Category: 3. Business

VANCOUVER, British Columbia, June 30, 2025 (GLOBE NEWSWIRE) — Cornish Metals Inc. (AIM/TSX-V: CUSN) (“Cornish Metals” or the “Company”), is pleased to announce the results of its 2025 Annual General and Special Meeting of the shareholders of the Company held via live audio teleconference on June 30, 2025 (the “Meeting”). A total of 909,699,906 common shares of the Company were voted at the Meeting, representing approximately 72.64% of the issued and outstanding common shares as at the record date of the Meeting. All resolutions were passed.

Meeting Results

Capitalised terms not otherwise defined in this news release shall have the meanings ascribed thereto in the Company’s Management Proxy Circular dated May 16, 2025.

The voting results of the business of the Meeting are summarised as follows:

MOTION	Votes For	% For	Votes Against	% Against	Votes Withheld	% Withheld
Number of directors set at eight	856,399,865	94.14	53,270,628	5.86	0	0
Election of Lodewyk Daniel Turvey	876,314,283	96.58	31,025,459	3.42	0	0
Election of Patrick F.N. Anderson	854,070,569	94.13	53,269,172	5.87	0	0
Election of Kenneth A. Armstrong	907,264,038	99.99	75,703	0.01	0	0
Election of John F.G. McGloin	854,076,294	94.13	53,263,447	5.87	0	0
Election of Stephen T. Gatley	907,252,657	99.99	87,085	0.01	0	0
Election of Anthony Trahar	907,257,380	99.99	82,362	0.01	0	0
Election of Samantha Hoe-Richardson	854,077,020	94.13	53,262,721	5.87	0	0
Election of James Whiteside	907,264,210	99.99	75,531	0.01	0	0
Appointment of Auditors	909,630,842	99.99	0	0.00	69,062	0.01
Approval of General Share Authority	907,107,016	99.97	255,447	0.03	0	0
Approval of Pre-Emptive Disapplication Authority	850,587,460	93.74	56,775,004	6.26	0	0

ABOUT CORNISH METALS

Cornish Metals is a dual-listed mineral exploration and development company (AIM and TSX-V: CUSN) that is advancing the South Crofty tin project towards production. South Crofty:

• is a historical, high-grade, underground tin mine located in Cornwall, United Kingdom and benefits from existing mine infrastructure including multiple shafts that can be used for future operations;
• is permitted to commence underground mining (valid to 2071), construct a new processing facility and for all necessary site infrastructure;
• would be the only primary producer of tin in Europe or North America. Tin is a Critical Mineral as defined by the UK, American, and Canadian governments as it is used in almost all electronic devices and electrical infrastructure. Approximately two-thirds of the tin mined today comes from China, Myanmar and Indonesia;
• benefits from strong local community, regional and national government support with a growing team of skilled people, local to Cornwall, and could generate up to 320 direct jobs.

ON BEHALF OF THE BOARD OF DIRECTORS

“Don Turvey”
Don Turvey
CEO and Director

Engage with us directly at our investor hub. Sign up at: https://investors.cornishmetals.com/link/0PQ9GP     

For additional information please contact:

Cornish Metals	Fawzi Hanano Irene Dorsman	investors@cornishmetals.com info@cornishmetals.com Tel: +1 (604) 200 6664
SP Angel Corporate Finance LLP (Nominated Adviser & Joint Broker)	Richard Morrison Charlie Bouverat Grant Barker	Tel: +44 203 470 0470
Hannam & Partners (Joint Broker)	Matthew Hasson Andrew Chubb Jay Ashfield	cornish@hannam.partners Tel: +44 207 907 8500
BlytheRay (Financial PR)	Tim Blythe  Megan Ray	cornishmetals@blytheray.com Tel: +44 207 138 3204

Neither the TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release.

