Category Archives: Cell Medicine

Based on pivotal DESTINY-Lung01 results showing Daiichi Sankyo and AstraZenecas ENHERTU demonstrated a 54.9% tumor response rate

If approved, ENHERTU to provide patients with a much-needed targeted therapy option

TOKYO & BASKING RIDGE, N.J., April 19, 2022--(BUSINESS WIRE)--Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN) have received notification of acceptance of the supplemental Biologics License Application (sBLA) of ENHERTU (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients in the U.S. with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy. The application has also been granted Priority Review.

ENHERTU is a HER2 directed antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca.

The U.S. Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for their regulatory decision, is during the third quarter of the 2022 calendar year. The Priority Review follows receipt of Breakthrough Therapy Designation, granted by the FDA in May 2020 for ENHERTU in this cancer type.

Lung cancer is the second most common form of cancer globally, with more than two million new cases diagnosed in 2020.1 For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.2 There are currently no HER2 directed therapies approved specifically for the treatment of HER2 mutant NSCLC, which occurs in approximately 2% to 4% of patients with non-squamous NSCLC.3,4

"The results of DESTINY-Lung-01 showed that ENHERTU is the first HER2 directed therapy to demonstrate a strong and robust tumor response in more than half of patients with previously treated HER2 mutant metastatic non-small cell lung cancer," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Seeking approval in the U.S. for a third tumor type in three years further demonstrates the significant potential of ENHERTU in treating multiple HER2 targetable cancers."

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"The DESTINY-Lung01 trial confirmed the HER2 mutation as an actionable biomarker in non-small cell lung cancer," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "If approved, ENHERTU has the potential to become a new standard treatment in this patient population, offering a much-needed option for patients with HER2 mutant metastatic non-small cell lung cancer who currently have no targeted treatment options."

The sBLA is based on data from the pivotal DESTINY-Lung01 phase 2 trial published in The New England Journal of Medicine, and is supported by the phase 1 trial (DS8201-A-J101) published in Cancer Discovery.

Primary results from the HER2 mutant cohort (cohort 2) of DESTINY-Lung01 in previously-treated HER2 mutant NSCLC demonstrated a confirmed objective response rate (ORR) of 54.9% (n=50; 95% confidence interval [CI]: 44.2-65.4) in patients treated with ENHERTU (6.4 mg/kg) as assessed by independent central review (ICR). Out of a total of 91 patients, one (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed. A confirmed disease control rate (DCR) of 92.3% (95% CI: 84.8-96.9) was seen with a reduction in tumor size observed in most patients. After a median follow-up of 13.1 months, the median duration of response (DoR) for ENHERTU was 9.3 months (95% CI: 5.7-14.7). The median progression-free survival (PFS) was 8.2 months (95% CI: 6.0-11.9) and the median overall survival (OS) was 17.8 months (95% CI: 13.8-22.1).

The safety profile of the most common adverse events with ENHERTU in DESTINY-Lung01 was consistent with previous clinical trials. The most common grade 3 or higher drug-related treatment-emergent adverse events were neutropenia (18.7%), anemia (9.9%), nausea (8.8%), fatigue (6.6%), leukopenia (4.4%), diarrhea (3.3%) and vomiting (3.3%). Twenty-three patients (25%) discontinued treatment due to drug-related treatment-emergent adverse events. Overall, 26% of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (75%) were low grade (grade 1 (12.5%) or grade 2 (62.5%)). Out of the total study population, four grade 3 (4.4%) and two grade 5 (2.2%) ILD or pneumonitis events were reported.

About DESTINY-Lung01 DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU in patients with HER2 mutant (6.4 mg/kg) or HER2 overexpressing (defined as IHC3+ or IHC2+) [6.4 mg/kg and 5.4 mg/kg] unresectable and/or metastatic non-squamous NSCLC who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by ICR. Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled approximately 180 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Mutant NSCLC Lung cancer is the second most common form of cancer globally, with more than two million new cases diagnosed in 2020.1 In the U.S., lung cancer is the second most commonly diagnosed cancer, with more than 236,000 new cases expected in 2022.5 For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. Certain HER2 gene alterations (called HER2 mutations) have been identified in NSCLC as distinct molecular targets and have been reported in approximately 2% to 4% of patients with non-squamous NSCLC.3,4 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Although the role of anti-HER2 treatment is well established in breast and gastric cancers, HER2 is an emerging biomarker in NSCLC with no approved HER2 directed therapies.3,8 Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations.9

About ENHERTU ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyos proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZenecas ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About the ENHERTU Clinical Development Program A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for ENHERTU are currently under review in Europe, Japan, U.S. and several other countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

ENHERTU also is currently under review in Europe for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2 based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. Important Safety Information for ENHERTU

Indications ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications None.

Warnings and Precautions Interstitial Lung Disease / Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in 28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU.Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3C or a sustained temperature of 38C for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4mg/kg, a decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: 6 to 547). Febrile neutropenia was reported in 1.7% of patients.

Locally Advanced or Metastatic Gastric Cancer In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Additional Dose Modifications Thrombocytopenia For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less. Reduce dose by one level.

Adverse Reactions Metastatic Breast Cancer The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (20%) adverse reactions, including laboratory abnormalities, were nausea (79%), white blood cell count decreased (70%), hemoglobin decreased (70%), neutrophil count decreased (62%), fatigue (59%), vomiting (47%), alopecia (46%), aspartate aminotransferase increased (41%), alanine aminotransferase increased (38%), platelet count decreased (37%), constipation (35%), decreased appetite (32%), anemia (31%), diarrhea (29%), hypokalemia (26%), and cough (20%).

Locally Advanced or Metastatic Gastric Cancer The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (75%), white blood cell count decreased (74%), neutrophil count decreased (72%), lymphocyte count decreased (70%), platelet count decreased (68%), nausea (63%), decreased appetite (60%), anemia (58%), aspartate aminotransferase increased (58%), fatigue (55%), blood alkaline phosphatase increased (54%), alanine aminotransferase increased (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), blood bilirubin increased (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.

Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.

Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.

Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.

Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were 65 years and 5% were 75 years. No overall differences in efficacy were observed between patients 65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years (53%) as compared to younger patients (42%). Of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years and 14% were 75 years. No overall differences in efficacy or safety were observed between patients 65 years of age compared to younger patients.

Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About Daiichi Sankyo Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose "to contribute to the enrichment of quality of life around the world." In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an "Innovative Global Healthcare Company Contributing to the Sustainable Development of Society." For more information, please visit http://www.daiichisankyo.com.

References1 WHO. Cancer Today. 2020. Accessed April 2022. 2 America Cancer Society. Lung Cancer Survival Rates. Accessed April 2022. 3 Liu S, et al. Clin Cancer Res. 2018;24(11):2594-2604. 4 Campbell JD, et al. Nat Genet. 2016 Jun;48(6):607-16. 5 American Cancer Society. Key Statistics for Lung Cancer. Accessed April 2022. 6 Pillai RN, et al. Cancer. 2017;123:4099-105. 7 Offin M, et al. Cancer. 2019;125:4380-7. 8 Zhou J, et al. Ther Adv Med Oncol. 2020;12. 9 Hechtman, J, et al. Cancer Cyto. 2019; 127 (7): 428-431.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220418005432/en/

Contacts

Media Contacts:Global: Victoria AmariDaiichi Sankyo, Inc.vamari@dsi.com +1 908 900 3010 (mobile)

US: Don MurphyDaiichi Sankyo, Inc.domurphy@dsi.com +1 917 817 2649 (mobile)

EU: Lydia WormsDaiichi Sankyo Europe GmbHlydia.worms@daiichi-sankyo.eu +49 (89) 7808751 (office)+49 176 11780861 (mobile)

Japan: Masashi KawaseDaiichi Sankyo Co., Ltd.kawase.masashi.a2@daiichisankyo.co.jp +81 3 6225 1126 (office)

Investor Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp

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ENHERTU Granted Priority Review in the U.S. for Patients with Previously Treated HER2 Mutant Metastatic Non-Small Cell Lung Cancer - Yahoo Finance

Clinical update expected in second half of 2023

CAMBRIDGE, Mass. and NEW YORK, April 18, 2022 (GLOBE NEWSWIRE) -- Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of MasterKey therapies, today announced the dosing of the first patient in the Phase 1 study evaluating BDTX-1535, a MasterKey inhibitor of epidermal growth factor receptor (EGFR) for the treatment of both non-small cell lung cancer (NSCLC) and glioblastoma (GBM)derived from Black Diamonds MAP discovery engine.

