stock units in connection with the acquisition of Atrin Pharmaceuticals Inc. in 2022 and insurance premiums.
The Company reported a net loss of $14.3 million ($3.95 per basic share) on approximately 3.6 million weighted-average common shares outstanding for the year ended December 31, 2023, compared to a net loss of $112.7 million ($67.99 per basic share) on approximately 1.7 million weighted average common shares outstanding for the comparable period in 2022.

On March 26, 2024 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported the publication of a scientific article featuring its novel bispecific antibody format RUBY in the peer-reviewed journal mAbs (Press release, Alligator Bioscience, MAR 26, 2024, View Source [SID1234641434]).

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RUBY is a novel bispecific antibody format with excellent functionality including IgG-like stability, pharmacology and developability properties
The RUBY format allows rapid generation of bispecific antibodies (bsAbs) that fulfill key drug development criteria and mitigates many of the challenges associated to other bsAb formats
The article, entitled "RUBY – A tetravalent (2+2) bispecific antibody format with excellent functionality and IgG-like stability, pharmacology and developability properties", highlights how:

RUBY allows rapid generation of bsAbs with high developability
RUBY bsAbs are compatible with small-scale production systems for screening purposes, can be produced at high yields from production cell lines, contain low amounts of aggregates, display favorable solubility and stress endurance profiles, are compatible with various IgG isotypes, and and allows for tailored Fc gamma receptor interactions
Retained interaction with Fc neonatal receptors is demonstrated to translate into a mAb-like pharmacokinetic profile
Functionality of conditionally active RUBY bsAbs is confirmed in vitro, and RUBY bsAbs are shown to penetrate and localize to tumor tissue in vivo
"The publication of this article in the renowned scientific journal mAbs is an important recognition of our bispecific antibody format RUBY. It demonstrates its great developability and its place as a key part of our proprietary drug discovery engine for the development of innovative drugs for hard-to-treat cancers," said Laura von Schantz, CTO at Alligator Bioscience. "The article in particular demonstrates how our RUBY format has attractive mAb-like attributes and offers the possibility to mitigate many of the development and bioprocessing challenges linked to other bsAb formats, facilitating both high functionality and developability and making it a valuable contributor to the next generation of bsAbs."

Alligator’s RUBY format is an important proprietary technology used both in internal and partnered programs.

On March 26, 2024 Clarity Pharmaceuticals (ASX: CU6) ("Clarity", "the Company"), a clinical stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported a fully underwritten $121 million equity raising comprising a pro rata accelerated non-renounceable entitlement offer and a placement to institutional investors (Press release, Clarity Pharmaceuticals, MAR 26, 2024, View Source [SID1234641416]).

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Clarity’s Executive Chairperson, Dr Alan Taylor, commented: "Clarity is very well positioned for what is quickly becoming a radiopharmaceuticals revolution. We are very proud of our achievements to date, and of being the only true Australian radiopharmaceutical company that has developed our products at the benchtop of Australian science. More importantly, these novel products are now in a position to change the treatment paradigm for cancer patients around the world, as we are well progressed in our clinical trials in Australia as well as in the largest market in the world, the US. This has been a phenomenal achievement so far for an Australian biotechnology company and the result of the hard work and dedication of our incredible team and collaborators in Australia and the US with the continued support of our shareholders.

"With a strong balance sheet, we are now incredibly excited about continuing our important work as we get closer to our ultimate goal of improving the lives of children and adults with cancer. Importantly, this funding will support the ongoing development of our bisPSMA product. In therapy, through our SECuRE trial, we are seeing responses in patients that have failed up to six lines of therapy prior to being treated with 67Cu-SAR-bisPSMA and we look forward to progressing SECuRE and generating further data on this product. In diagnostics, we are actively recruiting in our registrational Phase III CLARIFY trial in high-risk prostate cancer prior to radical prostatectomy and look forward to commencing our second pivotal Phase III trial in participants with biochemically recurrent (BCR) prostate cancer following positive initial data from our Phase I/II COBRA trial in this patient population. The funding from the capital raise will also enable us to continue progressing clinical trials across our SAR-Bombesin and SARTATE products.

"The remarkable progress with all three of our products in clinical development as well as the exceptional data we are generating in our trials put us in a unique position of having a strong proprietary platform of products in radiopharmaceuticals for first commercial launch in the US. As the sector is undergoing rapid consolidation and the pace of M&A activity accelerates, our team is very excited about Clarity’s future and we look forward to the path ahead."