Caution regarding forward looking statements

This news release may contain certain “forward-looking information” and “forward-looking statements” (collectively, “forward-looking statements”). Forward-looking statements include predictions, projections, outlook, guidance, estimates and forecasts and other statements regarding future plans, the realisation, cost, timing and extent of mineral resource or mineral reserve estimates, estimation of commodity prices, currency exchange rate fluctuations, estimated future exploration expenditures, costs and timing of the development of new deposits, success of exploration activities, permitting time lines, requirements for additional capital and the Company’s ability to obtain financing when required and on terms acceptable to the Company, future or estimated mine life and other activities or achievements of Cornish Metals. Forward-looking statements are often, but not always, identified by the use of words such as “seek”, “anticipate”, “believe”, “plan”, “estimate”, “forecast”, “expect”, “potential”, “project”, “target”, “schedule”, “budget” and “intend” and statements that an event or result “may”, “will”, “should”, “could”, “would” or “might” occur or be achieved and other similar expressions and includes the negatives thereof. All statements other than statements of historical fact included in this news release, are forward-looking statements that involve various risks and uncertainties and there can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements.

Forward-looking statements are subject to risks and uncertainties that may cause actual results to be materially different from those expressed or implied by such forward-looking statements, including but not limited to: risks related to receipt of regulatory approvals, risks related to general economic and market conditions; risks related to the availability of financing; the timing and content of upcoming work programmes; actual results of proposed exploration activities; possible variations in Mineral Resources or grade; projected dates to commence mining operations; failure of plant, equipment or processes to operate as anticipated; accidents, labour disputes, title disputes, claims and limitations on insurance coverage and other risks of the mining industry; changes in national and local government regulation of mining operations, tax rules and regulations. The list is not exhaustive of the factors that may affect Cornish’s forward-looking statements.

Cornish Metals’ forward-looking statements are based on the opinions and estimates of management and reflect their current expectations regarding future events and operating performance and speak only as of the date such statements are made. Although the Company has attempted to identify important factors that could cause actual actions, events or results to differ from those described in forward- looking statements, there may be other factors that cause such actions, events or results to differ materially from those anticipated. There can be no assurance that forward-looking statements will prove to be accurate and accordingly readers are cautioned not to place undue reliance on forward-looking statements. Cornish Metals does not assume any obligation to update forward-looking statements if circumstances or management’s beliefs, expectations or opinions should change other than as required by applicable law.

Salmonella-Related Recalls

June 4: TGD Cuts, LLC of Jessup, Maryland, recalled fresh cucumbers and related products containing cucumbers from Bedner Growers Inc. due to potential Salmonella contamination. These items, with use-by dates from May 19 to 28, 2025, were distributed across Maryland, Virginia, Pennsylvania, New Jersey, and North Carolina. The products are believed to be past their shelf life, and no illnesses have been reported.¹

June 6: August Egg Company in Hilmar, California, recalled approximately 1.7 million dozen brown cage-free and organic eggs due to possible contamination with Salmonella Enteritidis. Distributed between February 3 and May 15, 2025, these eggs bore plant codes P-6562 or CA-5330 and were sold in multiple western and midwestern states, including at major retailers such as Walmart and Safeway. The company ceased sales of fresh shell eggs and redirected eggs to pasteurization facilities.²

June 13: Fuentes Farms LLC of McAllen, Texas, recalled 71 boxes of fresh cucumbers (Lot #357) potentially contaminated with Salmonella. Distributed through flea markets in McAllen and Alamo, Texas, between May 31 and June 3, these cucumbers were packaged in 40 lb boxes with Fuentes Farm labels. No illnesses were reported. This recall was prompted by an FDA routine sample detecting the bacteria.³

Salmonella infections can cause fever, diarrhea, nausea, vomiting, and severe complications, especially in young children, elderly, and immunocompromised individuals.^1,2,3

Listeria-Related Recalls

June 10: Bornstein Seafoods Inc, Bellingham, Washington, recalled 44,550 pounds of cooked and peeled ready-to-eat coldwater shrimp due to potential Listeria monocytogenes contamination. Distributed mainly in the Pacific Northwest and British Columbia, these products were pulled after routine testing. No illnesses were reported.³

June 11: Hofood99 Inc. of Brooklyn, New York, recalled 200g packages of Enoki mushrooms nationwide following detection of Listeria monocytogenes by Michigan state authorities. Packaged in green plastic bags, these mushrooms are marked with UPC 6 976532 310051. Consumers were advised to destroy or return the product.⁴

June 21: Face Rock Creamery of Bandon, Oregon, is voluntarily recalling two lots of its Vampire Slayer Garlic Cheddar Curds sold at Trader Joe’s in Northern California and Northern Nevada due to potential contamination with Listeria monocytogenes, which can cause serious illness, especially in vulnerable populations. No illnesses have been reported. Consumers are urged not to eat the product and to return it for a full refund. The recall follows routine testing that detected the bacteria, and the company is working with regulators to address the issue.⁵