The dosing of the first patient in our Phase 1 study of BDTX-1535, a next generation brain-penetrant inhibitor of oncogenic EGFR MasterKey mutations is an important step as we believe this program is uniquely positioned to address the existing unmet needs of EGFR mutant NSCLC and GBM, said David M. Epstein, Ph.D., Chief Executive Officer of Black Diamond Therapeutics. This is the second MasterKey inhibitor derived from our MAP drug discovery engine; we are incredibly excited about BDTX-1535s advancement into the clinic and we look forward to providing a clinical update in the second half of 2023.

Despite recent successes in targeting EGFR-mutated NSCLC, there is still a need for better therapeutics for patients with disease progression following first-line EGFR inhibitors, said Melissa Johnson, MD, Director of Lung Cancer Research for Sarah Cannon Research Institute at Tennessee Oncology. We hope to assess the ability of BDTX-1535 to inhibit tumors with primary TKI-resistant EGFR mutations or those with on-target acquired resistance mutations.

NSCLC accounts for approximately 85% of lung cancer cases worldwide. About 10-20% of all lung cancer patients in North American and Europe, and up to 50% of those in Asia harbor mutations in EGFR. Intrinsic resistance EGFR mutations, of which G719X, S768I, L861Q are among the most frequent, account for 10-20% of EGFR mutations in NSCLC. The classical Exon19del and L858R mutations, which account for 80-90% of EGFR mutations in NSCLC, are well treated but resistance invariably emerges to current generation EGFR inhibitors.

"GBM is an aggressive form of brain cancer with limited treatment options, said Patrick Y. Wen, MD, Director, Center for Neuro-Oncology at Dana-Farber Cancer Institute. "A majority of GBM tumors will co-express EGFR alterations, including mutations, splice variants and amplification, making EGFR an attractive target for new therapies with CNS penetration and potency against the spectrum of co-expressed EGFR alterations.

Up to 50% of GBM tumors express one or more co-occurring oncogenic EGFR mutations that affect the extracellular region of the receptor tyrosine kinase, and consequently promote oncogenic activation. There are no precision oncology medicines approved to treat these patients. Black Diamond believes that current targeted therapies have been unsuccessful in treating GBM due to insufficiencies in (i) drug selectivity for EGFR GBM alterations versus EGFR wildtype, (ii) drug potency against the full spectrum of co-expressed EGFR alterations, and (iii) brain penetration.

About BDTX-1535BDTX-1535 is designed as an irreversible, mutant selective, brain-penetrant MasterKey inhibitor of oncogenic mutations of epidermal growth factor receptor (EGFR) expressed in glioblastoma multiforme (GBM) and intrinsic and acquired resistance EGFR mutations in non-small cell lung cancer (NSCLC). In pre-clinical studies, Black Diamond has demonstrated that oncogenic alterations of EGFR, particularly those associated with GBM, result in distinct conformations which impart unique pharmacology and drug resistance. It is estimated that approximately 50% of GBM patients harbor an oncogenic EGFR alteration that has the potential to be addressed by BDTX-1535, representing a potential patient population of greater than 60,000 patients annually across the US, EU, Japan and China. It is estimated that across the US, EU, Japan and China there are approximately 20,000 patients who are diagnosed annually with non-small cell lung cancer (NSCLC) harboring an EGFR intrinsic or acquired resistance mutation.

About Black DiamondBlack Diamond Therapeutics is a precision oncology medicine company pioneering the development of novel MasterKey therapies. Black Diamond is addressing the significant unmet need for novel precision oncology therapies for patients with genetically defined cancers who have limited treatment options. Black Diamond is built upon a deep understanding of cancer genetics, onco-protein function, and drug discovery. The Companys proprietary Mutation-Allostery-Pharmacology, or MAP drug discovery engine, is designed to allow Black Diamond to analyze population-level genetic sequencing tumor data to predict and validate oncogenic mutations that promote cancer across tumor types as MasterKey mutations. Black Diamond discovers and develops selective MasterKey therapies against these families of oncogenic mutations. Black Diamond was founded by David M. Epstein, Ph.D., and Elizabeth Buck, Ph.D. For more information, please visit http://www.blackdiamondtherapeutics.com.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the Phase 1 study of BDTX-1535, including timing for future clinical updates, and the unmet need in patients with glioblastoma. Any forward-looking statements in this statement are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include those risks and uncertainties set forth in the Companys 2021 annual report on Form 10-K filed with the United States Securities and Exchange Commission and its other filings filed with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

ContactsFor Investors:Julie Seidelinvestors@bdtx.com

For Media:Kathy Vincent(310) 403-8951media@bdtx.com

Originally posted here:
Black Diamond Therapeutics Announces First Patient Dosed in Phase 1 Study of BDTX-1535, a MasterKey Inhibitor of EGFR for the Treatment of...

Cancer cells can disrupt a metabolic pathway that breaks down fats and proteins to boost the levels of a byproduct called methylmalonic acid, thereby driving metastasis, according to research led by scientists at Weill Cornell Medicine. The findings open a new lead for understanding how tumors metastasize, or spread to other tissues, and hints at novel ways to block the spread of cancer by targeting the process.

The new results, published March 31 in Nature Metabolism, show that metastatic tumors suppress the activity of a key enzyme in propionate metabolism, the process by which cells digest certain fatty acids and protein components. Suppressing the enzyme increases production of methylmalonic acid (MMA). That, in turn, causes the cells to become more aggressive and invasive.

Cancer is the second leading cause of death worldwide, and metastasis drives much of that mortality. Once a tumor begins to metastasize to different tissues and organs around the body, it can quickly become difficult or impossible to treat. However, researchers have made few inroads in understanding how a tumor cell acquires the ability to metastasize.

A lot of work has been focused on primary tumor initiation and growth, or examining the metastatic tumor, but to go from the primary tumor to the metastatic tumor, that transition has not been studied very extensively, said co-senior author Dr. John Blenis, the Anna-Maria and Stephen Kellen Professor in Cancer Research, professor of pharmacology and associate director of basic science of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

To address that gap, Dr. Blenis and his colleagues have worked for several years to characterize the metabolic changes that cells undergo during the metastatic transition. That effort previously revealed that as people age, their bodies produce more serum MMA (although the source remains unknown), and that higher MMA levels drive worse cancer outcomes. Healthy cells also produce MMA, though, so in the new study Dr. Bleniss team probed the metabolites cancer-related activities more deeply.

Cancer cells themselves can hijack the pathway that makes methylmalonic acid and this forms a feed-forward cycle that drives cancer progression towards more aggressive and more metastatic forms, said co-first author Dr. Vivien Low, a postdoctoral fellow in Dr. Bleniss lab. The other co-first authors Dr. Ana Gomes and Dr. Didem Ilter, were also postdoctoral fellows in the lab at the time of the study. Dr. Gomes is now a faculty member and Dr. Ilter is a research scientist at H. Lee Moffitt Cancer Center & Research Institute.

The discovery adds to a growing body of work showing that specific products of metabolism, called oncometabolites, can drive many aspects of cancer progression and metastasis.

While the new paper focused on various models of breast cancer, Dr. Low said the team is now analyzing other types of cancer cells as well, where they expect to find similar mechanisms operating. The scientists are also searching for ways to attack the process.

Metastasis is responsible for about 80 to 90 percent of cancer-related mortality, so if we can predict when someone has the potential to develop metastatic tumors, or treat those metastatic tumors that might have this pathway up-regulated, then we might have a very effective, novel therapy, Dr. Blenis said.

Excerpt from:
Tumors Change Their Metabolism to Spread More Effectively - Weill Cornell Medicine Newsroom

- Pelareorep-CAR T combination may expand the commercial potential of CAR T cells to solid tumors

- Combining CAR T cells with pelareorep prevented antigen escape by creating CAR T cells with dual specificity through a novel mechanism

-Loading CAR T cells with pelareorep led to dramatic improvements in their persistence and anti-cancer activity as well as cures in multiple murine solid tumor models

SAN DIEGO, Calif. and CALGARY, AB, April 14, 2022 /PRNewswire/ --Oncolytics BiotechInc. (NASDAQ: ONCY) (TSX: ONC) today announced the publication of preclinical data demonstrating the synergistic anti-cancer activity of pelareorep combined with chimeric antigen receptor (CAR) T cell therapy in solid tumors. The paper, entitled "Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice," was published in Science Translational Medicine in collaboration with researchers at several prestigious institutions, including the Mayo Clinic and Duke University. A link to the paper can be found by clicking here.