DETAILS OF THE OFFER
The fully underwritten $121 million equity raising consists of a $101 million placement to institutional investors ("Placement") and a $20 million pro rata accelerated non-renounceable entitlement offer to existing eligible Clarity shareholders in Australia and New Zealand ("Entitlement Offer"). The offer price per new fully paid ordinary shares in Clarity ("New Shares") to be issued under the Placement and Entitlement Offer is $2.55 per New Share ("Offer Price"), which represents a:

5% discount to the last closing price of $2.85;
5% discount to the 5-day volume weighted average price of $2.915; and
1% discount to the Theoretical Ex-Rights Price (TERP) of $2.804.
Bell Potter is the sole underwriter and is acting as joint lead manager with Wilsons Corporate Finance, with Lander & Rogers the Australian legal adviser.

Sources and Uses of Funds
Proceeds from the equity raising will be used to advance Clarity’s clinical portfolio and strengthen the balance sheet.

Post completion of the Offer, Clarity will have a pro-forma cash balance of A$153.2 million (net of costs of the offer) and Clarity expects to be funded for its current clinical program through to early 2026.

This will fund the development of Clarity’s clinical portfolio of products, SAR-bisPSMA, SAR-Bombesin and SARTATE, as the Company progresses towards a number of clinical trial milestones. Please refer to Clarity’s investor presentation for further details.

Sources of Funds A$m
Est. Cash Reserves at Offer Date 28.1
Offer 121.0
R&D Tax Incentive 10.1
Total Sources 159.2
Uses of Funds A$m
Pre-Clinical 8.5
Clinical 111.0
Regulatory 7.1
Patents 1.8
Commercial 10.2
Working Capital and Costs of the Offer 20.6
Total Uses 159.2
Placement
The Company is undertaking the Placement to raise approximately $101 million (before costs) through the issue of approximately 39.5 million New Shares.

The New Shares issued under the Placement will be issued within Clarity’s existing placement capacity under ASX Listing Rule 7.1.

The Company will seek quotation of the New Shares issued under the Placement on ASX upon their issue. Participants in the Placement will not participate in the Entitlement Offer in respect of the New Shares issued under the Placement.

Entitlement Offer
The Entitlement Offer will raise approximately $20 million (before costs) through the issue of approximately 8 million New Shares.

Under the Entitlement Offer, eligible shareholders are invited to subscribe for one (1) New Share for every thirty-three (33) ordinary shares held in Clarity (the "Entitlement") as at 7.00pm (Sydney time) on 28 March 2024 (the "Record Date").

At the time of allotment, the New Shares issued under the Entitlement Offer rank equally with all existing ordinary shares in Clarity.

Institutional Entitlement Offer
Eligible institutional shareholders will be invited to participate in the institutional component of the Entitlement Offer (the "Institutional Entitlement Offer") which will commence on 26 March 2024 and is expected to close at 4pm on 26 March 2024.

Eligible institutional shareholders can choose to take up all, part, or none of their Entitlement ("Institutional Entitlements"). Institutional Entitlements cannot be traded on the ASX or transferred.

Institutional Entitlements that eligible institutional shareholders do not take up by the close of the Institutional Entitlement Offer, and Institutional Entitlements that would otherwise have been offered to ineligible institutional shareholders, will be offered to eligible new and existing institutional shareholders concurrently with the Institutional Entitlement Offer through a bookbuild process (or subscribed for by the Underwriter).

Clarity shares will remain in a trading halt pending completion of the Institutional Entitlement Offer and Placement (the "Institutional Offer").

Retail Entitlement Offer
Eligible Retail Shareholders (defined below) will be invited to participate in the retail component of the Entitlement Offer at the same Offer Price and Entitlement as the Institutional Entitlement Offer (the "Retail Entitlement Offer"). The Retail Entitlement Offer is expected to open on 4 April 2024 and close at 5.00pm (Sydney time) on 19 April 2024 (the "Retail Entitlement Offer Period").