Listeria monocytogenes poses serious risks to young children, elderly, pregnant women, and immunocompromised individuals, causing symptoms such as high fever, headache, nausea, and, in pregnant women, miscarriage or stillbirth.^3,4,5

Other Recalls

June 10: P East Trading Corp, Bronx, New York, recalled uneviscerated salted smoked split herring sold in New York, New Jersey, and Connecticut due to possible contamination with Clostridium botulinum. The product, packaged in 18-pound wooden boxes and made in Canada, was found to be over 5 inches long and improperly eviscerated, increasing botulism risk. Clostridium botulinum produces a toxin that causes botulism, a severe and potentially fatal illness characterized by symptoms including muscle weakness, dizziness, double vision, difficulty speaking or swallowing, and respiratory failure. Consumers were warned not to consume the product regardless of appearance or odor.⁶

June 17: Medtech Products Inc of Tarrytown, New York, announced a nationwide recall of five lots of Little Remedies Honey Cough Syrup due to contamination with Bacillus cereus. Distributed from December 2022 through June 2025, these syrups can cause foodborne illness with nausea, vomiting, and diarrhea; though typically mild, high exposure can be fatal.⁷

References
1. US Food and Drug Administration. Company Announcement: Tgd Cuts, LLC Initiated Voluntary Recall of Cucumber from Bedner Growers Inc., Which Had the Potential to Be Contaminated with Salmonella. FDA.gov. Published June 4, 2025. Accessed June 30 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/tgd-cuts-llc-initiated-voluntary-recall-cucumber-bedner-growers-inc-which-had-potential-be

2. US Food and Drug Administration. Company Announcement: August Egg Company Recalls Shell Eggs Because of Possible Health Risk. FDA.gov. Published June 6, 2025. Accessed June 30, 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/august-egg-company-recalls-shell-eggs-because-possible-health-risk

3. US Food and Drug Administration. Company Announcement: Fuentes Farms, LLC Recalls Product Because of Possible Health Risk. FDA.gov. Published June 16, 2025. Accessed June 30, 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/fuentes-farms-llc-recalls-product-because-possible-health-risk

4. US Food and Drug Administration. Company Announcement: Bornstein Seafoods Inc Recalls Cooked & Peeled Ready-To-Eat Coldwater Shrimp Meat Because of Possible Health Risk. FDA.gov. Published June 10, 2025. Accessed June 30, 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/bornstein-seafoods-inc-recalls-cooked-peeled-ready-eat-coldwater-shrimp-meat-because-possible-health

4. US Food and Drug Administration. Company Announcement: Hofood99 Inc Recalls Enoki Mushroom Due to Possible Health Risk. FDA.gov. Published June 11, 2025. Accessed June 30, 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/hofood99-inc-recalls-enoki-mushroom-due-possible-health-risk

5. Face Rock Creamery voluntarily recalls Vampire Slayer Garlic Cheddar Curds due to potential Listeria contamination. FDA. Published June 21, 2025. Accessed June 30, 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/face-rock-creamery-voluntarily-recalls-vampire-slayer-garlic-cheddar-curds

6. US Food and Drug Administration. Company Announcement: P. East Trading Corp Distributors Issues Alert on Uneviscerated ‘Salted Smoked Split Herring’ Due to Potential Clostridium Botulinum Contamination. FDA.gov. Published June 10, 2025. Accessed June 30, 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/p-east-trading-corp-distributors-issues-alert-uneviscerated-salted-smoked-split-herring-due

7. US Food and Drug Administration. Company Announcement: Medtech Products Inc. Issues Nationwide Recall of Little Remedies® Honey Cough Syrup Due to Microbial Contamination. FDA.gov. Published June 18, 2025. Accessed June 30, 2025. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/medtech-products-inc-issues-nationwide-recall-little-remediesr-honey-cough-syrup-due-microbial

Renier Brentjens, MD, PhD, one of the pioneers of cellular therapies for cancer, gave invited talks at national events this month for the Damon Runyon Cancer Research Foundation and The New York Academy of Sciences.