"Having these results published in such a high-impact journal provides important external validation of their significance," said Thomas Heineman, M.D., Ph.D., Chief Medical Officer of Oncolytics Biotech Inc. "While CAR T cells have generated long-term cures in hematologic malignancies1, the immunosuppressive tumor microenvironments (TMEs) of solid organ cancers have thus far limited their efficacy in these indications. Pelareorep has repeatedly been shown to reverse immunosuppressive TMEs, and in the present publication pelareorep is shown to enable the effectiveness of CAR T cells in multiple murine solid tumor models. This is a powerful finding that, if translated to the clinic, could significantly improve the prognosis of patients with a variety of highly prevalent cancers by providing a novel and potentially durable treatment option. By demonstrating the ability to improve T cell perseverance, reduce antigen escape, and overcome challenging solid tumor TMEs, the inclusion of pelareorep addresses the three most challenging roadblocks to effective CAR T therapy."

Andrew de Guttadauro, President of Oncolytics Biotech U.S. and Global Head of Business Development, added, "Despite revolutionizing the treatment of certain cancers and surpassing a billion dollars in sales last year, CAR T therapies currently only serve a small subset of patients suffering from hematologic malignancies. With these latest results, we now have strong preclinical evidence that pelareorep can fully unlock the value of CAR T therapies by expanding their commercial potential to the significantly larger market of cancer patients who are battling solid tumors."

Preclinical studies published in the paper evaluated the persistence and efficacy of pelareorep-loaded CAR T cells ("CAR/Pela therapy") in multiple murine solid tumor models. The effects of combining CAR/Pela therapy with a subsequent intravenous dose of pelareorep ("pelareorep boost") were also investigated. Key data and conclusions from the paper include:

Dr. Matt Coffey, President and Chief Executive Officer of Oncolytics Biotech Inc. and co-author of the paper commented, "These exciting results are an excellent example of how we are leveraging collaborations with key opinion leaders and premier research institutions to broaden pelareorep's potential therapeutic impact. This allows us to remain primarily focused on our lead breast cancer program, which has shown how pelareorep's ability to promote tumor T cell infiltration leads to synergy with checkpoint inhibitors in the clinic. These newly published preclinical findings show pelareorep's synergistic benefits extend even beyond checkpoint inhibitors and highlight an opportunity to increase our addressable patient population. As we pursue this opportunity moving forward, we intend to utilize relationships with academic or industry partners so that we can continue to execute on our clinical and corporate objectives with efficiency."

About CAR T cells and CAR T therapy

TheCAR T process begins when blood is drawn from a patient and their T cells are separated so they can be genetically engineered to produce chimeric antigen receptors (CARs). These receptors enable the T cells to recognize and attach to a specific protein or antigen on tumor cells. Once the engineering process is complete, a laboratory can increase the number of CAR T cells into the hundreds of millions. Finally, the CAR T cells will be infused back into the patient where, ideally, the engineered cells further multiply and recognize and kill cancer cells. Historically, solid tumors have been considered beyond the reach of CAR T therapy due to their tumor microenvironment, which is detrimental to CAR T cell entry and activity, amongst other challenges.2

About Science Translational Medicine

Science Translational Medicineis the leading weekly online journal publishing translational research at the intersection of science, engineering, and medicine. The goal of Science Translational Medicine is to promote human health by providing a forum for communicating the latest research advances from biomedical, translational, and clinical researchers from all established and emerging disciplines relevant to medicine. In addition to original research, Science Translational Medicine also publishes Reviews, Editorials, Focus articles, and Viewpoints.

About Oncolytics Biotech Inc.

Oncolytics is a biotechnology company developing pelareorep, an intravenously delivered immunotherapeutic agent. This compound induces anti-cancer immune responses and promotes an inflamed tumor phenotype -- turning "cold" tumors "hot" -- through innate and adaptive immune responses to treat a variety of cancers.

Pelareorep has demonstrated synergies with immune checkpoint inhibitors and may also be synergistic with other approved oncology treatments. Oncolytics is currently conducting and planning clinical trials evaluating pelareorep in combination with checkpoint inhibitors and targeted therapies in solid and hematological malignancies as it advances towards a registration study in metastatic breast cancer. For further information, please visit:www.oncolyticsbiotech.com.

References

1. Melenhorst, J.J., Chen, G.M., Wang, M.et al.Decade-long leukaemia remissions with persistence of CD4+CAR T cells.Nature(2022). https://doi.org/10.1038/s41586-021-04390-6

2. National Cancer Institute. CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers. Updated July 31, 2019. Accessed February 18, 2021.https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

This press release contains forward-looking statements, within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended and forward-looking information under applicable Canadian securities laws (such forward-looking statements and forward-looking information are collectively referred to herein as "forward-looking statements"). Forward-looking statements contained in this press release include statements regarding Oncolytics' belief as to the potential and benefits of pelareorep as a cancer therapeutic; Oncolytics' expectations as to the purpose, design, outcomes and benefits of its current or pending clinical trials involving pelareorep; including potentially significantly improving the prognosis of patients with a variety of highly-prevalent cancers by providing them with a novel and potentially durable treatment option and the opportunity to potentially expand our addressable patient population; our intention to utilize relationships with academic or industry partners so that we can continue to execute on our clinical and corporate objectives with efficiency; our leveraging of collaborations with key opinion leaders to broaden pelareorep's potential therapeutic impact; our plans to advance towards a registration study in metastatic breast cancer; and other statements related to anticipated developments in Oncolytics' business and technologies. In any forward-looking statement in which Oncolytics expresses an expectation or belief as to future results, such expectations or beliefs are expressed in good faith and are believed to have a reasonable basis, but there can be no assurance that the statement or expectation or belief will be achieved. Such forward-looking statements involve known and unknown risks and uncertainties, which could cause Oncolytics' actual results to differ materially from those in the forward-looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue research and development projects, the efficacy of pelareorep as a cancer treatment, the success and timely completion of clinical studies and trials, Oncolytics' ability to successfully commercialize pelareorep, uncertainties related to the research and development of pharmaceuticals, uncertainties related to the regulatory process and general changes to the economic environment. In particular, we may be impacted by business interruptions resulting from COVID-19 coronavirus, including operating, manufacturing supply chain, clinical trial and project development delays and disruptions, labour shortages, travel and shipping disruption, and shutdowns (including as a result of government regulation and prevention measures). It is unknown whether and how Oncolytics may be affected if the COVID-19 pandemic persists for an extended period of time. We may incur expenses or delays relating to such events outside of our control, which could have a material adverse impact on our business, operating results and financial condition.Investors should consult Oncolytics' quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statements. Investors are cautioned against placing undue reliance on forward-looking statements. The Company does not undertake any obligation to update these forward-looking statements, except as required by applicable laws.

Company Contact

Jon Patton

Director of IR & Communication

+1-858-886-7813

[emailprotected]

Investor Relations for Oncolytics

Timothy McCarthy

LifeSci Advisors

+1-917-679-9282

[emailprotected]

SOURCE Oncolytics Biotech Inc.

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Oncolytics Biotech Announces Publication of Preclinical Data Demonstrating the Synergistic Anti-Cancer Activity of Pelareorep Combined with CAR T Cell...

CARLSBAD, Calif.--(BUSINESS WIRE)-- Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, announced today that Cancer Research UK recently completed patient enrollment in the ongoing Phase 1 clinical trial of VAC2, an allogeneic cancer vaccine product candidate, for the treatment of non-small cell lung cancer (NSCLC). Under the terms of an existing agreement, Cancer Research UK will complete the ongoing clinical trial and Lineage has now assumed responsibility for further clinical development of the VAC2 product candidate and any future development opportunities derived from the VAC platform.

We are pleased that Cancer Research UK has successfully completed patient enrollment in the VAC2 Phase 1 clinical study and overcame substantial challenges stemming from the COVID pandemic. We look forward to initial clinical results from this study being available later this year, stated Brian M. Culley, Lineage CEO. Clinical data previously collected by Cancer Research UK demonstrated peripheral immunogenicity in patients with NSCLC treated with VAC2, providing support to the underlying mechanism of using allogeneic dendritic cells to present tumor-associated antigens to the bodys immune system. Simultaneous with Cancer Research UK efforts to complete enrollment in the current study, the focus at Lineage has been on making improvements and modernizations to the VAC manufacturing process, an approach which we similarly employed in the development of OpRegen. We believe our focus on manufacturing will help prepare VAC2 for additional clinical trials and provide a competitive advantage for any future VAC programs which we advance, either alone or through alliances. With Cancer Research UK having completed enrollment of the current study, the team at Lineage also has begun work towards the submission of an Investigational New Drug Application for clinical testing of VAC2 in the U.S., which we anticipate submitting to the FDA later this year.