Eligible Retail Shareholders are shareholders on the Record Date who are already registered as holders of Clarity shares at the Record Date and:

have a registered address on the Clarity register of members which is in Australia or New Zealand;
are not in the United States nor acting for the account or benefit of a person in the United States (to the extent such person holds existing shares for the account or benefit of such person in the United States);
were not invited to participate in the Institutional Entitlement Offer and were not treated as an ineligible institutional shareholder under the Institutional Entitlement Offer (other than as nominee or custodian, in each case in respect of other underlying holdings); and
are eligible under all applicable securities laws to receive an offer under the Retail Entitlement Offer (the "Eligible Retail Shareholders").
Eligible Retail Shareholders can choose to take up all, part or none of their Entitlement ("Retail Entitlement").

If an Eligible Retail Shareholder takes no action, they will not be allocated New Shares and their Retail Entitlement will lapse. Eligible Retail Shareholders who do not take up their Retail Entitlement in full under the Retail Entitlement Offer will not receive any value or payment for those Retail Entitlements they do not take up. A Retail Entitlement is non-renounceable and cannot be traded on ASX or any other exchange, nor can it be privately transferred.

Eligible Retail Shareholders wishing to participate in the Retail Entitlement Offer should carefully read the Retail Offer Booklet and accompanying personalised Entitlement and Acceptance Form which contains their Entitlement and the terms and conditions of the Retail Entitlement Offer.

The Retail Offer Booklet and accompanying personalised Entitlement and Acceptance Form are expected to be available to Eligible Retail Shareholders on or around 4 April 2024. A copy of the Retail Offer Booklet will be available on the ASX website (www.asx.com.au) from 4 April 2024.

Retail Entitlements that Eligible Retail Shareholders do not take up by the close of the Retail Entitlement Offer (being shortfall shares), will be subscribed for by the Underwriter.

Shortfall
If there is any shortfall under the Retail Entitlement Offer which is not acquired by the Underwriter (i.e. if the Underwriting Agreement were to be terminated), Clarity’s directors reserve the right to place any or all of the shortfall to one or more investors within three months of the closing date of the Retail Entitlement Offer, at Clarity’ directors’ discretion and at a price not less than the Offer Price.

Indicative Timetable
Event Date
Placement and Institutional Entitlement Offer open 26 March
Placement and Institutional Entitlement Offer closes 26 March
Results of Placement and Institutional Entitlement Offer announced; Trading Halt ceases 28 March
Record Date for the Retail Entitlement Offer 7.00pm, 28 March
Retail Offer Booklet dispatched to Eligible Retail Shareholders 4 April
Retail Entitlement Offer opens 4 April
Placement and Institutional Entitlement Offer settlement date 5 April
Issue and quotation of New Shares under Placement and Institutional Entitlement Offer 8 April
Retail Entitlement Offer closes (Retail Closing Date) 5:00pm, 19 April
Announcement of results of the Retail Entitlement Offer 24 April
Settlement of New Shares issued under the Retail Entitlement Offer 26 April
Issue of New Shares under the Retail Entitlement Offer 29 April
Quotation and trading commence on a normal settlement basis 30 April
The above timetable is indicative only (except where historical) and subject to change. All times and dates refer to Sydney time. Subject to the Listing Rules, Clarity in conjunction with the Joint Lead Managers reserves the right to vary any or all of these dates, including the Retail Closing Date, without prior notice or consultation with you. Any extension of the Retail Closing Date will have a consequential effect on the anticipated date for issue of the New Shares under the Retail Entitlement Offer. The Directors also reserve the right not to proceed with the whole or part of any of the Offer at any time prior to allotment. In that event, the relevant Application Monies will be returned without interest.

Shareholder Enquiries
Eligible Retail Shareholders will be sent further details about the Entitlement Offer via a shareholder letter to be dispatched on or around 4 April 2024 and a Retail Offer Booklet to be lodged with ASX on 4 April 2024. The Retail Entitlement Offer can only be accepted by Eligible Retail Shareholders.

Eligible Retail Shareholders who have questions relating to the Retail Entitlement Offer should call Clarity’s share registry, Link Market Services Limited, on 1300 494 861 (within Australia) or + 61 1300 494 861 (from outside Australia) from 8.30am to 5.30pm (Sydney time) Monday to Friday during the Retail Entitlement Offer Period.

Further information in relation to the Placement and the Entitlement Offer is set out in an investor presentation which Clarity has also filed with the ASX today. The investor presentation contains important information including key risks and assumptions and foreign selling restrictions with respect to the Placement.