At their annual breakfast on June 11, the cancer research foundation honored Dr. Brentjens for his critical role in the impact on cancer research, specifically CAR T cell therapy. Dr. Brentjens, a past recipient of the Damon Runyon Clinical Investigator Award, gave an invited address as featured honoree at the event.

“A founder of CAR T therapy, he was among the first to demonstrate that a patients immune cells could be ‘trained’ to target their cancer cells- a premise that now underlies the work of many current Damon Runyon scientists,” the Damon Runyon Cancer Research Foundation says. “Some (resarchers) are working to develop CAR T cells that persist longer in the body; others are using big data to optimize CAR T cell design and lower costs; all stand on the shoulder of Dr. Brentjens and his colleagues, whose impact extends beyond their scientific contributions.”

Dr. Brentjens also addressed The New York Academy of Sciences during its Frontiers in Cancer Immunotherapy symposium last week. The 12th annual event allows attendees to amplify research efforts, form professional connections and participate in conversations. Dr. Brentjens served on the scientific organizing committee for the event, and spoke on ways to deliver cellular therapies without depleting the immune system.

Prior to joining Roswell Park Comprehensive Cancer Center in 2021, Dr. Brentjens studied medicine at the University at Buffalo UB), completed a residency at Yale New Haven Hospital and served as a medical oncology fellow at Memorial Sloan Kettering Cancer Center. He then became the principal investigator of his own laboratory, where he focused on the development of CAR modified T-cells. He serves as Roswell Park’s Deputy Director, Chair of the Department of Medicine and The Katherine Anne Gioia Endowed Chair in Cancer Medicine. He holds a secondary appointment with UB’s Jacobs School of Medicine and Biomedical Sciences.

In 2024, Dr. Brentjens was one of four recipients of the prestigious Warren Alpert Foundation Prize for his role in the development of CAR T cells as a platform for treating cancer.

FOUR food manufacturers have pledged to eliminate synthetic dyes from products sold in the US by 2028, following on from health secretary Robert F Kennedy (RFK) Jr’s proposal to ban them entirely.

Kraft Heinz, General Mills, and Conagra Brands have announced plans to eliminate synthetic dyes from all US products by the end of 2027, while Nestlé said last week it would achieve this within the next 12 months.

Currently, seven certified Food, Drug, and Cosmetic (FD&C) dyes are approved for use in foods in the US by the Food and Drug Administration (FDA), including Yellow No. 5 (tartrazine). In March, RFK Jr warned food and drink manufacturers of his intent to ban all seven dyes entirely.  

Kraft Heinz said they will replace the synthetic dyes either with natural colourings, such as dyes from beetroots and grape skins, or by “reinventing” colours and shades if natural alternatives do not exist. They also said they will remove colourings without replacement “where it is not critical to the consumer experience”. Kraft Heinz says that around 90% of its US products by net sales are already free of synthetic dyes. General Mills, meanwhile, says 85% of its US products are already dye-free.  

In addition, Kraft Heinz will immediately cease the launch of new US products containing synthetic dyes.

Conagra, known for its Birds Eye and Healthy Choice brands, has also said it plans to remove synthetic dyes from all frozen products sold in the US by the end of 2025, while making a pledge to stop offering dye-containing products to US schools by the start of the 2026-27 school year. General Mills, which makes brands including Cheerios cereal and Häagen-Dazs ice cream, has made the same promise, adding that “nearly all” of its school products are already free of synthetic dyes.

Jeff Harmening, CEO of General Mills, said: “Across the long arc of our history, General Mills has moved quickly to meet evolving consumer needs, and reformulating our products portfolio to remove certified colours is yet another example”.  

Across the pond

The adverse health impacts of the seven FD&C dyes are debated. While the previous US administration banned Red No. 3 (erythrosine) in January, citing a 30-year-old study linking it to cancer in rats, the FDA maintained its belief that it was unlikely to have the link in humans.

The most cited health concern linked to synthetic dyes is their potential impact on children’s behaviour. A 2022 report by the National Institutes of Health reviewed 25 studies and found that just over half suggested a connection between food dye exposure and behavioural issues in children. However, only one of the seven dyes being phased out of US products – Green No. 3 (fast green) – is banned for use in food products in Europe.