Dr. Nigel Blackburn, Director of Cancer Research UKs Centre for Drug Development, added: We are delighted to see that this innovative VAC2 program has reached such an important milestone in its development and are extremely proud to have played an important role in establishing its tolerability in lung cancer patients. We look forward to seeing Lineage advance VAC2 under their leadership in the future.

About VAC2

VAC2 is an allogeneic, or non-patient specific off-the-shelf, cancer vaccine product candidate designed to stimulate patient immune responses to an antigen commonly expressed in cancerous cells but not in normal adult cells. VAC2, which is produced from a pluripotent cell technology using a directed differentiation method, is comprised of a population of nonproliferating mature dendritic cells. As the most potent type of antigen presenting cell in the body, dendritic cells instruct the bodys immune system to attack and eliminate harmful pathogens and unwanted cells. Because the tumor antigen is loaded exogenously into the dendritic cells prior to administration, VAC2 is a platform technology that could be modified to carry selected antigens, including patient-specific tumor neo-antigens or viral antigens. VAC2 is currently being tested in a Phase 1 study in adult patients with NSCLC in the advanced and adjuvant settings (NCT03371485), conducted by Cancer Research UK.

About Cancer Research UKs Centre for Drug Development

Cancer Research UK has an impressive record of developing novel treatments for cancer. The Cancer Research UK Centre for Drug Development has been pioneering the development of new cancer treatments for 25 years, taking over 140 potential new anti-cancer agents into clinical trials in patients. It currently has a portfolio of 21 new anti-cancer agents in preclinical development, Phase I or early Phase II clinical trials. Six of these new agents have made it to market including temozolomide for brain cancer, abiraterone for prostate cancer and rucaparib for ovarian cancer. Two other drugs are in late development Phase III trials.

About Cancer Research UKs Commercial Partnerships Team

Cancer Research UK is the worlds leading cancer charity dedicated to saving lives through research. Cancer Research UKs specialist Commercial Partnerships Team works closely with leading international cancer scientists and their institutes to protect intellectual property arising from their research and to establish links with commercial partners. Cancer Research UKs commercial activity operates through Cancer Research Technology Ltd., a wholly owned subsidiary of Cancer Research UK. It is the legal entity which pursues drug discovery research in themed alliance partnerships and delivers varied commercial partnering arrangements.

About Cancer Research UK

For further information about Cancer Research UKs work or to find out how to support the charity, please call 0300 123 1022 or visit http://www.cancerresearchuk.org. Follow us on Twitter and Facebook.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include four allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, which is now being developed under a worldwide collaboration with Roche and Genentech, a member of the Roche Group; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; (iii) VAC2, a dendritic cell therapy produced from Lineages VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer and (iv) ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, aim, may, will, estimate, continue, anticipate, design, intend, expect, could, can, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the efficacy of using allogeneic dendritic cells to present tumor-associated antigens to the bodys immune system the collaboration and license agreement with Roche and Genentech and activities expected to occur thereunder, the broad potential for Lineages regenerative medicine platform as well as the VAC technology platform, and Lineages ability to expand the same; the projected timing of milestones of future studies, including their initiation and completion, projected manufacturing plans and improvements; the potential for Lineages investigational allogeneic cell therapies to generate clinical outcomes beyond the reach of traditional methods and provide safe and effective treatment for multiple, diverse serious or life threatening conditions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, but not limited to, the risk that competing alternative therapies may adversely impact the commercial potential of OpRegen, which could materially adversely affect the milestone and royalty payments payable to Lineage under the collaboration and license agreement, the risk that Roche and Genentech may not be successful in completing further clinical trials for OpRegen and/or obtaining regulatory approval for OpRegen in any particular jurisdiction, the risk that Lineage might not succeed in developing products and technologies that are useful in medicine and demonstrate the requisite safety and efficacy to achieve regulatory approval in accordance with its projected timing, or at all; the risk that Lineage may not be able to manufacture sufficient clinical and, if approved, commercial quantities of its product candidates in accordance with current good manufacturing practice; the risks related to Lineages dependence on other third parties, and Lineages ability to establish and maintain its collaborations with these third parties; the risk that government-imposed bans or restrictions and religious, moral, and ethical concerns about the use of hES cells could prevent Lineage or its partners from developing and successfully marketing its stem cell product candidates; the risk that Lineages intellectual property may be insufficient to protect its products; the risk that the COVID-19 pandemic or geopolitical events may directly or indirectly cause significant delays in and substantially increase the cost of development of Lineages product candidates, as well as heighten other risks and uncertainties related to Lineages business and operations; risks and uncertainties inherent in Lineages business and other risks discussed in Lineages filings with the Securities and Exchange Commission (SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading Risk Factors in Lineages periodic reports with the SEC, including Lineages most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the SEC and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220413005356/en/

Excerpt from:
Lineage and Cancer Research UK Announce Completion of Patient Enrollment in Phase 1 Clinical Study of VAC2 for the Treatment of Non-small Cell Lung...

SAN DIEGO, April 13, 2022 (GLOBE NEWSWIRE) -- Oncternal TherapeuticsInc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, today announced that it has deprioritized further development of ONCT-216 to reallocate resources to zilovertamab, the Companys investigational anti-ROR1 monoclonal antibody, and its Phase 3 registrational trial that the Company expects to initiate in Q3 2022. As such, the Company has discontinued enrollment in the Phase 1/2 study evaluating ONCT-216 in patients with relapsed or refractory Ewing sarcoma.

This asset prioritization allows us to further sharpen our focus on hematological malignancies and prostate cancer, while deploying our capital towards meaningful catalysts as we navigate this historically challenging pandemic, geopolitical and capital markets macroenvironment, said James Breitmeyer, MD, PhD, Oncternals President and CEO. We believe this focused approach, along with prudent cash management, will enable us to fund our operations well into the third quarter of 2023, as we continue to explore all potential sources of capital to enable us to reach our milestones.

The Company expects to initiate its global registrational Phase 3 Study ZILO-301 in the third quarter of 2022, taking into account the impact of geopolitical factors and COVID-19 related supply chain issues. The study will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo, and all patients will continue receiving oral ibrutinib. The novel ZILO-301 design is supported by encouraging data from the Companys ongoing Phase 1/2 clinical trial of zilovertamab plus ibrutinib for patients with MCL or CLL, as well as by a successful End-of-Phase-2 meeting with the U.S. Food and Drug Administration (FDA).

The Companys lead autologous ROR1-targeted CAR-T cell therapy program candidate, ONCT-808, is advancing according to plan towards an Investigational New Drug (IND) application submission expected in mid-2022, based on supportive manufacturing and preclinical data as well as a productive pre-IND meeting with the FDA earlier this year.

Finally, the Company continues to advance ONCT-534, its lead candidate in its DAARI program, and expects to initiate IND-enabling GLP toxicology studies and GMP manufacturing later this quarter. ONCT-534 has shown anti-tumor activity in preclinical studies relevant to multiple clinically important forms of resistance for patients with prostate cancer, including those involving overexpression of the androgen receptor, or expression of mutants of the androgen receptor, or splice variants such as AR-V7.

AboutZilovertamab (formerly Cirmtuzumab)Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL or chronic lymphocytic leukemia (CLL), in a collaboration with theUniversity of California San Diego(UC San Diego) School of Medicine and theCalifornia Institute for Regenerative Medicine(CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at theUC San Diego School of Medicinediscovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1 expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.

About Oncternal TherapeuticsOncternal Therapeuticsis a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of patients with cancers that have critical unmet medical need. Oncternal pursues drug development targeting promising, yet untapped biological pathways implicated in cancer generation or progression, focusing on hematological malignancies and prostate cancer. The clinical pipeline includeszilovertamab, an investigational monoclonal antibody designed to inhibit ROR1, a type I tyrosine kinase-like orphan receptor. Zilovertamab is being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), in investigator-initiated studies, including a Phase 1b clinical trial in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, in a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL, and in a Phase 1b study of zilovertamab in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). Oncternal is also developingONCT-808, a chimeric antigen receptor T cell (CAR-T) therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors. The early-stage pipeline also includesONCT-534, a dual-action androgen receptor inhibitor (DAARI), that is in preclinical development as a potential treatment for castration resistant prostate cancer and other androgen-receptor dependent diseases. More information is available athttps://oncternal.com/.