ADDITIONAL INFORMATION
This announcement has been authorised and approved by the Board of Directors of Clarity for lodgement with ASX.

All the amounts are in Australian dollars unless otherwise indicated.

On March 26, 2024 Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") reported that on March 26, 2024, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved VYLOY (zolbetuximab), an anti-claudin 18.2 (CLDN18.2) monoclonal antibody for patients with CLDN18.2 positive, unresectable, advanced or recurrent gastric cancer (Press release, Astellas, MAR 26, 2024, View Source [SID1234641415]). VYLOY is the first and only CLDN18.2-targeted therapy approved by any regulatory agency in the world.

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Gastric cancer is frequently diagnosed in the advanced or metastatic stage due to overlapping early-stage symptoms with other more common stomach conditions.1 Despite efforts to reduce its impact, gastric cancer is the third deadliest cancer in Japan, with 126,724 cases diagnosed in 2022.2

Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Senior Vice President and Head of Immuno-Oncology Development, Astellas
"The approval of VYLOY by the MHLW marks a new era in the treatment of gastric cancer, offering the first and only targeted therapy option for CLDN18.2-positive patients living with this devastating disease. Astellas is proud to help address the urgent therapeutic need for this hard-to-treat cancer in Japan, where incidence rates are among the highest globally. Importantly, this approval holds the potential to provide eligible patients with more precious time with their loved ones, delivering on our commitment to improve patient outcomes."

Kohei Shitara, MD, Primary Investigator for the SPOTLIGHT Trial and Head, Department of Gastrointestinal Oncology, the National Cancer Center Hospital East in Kashiwa, Japan
"Developing new targeted therapies is critical for diseases like advanced gastric adenocarcinoma, which has had very limited treatment options and is often discovered at an advanced stage. As the primary investigator for the Phase 3 SPOTLIGHT clinical trial, I witnessed firsthand the significant improvement in progression-free survival and overall survival for patients treated with VYLOY in combination with chemotherapy compared to those treated with placebo plus chemotherapy. These results support VYLOY as a new treatment option for the CLDN18.2-positive population in Japan, where there were nearly 44,000 deaths caused by gastric cancer in 2022 alone."

The approval is based on results from the Phase 3 SPOTLIGHT and GLOW clinical trials for first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors were CLDN18.2 positive.3,4 The SPOTLIGHT study evaluated VYLOY plus mFOLFOX6 (a combination chemotherapy regimen that includes oxaliplatin, leucovorin, and fluorouracil) compared to placebo plus mFOLFOX6.4 The GLOW study evaluated VYLOY plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX.3 Both trials met their primary endpoint, progression-free survival (PFS), as well as a key secondary endpoint, overall survival (OS), showing statistical significance in patients treated with VYLOY plus chemotherapy compared to placebo plus chemotherapy. The most frequent treatment-emergent adverse events (TEAEs) ≥20% for VYLOY in combination with mFOLFOX6 or CAPOX were nausea, vomiting, decreased appetite, neutropenia, and decreased weight. In clinical trials, adverse reactions were managed by antiemetics, dose interruptions, and infusion rate adjustments.3,4

In both SPOTLIGHT and GLOW, approximately 38% of patients screened had tumors that were CLDN18.2 positive.3,4 CLDN18.2 positivity is defined as ≥75% of tumor cells showing moderate-to-strong membranous CLDN18 staining, which should be confirmed by a pathologist or laboratory with adequate experience using the approved in-vitro diagnostic agent or medical device.3,4 Astellas collaborated with Roche Diagnostics on the newly approved VENTANA CLDN18 (43-14A) RxDx Assay, an immunohistochemistry (IHC) companion diagnostic (CDx) test, to identify patients who may be eligible for VYLOY.5 Testing will be available in Japan at multiple central laboratories and is expected to expand to additional laboratories over time.

Astellas has also submitted applications for VYLOY to regulatory agencies around the world, and review is ongoing.

Astellas has already reflected the impact from this approval in its financial forecast for the current fiscal year ending March 31, 2024.