More serious health risks are thought to arise from other food additives banned in Europe but certified in the US. These include potassium bromide, added to white flour to make dough rise higher and banned in the UK since 1990 owing to cancer links in animals; azodicarbonamide, a whitening agent used in dough and banned in the EU for over 15 years as a possible carcinogen; butylated hydroxyanisole and butylated hydroxytoluene, used as preservatives and banned in Europe as possible carcinogens.

The colouring titanium dioxide is also banned in Europe, owing to potential genotoxicity, but not in the US. It does not come under the FDA’s seven FD&C dyes and will be unaffected by the changes planned by the four food giants.  

Oxylanthanum carbonate (OLC) received a Complete Response Letter (CRL) from the FDA for the treatment of hyperphosphatemia in patients with chronic kidney disease (CKD) on dialysis, according to an announcement from Unicycive Therapeutics.¹ OLC is a next-generation lanthanum-based phosphate binder that utilizes proprietary nanoparticle technology.

“We plan to immediately seek a Type A meeting with the Agency to gain alignment on the best strategy to ensure rapid resolution of the CRL,” Shalabh Gupta, MD, chief executive officer of Unicycive, said in the statement.

Hyperphosphatemia, or high phosphate levels in the blood, impacts nearly all patients with end-stage renal disease and is linked to higher mortality among those on dialysis.² Untreated, it can lead to serious complications like cardiovascular disease. Despite available phosphate binders, about 75% of dialysis patients in the US do not meet recommended phosphorus levels.

If approved in the future, OLC has the potential to advance treatment by reducing the pill burden that currently impacts adherence among this patient population, who often face a regimen that can involve up to 12 pills daily, according to Unicycive. In addition to reduced pill count per dose, OLC is designed to be easily swallowed rather than chewed.

On June 10, Unicycive Therapeutics announced that the FDA had identified manufacturing deficiencies at a third-party subcontractor involved in producing OLC and that the agency had paused any label discussions related to the drug.³ At the time, Unicycive stated it was working with its partners to address the concerns; according to today’s statement,¹ this citation was unrelated to OLC and no other technical concerns related to the submitted CMC documentation or testing of OLC itself were noted by the FDA in the application review.

“With a second manufacturing vendor identified that has produced OLC drug product, we remain optimistic about our ability to bring this promising new treatment option to patients with CKD on dialysis who are managing hyperphosphatemia, and we plan to provide an update as soon as we have additional clarity on next steps from the FDA,” Gupta continued.

Reduced Treatment Burden; Improved Adherence

Patient-reported outcomes from the phase 2 UNI-OLC-201 study presented at the 2025 National Kidney Foundation Spring Clinical Meetings suggest that OLC may significantly improve treatment satisfaction, reduce pill burden, and enhance adherence among patients with CKD on dialysis.⁴ The open-label, single-arm, multicenter trial enrolled 86 dialysis patients with elevated serum phosphate levels to assess the impact of OLC on adherence and patient experience compared with their existing phosphate binder regimens.

At baseline, patients reported a median daily intake of six phosphate binder tablets, with only 58% indicating adherence to their prescribed treatment. After a washout period and a 10-week regimen of OLC, which included dose titration followed by a maintenance phase, patients reported taking a median of just three OLC tablets per day. Notably, 70% of patients were adherent to OLC treatment, reflecting a meaningful improvement over pre-trial adherence rates.

The results further showed that 79% of participants preferred OLC over their previous phosphate binder, and nearly all (98%) described OLC as easy to take, a stark contrast to the 38% who found their prior medication easy to use. Patient satisfaction with treatment also increased considerably, with 89% reporting satisfaction with OLC compared to 49% who were satisfied with their earlier phosphate binder.

The NDA for OLC was submitted under the FDA’s 505(b)(2) pathway, leveraging data from 3 clinical studies and multiple preclinical evaluations.² The product is protected by a broad global patent portfolio, with exclusivity extending through at least 2031 and possibly until 2035 with patent term extensions.

Unicycive received a waiver for the PDUFA application fees, saving the company approximately $4 million as it prepares for potential commercialization of OLC in the second half of 2025. The global market for hyperphosphatemia treatments is estimated to exceed $2.5 billion, with the US market accounting for over $1 billion of that total.