Forward-Looking Information

Oncternal cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as may, will, should, expect, plan, anticipate, could, intend, target, project, contemplates, believes, estimates, predicts, potential or continue or the negatives of these terms or other similar expressions. These statements are based on Oncternals current beliefs and expectations. Forward-looking statements include statements regarding Oncternals development programs, including Oncternals estimated cash and cash equivalents as of March 31, 2022, the anticipated timing for announcing additional preclinical and clinical data; timing of reaching any milestones, including IND submissions; timing for regulatory communications; Oncternals expected cash runway; and the potential that Study ZILO-301 can serve as a registrational clinical trial; and the expected initiation of clinical trials, including Study ZILO-301. Forward-looking statements are subject to risks and uncertainties inherent in Oncternals business, including risks associated with the clinical development and process for obtaining regulatory approval of Oncternals product candidates, such as potential delays in the commencement, enrollment and completion of clinical trials; we have not conducted head-to-head studies of zilovertamab in combination with ibrutinib compared to ibrutinib monotherapy and data from separate studies may not be directly comparable due to the differences in study protocols, conditions and patient populations; the risk that interim results of a clinical trial do not predict final results and that one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data, as follow-up on the outcome of any particular patient continues, and as more patient data become available; later developments with the FDA may be inconsistent with the minutes from the completed end of Phase 2 meeting, including that the proposed Study ZILO-301 that may not support registration of zilovertamab in combination with ibrutinib which is a review issue with the FDA upon submission of a BLA; and other risks described in Oncternals filings with theU.S. Securities and Exchange Commission. All forward-looking statements in this press release are current only as of the date hereof and, except as required by applicable law, Oncternal undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Contact Information:

InvestorsRichard Vincent858-434-1113rvincent@oncternal.com

MediaCorey Davis, Ph.D. LifeSci Advisors 212-915-2577 cdavis@lifesciadvisors.com

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Oncternal Therapeutics Deprioritizes Development of ONCT-216 to Focus Resources on Phase 3 Trial for Zilovertamab in the Treatment of Mantle Cell...

Autoimmune hepatitis (AIH) is a chronic progressive inflammatory disorder commonly identified in females with a tendency to occur during the teen years and the fourth to sixth decades of life. Its distinguishing features include the presence of serum-specific autoantibodies and histopathology features of interface hepatitis [1-3]. Etiopathogenesis involves a multitude of independent factors such as human leukocyte antigen (HLA) allelic variants, infections, drugs, and the prevalence of autoimmune tautology, which cause an immunoregulatory imbalance, leading to a resultant T-cell mediated inflammation [1]. Steroids and immunosuppressants form the primary pillars of treatment, along with close monitoring of liver function tests to assess therapeutic response. The recommended duration of treatment is approximately two years, after which withdrawal can be considered. However, given the high risk of relapse, lifelong immunosuppressive therapy may be essential in most cases [3].

Natural supplements have been in use for decades in conjunction with modern medicine by mankind to treat a variety of common ailments. The rationale behind the use of such supplements is their presumed regulatory effect on the immune system, although studies conducted over the years have had mixed results [4-6]. One of the commonly used botanical supplements of interest with immunomodulatory effects is Sambucus nigra, also commonly known as elderberry, frequently used for the treatment of the common cold. The effects of elderberry on the production of pro-inflammatory cytokines such as IL-6,IL-8, and TNF have been controversial, with studies indicating a stimulatory versus inhibitory effect, leading to inconsistent interpretation [4]. We present a case of autoimmune hepatitis in a middle-aged female who was on long-term elderberry-containing supplements and developed autoimmune hepatitis. This case report aims to identify the risk factors associated with autoimmune hepatitis, debate the effects of elderberry on the immune system, and consider a causal association between the two entities.

A 60-year-old Caucasian female with a medical history of Hashimoto thyroiditis and Medullary sponge kidneys presented to the hospital with nausea, decreased appetite, abdominal pain, and bloating for two days. She was on levothyroxine, indapamide, tamsulosin, potassium citrate supplements, and an over-the-counter elderberry supplement for several years. Her vital signs were stable. Physical examination findings were remarkable for scleral icterus, generalized jaundice, and abdominal distention without tenderness.

Initial laboratory studies revealed transaminitis with elevation of AST to 1821 IU/L (13-39 IU/L), ALT >2500 IU/L (7-52 IU/L), ALP of 232 IU/L (35-104 IU/L), total bilirubin of 10.5 mg/dL (0.0-1.0 mg/dL), and direct bilirubin of 5.66 mg/dL (0.00-0.20 mg/dL) (Table 1). Abdominal imaging studies, including ultrasound and CT scans, showed mild peri hepatic inflammation and a contracted gallbladder with no obvious stones or intrahepatic dilation. The acute hepatitis panel was negative;however, she was found to have a positive antinuclear antibody (ANA) screen and SSA (RO) Ab 1.4 (<1.0) (Table 1), which raised a concern for autoimmune hepatitis.

Subsequent evaluation with a liver biopsy revealed extensive interface hepatitis, lymphohistiocytic infiltrate, eosinophils and neutrophils in the portal areas, periportal and lobular liver cell damage with piecemeal necrosis (Figure 1, 2).

Based on histological findings of the portal tract, the differential diagnoses included autoimmune hepatitis versus drug-induced hepatitis. She was instructed to stop taking natural supplements, and immunosuppressive therapy with daily Prednisone 40 mg was started for four weeks.

At a follow-up visit four weeks later, her repeat liver function tests improved to baseline. As elderberry supplements were presumed causes of hepatitis, they were not rechallenged. Prednisone therapy was tapered over two weeks, after which she was started on long-term maintenance therapy with azathioprine.

Autoimmune hepatitis is a chronic inflammatory liver disease depicted by a combination of elevated liver enzymes, the presence of specific serum autoantibodies and histological features of interface hepatitis, infiltration of lobules with lymphocytes, and plasma cells [3]. AIH is further classified into two types depending on the presence of autoantibodies: type 1 is positive for ANAand/or anti-smooth muscle antibodies (SMA), while type 2 is positive for liver-kidney-microsomal-type-1 (LKM-1) antibodies [2,3].While studies have shown that it affects all ages, ethnicities, and genders, it has a bimodal distribution with peaks in the teens and the fourth to the sixth decadeof life, with a female preponderance [1-3]. Literature suggests that the presence of one autoimmune disorder can increase the risk of an individual developing other autoimmune disorders [7]. One such commonly studied association with AIH is the presence of autoimmune thyroiditis [8,9]. In a case-control study, it was found that 30% of patients with AIH have concurrent extrahepatic autoimmune manifestations, out of which 51.4% were found to be diagnosed with autoimmune thyroid disease [9]. Another similar study revealed that autoimmune thyroid disease was the most common concurrent extrahepatic autoimmune disease with an 18% prevalence in those with autoimmune hepatitis [8]. On the other hand, in another cohort study, autoimmune hepatitis was found in 8.69% of patients with Hashimoto thyroiditis [10]. Uncertainty lies within the issue of whether autoimmune thyroid disorder is a risk factor or a cause of autoimmune liver disease, or vice versa, warranting further exploration.

The mechanism behind the development of autoimmune hepatitis is still not completely clear. A complex interplay between genetic predisposition, molecular mimicry, and effector-regulatory immunity is thought to be involved in the pathogenesis of autoimmune hepatitis. The presentation of an autoantigenic peptide to nave CD4 T-helper cells (Th0) causes the secretion of proinflammatory cytokines like IL-12, IL-6, and TGF-B which leads to the development of Th1, Th2, and Th17 cells [11]. Th1 cells produce IL-2 and IFN-y, which activate cytotoxic T lymphocytes (CD8), thereby inducing the expression of HLA class I and II molecules on hepatocytes with further stimulation of macrophages. Th2 cells secrete IL-4, IL-10, and IL-14, leading to the maturation of B cells and plasma cells that produce autoantibodies [11]. Regulatory T cells (Treg) derived from Th0 cells are responsible for restricting hepatocellular injury by Th1, Th17, macrophages, complement, and natural killer cells [8,12]. Th17 cells produce cytokines that suppress Treg cells, thus amplifying liver damage along with the cascading effects of Th1 and Th2 cells, leading to the formation of characteristic lymphocytic and plasma cell infiltrates termed interface hepatitis [8].