About VYLOY
VYLOY (zolbetuximab) is an anti-claudin 18.2 (CLDN18.2) monoclonal antibody that is approved by Japan’s Ministry of Health, Labour and Welfare (MHLW) for patients with CLDN18.2 positive, unresectable, advanced or recurrent gastric cancer. VYLOY is used in combination with chemotherapy for patients whose tumors are human epidermal growth factor receptor 2 (HER2)-negative. VYLOY is the first and only CLDN18.2-targeted therapy approved by any regulatory agency in the world. CLDN18.2 positivity should be confirmed by a pathologist or laboratory with adequate experience using the approved in-vitro diagnostic agent or medical device. As an antibody directed against human CLDN18.2, VYLOY binds to CLDN18.2 expressed on cell membrane in cancer cells such as gastric cancer and shows antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), leading to tumor growth inhibition.3,4

Important Safety Information
For important Safety Information for VYLOY, please see the Package Insert.

About Unresectable, Advanced or Recurrent Gastric Cancer
Gastric cancer, also known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide.6 Gastric cancer killed 43,807 people in Japan in 2022, making it the third deadliest cancer by number of deaths in the country.2 Signs and symptoms can include indigestion or heartburn, pain or discomfort in the abdomen, nausea and vomiting, diarrhea or constipation, bloating of the stomach after meals, loss of appetite, and sensation of food getting stuck in the throat while eating.1 Signs of more advanced gastric cancer can include unexplained weight loss, weakness and fatigue, and vomiting blood or having blood in the stool.7 Risk factors associated with gastric cancer can include older age, male gender, family history, H. pylori infection, and smoking.8 Because early-stage gastric cancer symptoms frequently overlap with more common stomach-related conditions, gastric cancer is often diagnosed in the advanced or metastatic stage, or once it has spread from the tumor’s origin to other body tissues or organs.1 The five-year relative survival rate for patients at the metastatic stage is 6.6%.9

INVESTIGATIONAL STUDIES

About SPOTLIGHT Phase 3 Clinical Trial
SPOTLIGHT is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab plus mFOLFOX6 (a combination chemotherapy regimen that includes oxaliplatin, leucovorin, and fluorouracil) compared to placebo plus mFOLFOX6 as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors were CLDN18.2 positive. The study enrolled 565 patients at 215 study locations in the U.S., Canada, United Kingdom, Australia, Europe, South America, and Asia, including Japan. The primary endpoint is progression-free survival (PFS) of participants treated with the combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), safety and tolerability, and quality-of-life parameters.

Data from the SPOTLIGHT clinical trial were presented during the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal (GI) Cancers Symposium in an oral presentation on January 19, 2023, and were subsequently published in The Lancet on April 14, 2023.4

For more information, please visit clinicaltrials.gov under Identifier NCT03504397.

About GLOW Phase 3 Clinical Trial
GLOW is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. The study enrolled 507 patients at 166 study locations in the U.S., Canada, United Kingdom, Europe, South America, and Asia, including Japan. The primary endpoint is PFS in participants treated with the combination of zolbetuximab plus CAPOX compared to those treated with placebo plus CAPOX. Secondary endpoints include OS, ORR, DOR, safety and tolerability, and quality-of-life parameters.

Data from the GLOW study were initially presented at the March 2023 ASCO (Free ASCO Whitepaper) Plenary Series with an updated oral presentation at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting on June 3, 2023, and were subsequently published in Nature Medicine on July 31, 2023.3

For more information, please visit clinicaltrials.gov under Identifier NCT03653507.

Investigational Pipeline in Targeting CLDN18.2
An expanded Phase 2 trial of zolbetuximab in metastatic pancreatic adenocarcinoma is in progress. The trial is a randomized, multi-center, open-label study, evaluating the safety and efficacy of investigational zolbetuximab in combination with gemcitabine plus nab-paclitaxel as a first-line treatment in patients with metastatic pancreatic adenocarcinoma with CLDN18.2 positive tumors (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining based on a validated immunohistochemistry assay). For more information, please visit clinicaltrials.gov under Identifier NCT03816163.

In addition to zolbetuximab, ASP2138 is under development in our Primary Focus Immuno-Oncology. ASP2138 is a bispecific monoclonal antibody that binds to CD3 and CLDN18.2, and it is currently in a Phase 1/1b study in participants with metastatic or locally advanced unresectable gastric or GEJ adenocarcinoma or metastatic pancreatic adenocarcinoma whose tumors have CLDN18.2 expression. The safety and efficacy of the agent under investigation have not been established for the uses being considered. For more information, please visit clinicaltrials.gov under Identifier NCT05365581.