References

1. Unicycive Therapeutics announces receipt of Complete Response Letter for oxylanthanum carbonate for the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. News release. Unicycive Therapeutics. June 30, 2025. Accessed June 30, 2025. https://www.globenewswire.com/news-release/2025/06/30/3107365/0/en/Unicycive-Therapeutics-Announces-Receipt-of-Complete-Response-Letter-for-Oxylanthanum-Carbonate-for-the-Treatment-of-Hyperphosphatemia-in-Patients-with-Chronic-Kidney-Disease-on-Di.html

2. Unicycive Therapeutics announces U.S. FDA acceptance of the New Drug Application (NDA) for oxylanthanum carbonate (OLC) for the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. News release. Unicycive Therapeutics. November 11, 2024. Accessed June 24, 2025. https://www.globenewswire.com/en/news-release/2024/11/11/2978178/0/en/Unicycive-Therapeutics-Announces-U-S-FDA-Acceptance-of-the-New-Drug-Application-NDA-for-Oxylanthanum-Carbonate-OLC-for-the-Treatment-of-Hyperphosphatemia-in-Patients-with-Chronic-K.html

3. Unicycive provides update on New Drug Application for oxylanthanum carbonate to treat hyperphosphatemia in patients with chronic kidney disease on dialysis. News release. Unicycive Therapeutics. June 10, 2025. Accessed June 24, 2025. https://www.globenewswire.com/news-release/2025/06/10/3096422/0/en/Unicycive-Provides-Update-on-New-Drug-Application-for-Oxylanthanum-Carbonate-to-Treat-Hyperphosphatemia-in-Patients-with-Chronic-Kidney-Disease-on-Dialysis.html

4. Brooks A. Oxylanthanum carbonate may offer desirable alternative to current phosphate binders. HCPLive. April 10, 2025. Accessed June 24, 2025. https://www.hcplive.com/view/oxylanthanum-carbonate-may-offer-desirable-alternative-current-phosphate-binders

Public limited company (SA) with capital of €1,460,429,245.00
Registered office : 1973, boulevard de la Défense, 92000 Nanterre
Nanterre TCR 552 037 806
www.vinci.com

___________________________________________________

Report on payments made
during fiscal year 2024
by VINCI group subsidiaries
to public authorities
for their extractive activities

___________________________________________________

This report, drawn up in accordance with the provisions of article L. 232-6-2 of the French Commercial Code, reports on payments made during the 2024 fiscal year by VINCI Group subsidiaries engaged in extractive activities to the public authorities of each of the States or territories in which they operate.

In accordance with legal and regulatory provisions, the disclosure covers the amounts of individual payments, or sets of payments where these are linked together, equal to or more than €100,000, made per site, per country and per type of contribution, during fiscal year 2024, to public authorities. If no payments have been made by a subsidiary, or if a subsidiary carrying out an extractive project has only made payments below the €100,000 threshold, these projects or types of payment have not been included in the table in this report.

Taxes mainly concern corporate income tax due for the year, as well as taxes related to the income and production of project companies. This report does not include taxes levied on consumption or sales, such as value-added taxes.

Royalties and rents represent payments in return for rights to exploit quarries or hydrocarbon deposits.

In fiscal year 2024, these payments were the following as attached:

This report was approved by the VINCI Board of Directors during its meeting on 18 June 2025.

Nanterre, 18 June 2025

The VINCI Board of Directors
and, by delegation of the Board of Directors,

________________________

Pierre Anjolras
Chief Executive Officer

• Rapport-signe-activites-extractives-exercice2024_UK

Minimal residual disease (MRD)-guided cessation and reinitiation of ibrutinib (Imbruvica; Johnson & Johnson) plus venetoclax (Venclexta; Genentech, Abbvie) is a safe treatment approach for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a new report suggests.¹ The study, which was published in Blood Advances, suggests that MRD-guided therapy offers a way to balance the risks of cessation with those of cumulative toxicity.

The combination of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the BCL-2 inhibitor venetoclax has become a transformative therapeutic option for people with relapsed or refractory CLL, the authors noted. It is sometimes combined with CD20-targeting monoclonal antibodies. Yet, it is not curative, and it comes with significant concerns.

“While continuous treatment may lead to cumulative toxicity or resistance, fixed-duration treatment may lead to undertreatment and early relapse,” they wrote.