As per another study, SPW 2, a neutral polysaccharide derived from Sambucus leaves, induced the secretion of IL-beta, IL-6, and TNF-alpha and increased the mRNA expression level of IL-6 and TNF-alpha in macrophages in vitro [6].

Sambucus species, commonly known as elderberry, is a traditional dietary supplement used to treat minor health conditions, particularly influenza [5]. While there are insufficient data to substantiate the effectiveness of elderberry, some studies have displayed its immunomodulatory effects. In a study done by Barak et al., Sambucol (elderberry) extract led to the production of inflammatory cytokines including IL-1 beta, TNF-alpha, IL-6, and IL-8 (2-45 fold) as compared to lipopolysaccharide, a known monocyte activator (3.6-10.7 fold) in vitro, thereby concluding that Sambucol extract activates the immune system by increasing inflammatory cytokine production [5]. Another comparable study revealed similar in vitro effects of Sambucus as well as its ability to stimulate the mRNA expression of inducible Nitric oxide synthase in macrophages, supporting the notion of elderberrys potential regulatory effects on the immune system [6]. Considering the aforementioned discussion, it is worth debating whether elderberry may be contributing to the amplification of the cytokine production in vivo, inciting autoimmunity in genetically predisposed individuals - parallel to the development of autoimmune hepatitis in our patient with a history of a known autoimmune condition (Hashimoto's thyroiditis) on long-term elderberry supplements.

In addition to playing a vital role in the diagnosis, the purpose of a liver biopsy in AIH is to determine the prognosis, severity of the disease, and therapeutic response. The characteristic histological features of AIH are depicted by the presence of interface hepatitis or piecemeal necrosis, which is the inflammation of hepatocytes at the junction of the portal tract and hepatic parenchyma consisting of lymphocytes and plasma cells [13]. However, there exists approximately 25% overlap between AIH and acute viral hepatitis, with the degree of plasmacytosis being the discriminating factor, although 33% of patients with AIH do not exhibit plasma cells in the portal tract, and thus diagnosis should be made in the context of a clinical and serological background [13]. The presence of eosinophils seen in Figure 1can correspond to a differential diagnosis of drug-induced hepatitis, although these findings can also be seen with AIH, making it difficult to differentiate between the two and establish a clear diagnosis. At the same time, our patient had a negative hepatitis serology, which helped in making the distinction.Another entity that is relevant to our case is a drug-induced liver injury with autoimmune features, which is a syndrome where one develops biochemical and histological features of autoimmune hepatitis after the ingestion of a drug or a herbal product [14,15]. It has a shorter incubation period with a gradual improvement observed after the inciting drug is stopped and can recur if it is re-introduced, whereas idiopathic AIH requires long-term immunosuppression [14,15]. In addition to the presence of a pre-existing autoimmune condition (Hashimotos thyroiditis) in our patient, there is a possibility that elderberry supplements could have initiated a self-propagating autoimmune process that could have caused the liver injury.

The cornerstone of treatment in AIH lies in limiting inflammation and preventing the progression to end-stage liver disease [11]. Debilitating symptoms like arthralgia and fatigue accompanied by hepatic inflammation, serum AST elevation 10-fold upper normal limit or AST elevation 5-fold upper normal limit concurrent with -globulin level 2-fold upper normal limit, and histological findings of bridging necrosis are absolute indications for treatment [16]. Treatment regimens include prednisone alone or in conjunction with azathioprine, which is continued until normalization of transaminases and IgG is achieved and is further maintained depending on the individuals response and tolerance to therapy [2,11,16]. Considering the possibility of drug-induced hepatitis, our patient was instructed to stop the elderberry supplement and not to reuse it again. In addition, she was given immunosuppressive therapy to treat the significant hepatic inflammation as evidenced by severely elevated transaminases and liver biopsy. A four-week course of prednisone resulted in the resolution of symptoms and normalization of liver function tests. She was started on azathioprine maintenance therapy with a plan to potentially discontinue it after sustained remission for 18 months. Follow-up over time regarding the development of flare-ups, should they arise, will shed light on the subject of autoimmune hepatitis triggered by elderberry, as opposed to elderberry-induced hepatic injury. This could aid in recognizing the significance of using elderberry judiciously in patients with a history or predisposition to autoimmune disorders.

Exposure to elderberry could be responsible for either the initiation or progression of autoimmune liver disease in the setting of genetic predisposition and molecular mimicry. Therefore, obtaining a meticulous history pertaining to medications is warranted, with an emphasis on over-the-counter supplements. A combination of serum-specific antibodies and distinct histological features in the liver biopsy can aid in formulating a diagnosis, while an initial course of steroids along with indefinite immunosuppressive therapy is essential to control inflammation as well as avert relapses.

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A Plausible Association Between the Use of Elderberry and Autoimmune Hepatitis - Cureus

Introduction

Staphylococcus aureus (S. aureus), a major pathogen of healthcare-associated infections, causes many infectious diseases in hospital and community (eg, pneumonia, endocarditis, and bacteremia).1 Due to its well-known exotoxins and ability to form biofilms,2 the S. aureus infections are particularly difficult to treat. Furthermore, S. aureus rapidly develops resistance to the -lactams antibiotics via the acquisition of the staphylococcal chromosome cassette carrying mecA gene.35 The Methicillin-resistance S. aureus (MRSA) has become one of the most lethal pathogen in bacteremia. The case fatality rate of MRSA bacteremia has been reported to be up to 27.3%, with a mortality rate approximately 23 times higher than those infected with methicillin-susceptible S. aureus.6 Although vancomycin remains the most effective antibiotic currently, the treatment of MRSA infections is still challenging due to the dramatic increase in MRSA isolation and the limited clinical treatment options.7,8 Thus, there is a strong need to develop novel antibiotics for the treatment of MRSA.

Berberine (BER) is an isoquinoline quaternary alkaloid (5,6-dihydrodibenzo quinolizinium derivative) isolated from many medicinal plants, such as Hydrastis canadensis, Berberis aristata, Coptis chinensis, Coptis rhizome, Coptis japonica, Phellodendron amurense, and Phellodendron chinense schneid.9 BER is used to treat diarrhea and bowel disorders in China, with the potential to be used for the treatment of many diseases.10 Furthermore, BER has received extensive attention for its role as an antimicrobial,1113 antifungal,14 anti-tumor,15,16 and anti-diabetes drug.17 However, the anti-MRSA mechanism of BER is still unclear.

Therefore, the current study evaluated the effects of BER on MRSA using the minimum inhibitory concentration (MIC) and time-killing test. Moreover, the potential mechanism of BERs activities on MRSA, including biofilm formation, cell membrane integrity, and cell morphology variation were investigated. We also explored the synergistic effect of BER combined with rifampicin and clindamycin against MRSA in vitro.

Fifteen MRSA isolates were collected from blood cultures between March and September 2021 at Beijing Friendship Hospital, affiliated with the Capital Medical University of China. After collection, the bacteria were labeled AO and stored in skim milk at 80C for further use. Subsequently, American Type Culture Collection (ATCC) 43300 was selected as the control strain. Bacteria were routinely grown in a Columbia blood plate (Thermo Fisher Scientific, Waltham, MA, USA) at 37C for 18h unless otherwise specified.

The minimum inhibitory concentration (MIC) of each antibacterial agents is defined as the lowest concentration of the drug that resulted in no visible growth.18 Berberine (BER), clindamycin (CLI), and rifampicin (RIF) were acquired from the National Institutes for Food and Drug Control (Beijing, China). The MICs of BER were determined based on the agar dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI, PA, USA). Mueller-Hinton agar (MHA, OXOID) was mixed with BER in dishes, where the final concentration of BER was 1, 2, 4, 8, 16, 32, 64, 128, 256, 512, 1024, 2048 mg*L.1 The MICs of antibiotics, including RIF and CLI, against MRSA strains were determined using a standard broth microdilution method recommended by the CLSI.19 Cation adjusted Mueller-Hinton broth (CAMHB, OXOID) was mixed with RIF and CLI separately, where the final concentration of RIF and CLI was twofold series dilution concentration from 0.015625 to 2048 mg*L1 in triplicate. Then, the tested bacterial were spotted on the medium and incubated at 37C for 18h. All experiments were conducted at least three times on different days, and the most consistent results were presented.

MLST was determined by the PCR amplification of seven housekeeper genes (aro, arc, glp, gmk, pta, tpi, and yqi), according to the conditions published in https://pubmlst.org/. The PCR products were bidirectionally sequenced, and all sequences in the online database were analyzed to determine the allele number and respective ST types.