There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated.

On March 25, 2024 BeyondSpring Inc. (NASDAQ: BYSI) ("BeyondSpring" or the "Company"), a clinical-stage global biopharmaceutical company focused on developing innovative cancer therapies, reported that the first patient has been dosed in a Phase 2 investigator-initiated trial (IIT) with Pembrolizumab, Plinabulin, BeyondSpring’s lead asset, plus Etoposide/Platinum (EP) for first-line (1L) Extensive-Stage Small-Cell Lung Cancer (ES-SCLC) [NCT05745350] (Press release, BeyondSpring Pharmaceuticals, MAR 25, 2024, View Source;utm_medium=rss&utm_campaign=beyondspring-announces-first-patient-dosed-with-pembrolizumab-plinabulin-plus-etoposide-platinum-in-a-phase-2-investigator-initiated-study-of-first-line-extensive-stage-small-cell-lung-cancer [SID1234641486]).

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Current treatment for first-line ES-SCLC includes EP and EP plus PD-L1 antibodies. Although the objective response rate (ORR) is high (around 60-65%), median progression free survival (PFS) remains low (< 6 months), with median overall survival at 10-13 months1,2. Therefore, 1L ES-SCLC remains a serious unmet medical need.

Plinabulin, a potent dendritic cell (DC) maturation agent3, has been studied in a triple combination with various immuno-oncology agents and chemotherapy or radiation, with the potential to enhance the efficacy of PD-1/PD-L1 blockade and restore sensitivity in patients who become resistant [NCT04902040, NCT05599789]. Preliminary re-sensitization data in PD-1/PD-L1 antibody failed patients in 8 cancer types [NCT04902040, IIT at MD Anderson] corresponding response with Plinabulin DC maturation was presented at SITC (Free SITC Whitepaper) conference in Nov 20234.

This Phase 2 trial will evaluate the efficacy and safety of Pembrolizumab, Plinabulin plus EP in 1L ES-SCLC. The study5 is conducted in Wuhan Union Hospital in China, with Dr. Xiaorong Dong, Deputy Director of the Oncology Research Department and Director of the Thoracic Oncology Department, as the principal investigator. Patients enrolled are receiving the following interventional treatments. The primary endpoint is the 12-month PFS rate.

Pembrolizumab 200 mg IV every 3 weeks (Q3W) on Day 1
Etoposide 100 mg/m2 IV Q3W on Days 1, 2, and 3
Carboplatin AUC 5 IV Q3W on Day 1 or Cisplatin 75 mg/m2 IV Q3W on Day 1
Plinabulin 30mg/m2 IV Q3W on Day 1
"Although the current therapies in first-line ES-SCLC, including PD-L1 antibody and EP combination have had a high ORR, the duration of response is still short with median PFS of < 6 months. KEYNOTE-604 study revealed that 12-month PFS rate in patients with pembrolizumab plus EP is 13.6% vs. 3.1% with placebo plus EP. According to Dr. Mellman’s recent review on cancer immunity cycle6, mature DC is critical for the maintenance of cytotoxic T-cell response against the tumor. By adding Plinabulin, a potent DC maturation agent, to pembrolizumab plus EP, could potentially enable a durable response and improve PFS. This combination study represents an important step forward to address this unmet medical need. I am eager to evaluate this treatment in clinical settings, ensuring that cutting-edge, advanced therapies are translated to cancer care worldwide," said Dr. Xiaorong Dong, principal investigator for the study.

"We are pleased to start this second IIT study with Merck. Our first Merck IIT study initiated in March 2023 was in 2L/3L NSCLC cancer patients who had failed prior PD-1/PD-L1 blockade [NCT05599789]. We believe in the collateral sensitivity and efficacy potential of this triple IO combination in both front and later lines of cancer treatment. Plinabulin’s unique DC maturation mechanism may pose to be the ‘bridge’ between tumor neo-antigen generation from chemotherapy, and T cells action enabled by PD-1 antibodies. Potential improvements in both duration-of-response and quality-of-life could translate into overall survival benefit. Every moment of a cancer patient’s life is valuable, and our primary goal is to discover innovative treatment strategies that prolong their lives," added Dr. Lan Huang, Co-Founder, Chairman and CEO at BeyondSpring.