One possible solution, the authors wrote, is the use of MRD to guide therapy. Previous research has shown that undetectable MRD following treatment is an independent prognostic indicator of progression-free and overall survival (PFS and OS, respectively) in patients with CLL.² However, at the time the investigators initiated their trial, there had not been any studies specifically examining response-guided, time-limited use of ibrutinib plus venetoclax in relapsed or refractory CLL.¹

In the phase 2 VISION/HOVON141 trial (NCT03226301), a subset of patients had undetectable MRD (sensitivity < 10^-4 assessed by flow cytometry; abbreviated as uMRD4) in the bone marrow and peripheral blood after 15 cycles of venetoclax plus ibrutinib.³ Those patients could safely stop therapy, the authors found. The new report expands on those findings with updated 4-year follow-up data.¹

A total of 225 patients, treated at 47 sites across 6 European countries, were initially enrolled in the trial. Patients who achieved uMRD4 after 15 cycles (n = 72) were randomized on a 1:2 basis to continue on ibrutinib until toxicity or progression (n = 24) or to stop treatment after the 15th cycle (n = 48). In the cessation cohort, patients were reinitiated on ibrutinib and venetoclax if they met the threshold of detectable MRD (≥ 10^-2; abbreviated as dMRD2). Patients who were MRD4 positive (dMRD4) after cycle 15 remained on ibrutinib.

The investigators found that, at a median follow-up of 51.7 months, the estimated 4-year OS rate was 88%, the 4-year PFS rate was 81%, and 14% of participants required another line of therapy. Within the cessation cohort, 40% of participants reinstated therapy due to dMRD2.

However, there was no statistically significant gap between the different cohorts. Within the ibrutinib maintenance arm, the OS was 95%, PFS was 90%, and next-therapy rate was 14%. For those in the cessation arm, the OS was 91%, PFS was 85%, and the next-therapy rate was 12%. Among those who continued on ibrutinib because they did not achieve uMRD4 after 15 weeks, the OS was 86%, PFS was 76%, and next-therapy rate was 19%.

“Importantly, PFS rates were equally high in patients randomized to MRD-guided treatment cessation and reinitiation, emphasizing the potential to reduce treatment exposure and toxicity by MRD-guided treatment in the R/R CLL setting,” the authors wrote.

They concluded that the cessation and reinitiation of ibrutinib plus venetoclax for relapsed or refractory CLL is feasible and results in lower toxicity compared to indefinite therapy with a BTK inhibitor.

“The MRD-guided approach may also allow for improved patient compliance, thus offering an alternative to the high discontinuation rate reported outside clinical trials for continuous BTK inhibitors,” they concluded.

References

1. Niemann CU, Dubois J, Nasserinejad K, et al. Long-term follow-up of MRD-guided treatment of ibrutinib plus venetoclax for relapsed CLL: phase 2 VISION/HO141 trial. Blood Adv. Published online April 18, 2025. doi:10.1182/bloodadvances.2024015180

2. Wierda WG, Rawstron A, Cymbalista F, et al. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations. Leukemia. 2021;35(11):3059-3072. doi:10.1038/s41375-021-01241-1

3. Kater AP, Levin MD, Dubois J, et al. Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial. Lancet Oncol. 2022;23(6):818-828. doi:10.1016/S1470-2045(22)00220-0

A new study led by Johns Hopkins researchers has identified a significant gap between the number of U.S. patients for whom cholesterol-lowering drugs such as statins are recommended and the actual number of patients who take them. 

Coronary artery disease remains a leading cause of death in the U.S. and globally, despite the development of statins and other cholesterol-lowering medications in recent decades. Many adults who should be taking these drugs to lower their low-density-lipoprotein (LDL) levels are not—even though these drugs are considered safe and there is a large body of evidence supporting their effectiveness. In their new study, the researchers sought to quantify this treatment gap.

In a nationally representative analysis of nearly 5,000 U.S. adults, the researchers found that among those who had never had a major cardiovascular event, just under half—47%—were eligible for cholesterol-lowering drugs under U.S. guidelines but only 23% were taking them. Among those who had a record of a major cardiovascular event, just over two-thirds—68%—were receiving cholesterol-lowering treatment when 100% were eligible for them under 2018 U.S. guidelines.

The researchers estimate that closing this treatment gap could help prevent nearly 100,000 non-fatal heart attacks in the U.S. each year and up to 65,000 strokes overall in the U.S. each year, and also prevent tens of thousands of heart bypass surgeries and stent-placement procedures annually in the U.S. 