Checkerboard assays were used to determine the interactions between BER and antibiotics on the tested MRSA strains, as recommended by the CLSI guidelines. The concentration gradients of BER and antibiotics were selected based on the MICs. After MRSA cells were cultured in CAMHB medium with continuous shaking at 37C, the cells were grown to 0.5McF (1.5108 colony forming unit*mL1, CFU*mL1); then, the cultures were diluted 32-fold with sterile broth (approximately 5106CFU*mL1). Delivering 10L aliquots of cultures to 96-well plates containing 100L of two-fold diluted BER and antibiotics in cation-adjusted Mueller Hinton broth, where the final concentration of bacterial culture was approximately 5105 CFU*mL1.20 The plates were incubated for 18 h at 37C. Finally, each well was examined for signs of MRSA growth. For each interaction, the fractional inhibitory concentration (FIC) was calculated for each agent: synergism, antagonism, and indifference correlated with FIC 0.5, FIC > 4, and 0.5 < FIC 4, respectively.21

Growth kinetics were used to assess the antimicrobial effect of BER against MRSA and sensitization to other antibiotics.22 The tested MRSA strain was selected based on MLST types. The experiments were performed using CAMHB in 10mL with an initial inoculum of 5105 CFU/mL. The cultures were transferred to tubes with individual compounds and in combination (2 MIC, 1 MIC, 1/2 MIC, 1/4 MIC of BER, 1/8 MIC, 1/32 MIC of RIF, or 1/4 MIC of CLI) treated and incubated. The concentration of BER and antibiotics were chosen based on the MIC assay and synergistic effects assay. A kinetic growth or inactivation curve was constructed for each treatment using the viable cell counts performed at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24h of incubation at 37C. The cultures containing 1% DMSO and bacterial inoculum served as the bacterial DMSO control (DC) and growth control (GC) separately.

The effect of BER on MRSA biofilm formation was tested. Static biofilm formation assay was performed in 96-well microtiter plates, as previously reported.23 Delivering approximately 5105 CFU*mL1 of MRSA cells to 96-well plates containing diluted BER and antibiotics in brain heart infusion broth (BHI, OXIOD) supplemented with 0.5% glucose.21 Wells containing only the BHI were used as the negative control, whereas wells containing bacteria grown in BHI were used as the positive control. The suspension was transferred to 96-well plates with individual compounds and combinations (4 MIC, 2 MIC, 1 MIC, 1/2 MIC, 1/4 MIC of BER, 1/16 MIC, 1/32 MIC of RIF, or 1/4 MIC of CLI) treated and incubated for 18 h at 37C. The concentrations of BER, RIF, and CLI were selected based on the previous MIC assays and synergistic effects assays. The tested MRSA strain was selected based on the MLST types, consistent with kinetics assay. After incubation, each well was washed three times with PBS to remove the planktonic cells, fixed for 15 min with methanol to stabilize biofilm, stained for 5 min with crystal violet (0.5% in methanol), and washed two times again with deionized water. The adhering dye was dissolved in 200L of 33% acetic acid and the absorbance was measured at OD600 to quantify biofilm formation.

Cell membrane permeability of MRSA cells was assessed by confocal laser scanning microscopy (CLSM) (TCS-SP5, Leica, GER), similar to the previous description.24 To test membrane integrity, fluorescence images were acquired using fluorochrome, which were carboxyfluorescein diacetate (CFDA SE; Sigma-Aldrich, St. Louis, MO, USA) and propidium iodide (PI; Sigma-Aldrich, St. Louis, MO, USA) at final concentrations of 10 mmol*L1 and 5 mg*L1, separately. CFDA SE is a nonfluorescent precursor that only passing through intact cell membranes, producing a fluorescent compound. When the cell membrane is damaged, PI can enter the cells and bind to the DNA to form a red fluorescent DNA-complex.25 S. aureus are gram-positive cocci with a cytoderm structure. However, cytomembrane was essential to maintain cell function and prevent cytoplasmic leakage. Fluorescent staining was used to examine cell membrane integrity as previously reported.24 After MRSA cells were grown to an approximately 1.5108CFU*mL1 in CAMHB at 37C, delivering 10 mL of volume cultures to tubes. Then, the cells were treated with BER at 0 MIC, 1 MIC, or 2 MIC for 4 h, centrifuged at 5000g for 5 min, and resuspended with equivalent volumes of 0.9% NaCl. After incubation with cFDA SE for 15 min and PI for 1 min at room temperature away from light, the suspension was fixed on a glass slide using agar. Finally, the bacteria were examined by confocal laser scanning microscopy (CLSM, OLYMPUS, FV1000, Japan) at the excitation-emission wavelengths of 530nm for PI and 488nm for CFDA SE.

Field emission scanning electron microscopy (FESEM, Joel JSM-7900F, Japan) was used to detect morphological changes after BER treatment, according to the published protocols.26 Subsequently, approximately 1.5108CFU*mL1 of MRSA cells were incubated in CAMHB of 10mL volume supplemented with BER at 0 MIC, 1 MIC, 2 MIC, and 4 MIC for 4 h at 37C. The treated cells were washed with PBS three times and fixed with 2.5% glutaraldehyde for 4 h and 1% osmic acid for 2 h. Then, the cells were washed with PBS again. After dehydrating with different concentrations of ethanol, the cells were fixed on silicon slices, sputter-coated with gold under vacuum, and observed using FESEM.

Assays were conducted with at least two biological replications. The KruskalWallis analysis was used to determine the differences between the multiple groups. Data are expressed as mean SD, and p-values <0.05 are considered statistically significant. No adjustments were made for the p-values reported in this study.

The MLST determination showed 15 MRSA clinical isolates and distinguished them into five subtypes. The MIC values of BER varying from 256 to 64 mg*L1 (Table 1); however, among ST5 subtypes, only one strain had a MIC significantly different from the others (ie, >2048 mg*L1). Excluding this strain, the highest MIC value was 256 mg*L1 for ATCC 43300, and the lowest MIC value was 64 mg*L1 for ST239 and ST5. Six clinical isolates were resistant to CLI, and eight strains were susceptible, whereas 11 isolates were resistant to RIF, and three isolates were susceptible. The MRSA control strain was resistant to CLI at MIC of 1024 mg*L1 and susceptible to RIF at MIC of 0.06 mg*L1 (Table 2). Using the checkerboard assay, BER in combination with RIF and CLI showed a significant effect against the MRSA strain, leading to a reduction in MIC values. Synergistic activity was observed for the combination of BER with CLI or RIF with FIC index values of 0.190.5 (Table 2). However, two isolates showed indifferent effects compared to others when BER was combined with CLI, and one isolate showed indifferent effects when BER was combined with RIF (Table 3).

Table 1 The MIC Value of Berberine Among Different MLST Types of MRSA

Table 2 MIC and FIC Index of CLI and RIF in the Presence of BER Against MRSA Strains

Table 3 The Antibacterial Activity of BER in Combination with CLI and RIF Against MRSA Strains (%, n/N)

The time-killing curves for BER alone and in combination with RIF or CLI against ATCC 43300 (control strain) and clinical isolate ST239 are presented in Figure 1. Growth cultures without BER treatment increased to 7lg (CFU*mL1) for the control strain and 9lg (CFU*mL1) at ST239 after 24 h of incubation. The DMSO control group showed similar results to the growth cultures, suggesting that DMSO does not affect the growth of cells. Furthermore, BER at its MIC value showed dramatic inhibition of bacterial growth during 24 h of incubation, and showed stronger inhibition at 2 MIC than at MIC after 12 h of incubation with similar bacterial growth compared to that at MIC after 24 h of incubation (reduction of 2lg (CFU*mL1) and 1lg (CFU*mL1) for ATCC 43300 and ST239, separately). BER at sub-MIC had a weak effect on the growth of the MRSA strain over 24 h; however, bacterial growth was positive (Figure 1A and D). Importantly, the combination of BER with CLI showed a synergistic effect against the MRSA control strain and clinical isolate ST239 with ~2lg (CFU*mL1) killing compared to the single drug applied during 24 h (Figure 1B and E). In addition, the combination of BER with RIF showed more remarkable synergistic effects against MRSA than those of BER and CLI. As such, the combination of BER with RIF resulted in a > 2L g (CFU*mL1) inhibition compared to the combination of BER with CLI at 24 h (Figure 1C and F).

Figure 1 The time-killing curves for BER alone and in combination with RIF or CLI against MRSA strains; (AC): Control (DF): ST239. The data are the mean SD of colony counts at least two biological replicates in each group.