Bringing treatment in line with recommended U.S. guidelines could save up to $30.6 billion in annual medical costs in the U.S. for these prevented events, the researchers estimate.

The findings were published online June 30 in the Journal of General Internal Medicine.

“These results add to a growing body of evidence that there are important shortcomings in the quality of care for common and costly chronic diseases such as high cholesterol, and that addressing those shortcomings would yield major public health benefits,” says study lead author G. Caleb Alexander, MD, a practicing internist and professor in the Johns Hopkins Bloomberg School of Public Health’s Department of Epidemiology.

For their study, the researchers analyzed data on a nationally representative sample of 4,980 American adults, ages 40–75, from U.S. National Health and Nutrition Examination Surveys taken from 2013 to 2020. The researchers used data for each individual that included LDL-cholesterol levels and cardiovascular risk profiles to determine eligibility for lipid-lowering medications based on 2018 U.S. guidelines, as well as actual use of such medications by U.S. patients. 

The researchers also analyzed U.S. patient data applying E.U. guidelines. The European guidelines had more aggressive LDL-C goals compared to U.S. guidelines, resulting in wider gaps between observed and recommend care.

The vast majority of the individuals in the sample—89%—didn’t have a record of a major cardiovascular event such as a stroke, heart attack, or coronary bypass surgery. In this “primary prevention” group, representing about 116 million U.S. adults, only 23% were using lipid-lowering drugs to prevent such events, although 47% were eligible for such drugs under U.S. guidelines.

Among the 11% of the sample who did have a record of a major cardiovascular event—a “secondary prevention” sample representing about 15 million U.S. adults—only 68% received any LDL-lowering treatment, despite 100% being eligible under both the U.S. and E.U guidelines examined.

The researchers estimated that if treatment for all eligible individuals were fully aligned with U.S. or E.U. guidelines, including the use of non-statin LDL-lowering drugs in many cases, median levels of LDL cholesterol would drop sharply, reducing the risk of major cardiovascular events in the U.S. by up to 27%. 

“Several factors account for the gaps that we document,” says Alexander. “They include differences in clinician training, patient preferences, barriers to accessing care, financial incentives that don’t always support best practices, and the difficulty of putting clinical guidelines into practice in busy, real-world settings.”

Bringing actual treatment closer to what guidelines recommend could be achieved through various measures including better patient education on the benefits of treatment for those who know they have high LDL-cholesterol levels, and better screening for everyone else, the researchers say.

“High cholesterol is an important chronic health condition that silently claims far too many lives —there are millions of people walking around with this condition that don’t even know they have it, and then when it is recognized it too often goes undertreated. Evidence-based action is critical to close the gap and prevent devastating cardiovascular events,” says study senior author Seth S. Martin, MD, MHS, a practicing cardiologist and professor at the Johns Hopkins University School of Medicine.

“U.S. Public Health Gains from Improved Treatment of Hypercholesterolemia: A Simulation Study of NHANES Adults Treated to Guideline-Directed Therapy” was co-authored by G. Caleb Alexander, Jill Curran, Alejandro Victores, Hemalkumar Mehta, Shanshan Lin, Xuya Xiao, Erin Michos, Jeromie Ballreich, Lori Bash, Jason Exter, Kathryn Foti, and Seth Martin.

Funding was provided by Merck Sharp & Dohme LLC.

Disclosures: Caleb Alexander is past chair of FDA’s Peripheral and Central Nervous System Advisory Committee and is a co-founding principal and equity holder in Stage Analytics. Outside of this work, Seth Martin has received personal consulting fees from Amgen, AstraZeneca, BMS, Kaneka, Merck, NewAmsterdam, Novartis, Novo Nordisk, Premier, Sanofi, and 89bio. Outside of this work, Erin Michos has received personal consulting fees from Amgen, Arrowhead, AstraZeneca, Boehringer Ingelheim, Edwards Lifescience, Esperion, Ionis, Lilly, Medtronic, Merck, NewAmsterdam, Novartis, Novo Nordisk, and Pfizer. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. Alejandro Victores, Lori Bash and Jason Exter are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA. Jill Curran is now employed by Boehringer Ingelheim.

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Media contacts: Jon Eichberger je@jhu.edu or Kris Henry khenry39@jhu.edu