According to the assay of biofilm formation, BER possessed an excellent inhibitory effect on the biofilm in a dose-dependent manner, especially at the MIC or higher concentrations, which was more prominent than that of the sub-MIC and control groups. Interestingly, biofilm formation sharply increased at sub-MIC in the ST 239 strain (Figure 2). In addition, the combination of BER with RIF or CLI at sub-MIC significantly inhibited biofilm formation compared to each drug separately in the control strain and clinical isolate (Figure 3). The percentages of biofilm reduction, which were compared with positive control in each group, are presented at Table 4.

Table 4 The Percentage of Biofilm Formation Inhibited

Figure 2 The effects of BER alone on biofilm formation of MRSA strains. (A) Control (B) ST 239; relative biofilm formation levels were represented as meanSD of at least two biological replicates; significant difference was determined at P < 0.0001 with comparison between the groups.

Figure 3 The effects of BER in combination with RIF or CLI on biofilm formation of MRSA strains. (A and B): Control (C and D): ST 239; relative biofilm formation levels were represented as meanSD of at least two biological replicates; significant difference was determined at P < 0.0001 with comparison between the groups.

According to the images, untreated MRSA cells emitted green fluorescence, showing that the cell membrane was intact. Conversely, BER-treated MRSA appeared red and the proportion of red fluorescence increased with increasing BER concentrations, suggesting a damaged cell membrane (Figure 4). Meanwhile, the total number of cells declined after BER treatment, and the reduction was proportional to the BER concentration.

Figure 4 The effect of BER on cell membrane integrity of MRSA strain by confocal laser scanning microscopy.

The FESEM images illustrated significant changes in the morphology of MRSA cells with BER (Figure 5) at low magnification (10,00015,000) and high magnification (45,00050,000). Untreated control S. aureus exhibited arrangement in clusters and smooth surface and spherical contour at 10,000 and 50,000, separately (Figure 5A and E). However, the number of MRSA cells in the field of vision decreased and the morphology of the clusters was changed with increasing BER concentrations (Figure 5BD). Remarkably, numerous flocculent substances were adhering to the cells that were not significantly cleaned by PBS. These flocculent substances increased with the increase in BER concentration compared to the untreated control. Furthermore, the cells were less uniform in size and had a rough surface (50,000) compared to the untreated cells. When treated with MIC or higher concentrations of BER, the cell morphology exhibited shrinkage and deformation (Figure 5F); some cells even had a defective and punched surface, suggesting that the content was released (Figure 5G and H).

Figure 5 The changes in the morphology of MRSA cells with BER by field emission scanning electron microscope. (A and E): 0MIC; (B and F): 1MIC; (C and G): 2MIC; (D and H): 4MIC. Shown by the arrow is flocculent substances.

The dramatic increase and global spread of MRSA strains pose a serious threat to human health since it was first identified in 1960.27 Vancomycin and daptomycin are recommended as the first-line antibiotics by the 2011 Infectious Diseases Society of America guidelines for MRSA.28 However, each antimicrobial agent has limitations29 related to its effectiveness against bacteria30 or its increasing resistance.31,32 What is more, the emergence of vancomycin-resistant S. aureus leaves physicians with limited therapeutic options. Therefore, there is an urgent need in the development of new therapeutics to aid in the treatment of infectious diseases caused by MRSA. BER, an alkaloid extracted from a traditional Chinese herb, has emerged as a promising antibacterial agent.

In the current study, we observed that BER had anti-MRSA activities at MIC of 64256 mg*L1, which related to the subtype of MRSA strains. As previously reported, subtype strains within the same bacterial species may have different clinical uses.2 In this study, 15 strains were divided into five subtypes. We found that the MIC value of BER differed among various MLST types, and many strains showed diverse BER MIC values even in the same subtype. The MIC showed three values for ST5 and two values for ST239, unlike what has been reported in previous studies.2 In this study, a subtype was matched with a MIC value. However, the MIC value of ST239 and ST39 in our study which was 64 or 128 mg*L1 and 256mg*L1, was different with this study (64 mg*L1 and 512 mg*L1).2 Therefore, we recommend that the types of MLST should be expanded to verify the results.

In the current investigation, a synergistic effect of BER with CLI and RIF was observed against MRSA. As such, BER can markedly reduce the MIC value of antibacterial agents against MRSA. A synergistic effect of BER has also been reported in combination with oxacillin,33 azithromycin,34 and levofloxacin,34 whereas an additive effect has been reported for BER in combination with ampicillin33,34 and cefazolin.34 This study is the first one to report the synergistic effects of BER in combination with CLI and RIF.

The time-killing assays showed similar results. The time-killing test of the control strains, the strain ST239 for BER alone, and the combination of BER with CLI or RIF separately showed significant growth inhibition. The inhibition of growth by BER alone strengthened with the increasing concentration. Notably, the test strain ST239 and the control strain showed attenuation of inhibition with the increase in curve after 12 h, suggesting that BER alone may not kill all the cells, but it maintains the bacteria at low levels when the BER gradually expands. When this occurs, the remaining cells are reduced, which is similar to the results of a previous study on the antimicrobial activity of a Chinese herb.35 Therefore, there is a significant effect of BER concentration on its antimicrobial activity, suggesting that BER must maintain a persistently high blood concentration. In addition, the combined treatment resulted in obvious reduction in the cell quantity within 824 h of incubation in the control strain and 1024 h of incubation in ST239, compared to CLI or RIF separately. These results suggest that BER has excellent anti-MRSA activity, which is enhanced when combined with other antibiotics, such as CLI and RIF.33,34,3639

Biofilm formation plays an essential role in the persistence of pathogens.34,40 Biofilms harbor bacteria that are irreversibly attached to cell surfaces and prevent antibiotic exposure.41 In light of this, BER showed excellent inhibition of biofilm formation with increasing concentrations, similar to previous studies.2,42 However, biofilm formation increased at sub-MIC in the ST 239 strain in our study, similar to other studies.2 The concentration of BER cannot increase slowly when treating MRSA infections, because low concentration of BER may promote biofilm formation. Importantly, BER, in combination with CLI or RIF separately, also inhibited biofilm formation better than either drug alone. These data are consistent with previous studies that suggest the existence of synergistic effects of BER with those of CLI and RIF against MRSA. Therefore, antibacterial activity and anti-biofilm formation character of BER can be used as the basis of clinical practice and the synergistic effect of BER with CLI and RIF can be used as the alternative treatment when the bacterial infection was difficult to treat. However, the specific mechanism underlying the effects of BER in combination with CLI or RIF separately remains unclear and should be explored in future studies.

Morphological analysis was used to explore the mechanism of the BER effect against MRSA. In the current study, we observed cell wall alteration and its punched appearance due to BER exposure at high magnification. Flocculent substances were observed to adhere to the cells. Zhang et al found that BER could damage the cell surface of MRSA.43 Therefore, it is reasonable to speculate that the substances may include the contents of punched bacterial cells due to BER treatment. This observation is consistent with the above findings, illustrating that BER can destroy MRSA cell walls in a concentration-dependent manner.

The cytoplasmic membrane is an important dynamic structure that allows cells to interact with other cells and environmental molecules.44 While the cytoplasmic membrane integrity of MRSA has not been studied previously, the function of the gram-positive bacterial membrane is essential for subsisting membrane proteins and transportation.45 As assessed by CLSM, our results showed that the integrity of the MRSA cytoplasmic membrane was compromised at increased BER concentrations. This finding showed that BER possessed anti-MRSA activities by damaging the cell wall and cytoplasmic membrane to perturb cell functions and release intracellular contents. Although BER could exert an influence on the cell wall and cytoplasmic membrane, the mechanism here is unclear and needs to be investigated further. Meanwhile, combination antibacterial assays would verify the hypothesis that BER could damage the cytoderm and cytoplasmic membrane to kill MRSA. Because CLI and RIF play antibacterial roles inside the cells,46,47 they may easily enter the cells in the presence of BER.

The current study demonstrated that BER has remarkable antimicrobial effects against MRSA with favorable MIC. It can also be used as an adjuvant to RIF or CLI to treat MRSA infections. BER alone and in combination with RIF or CLI reduces biofilm formation. In addition, BER significantly damages the cell wall and membrane of MRSA to kill the bacteria. This study provides novel mechanistic insight into supporting the development of BER as an antibacterial drug.

The datasets generated for this study are available from the corresponding author Miaorong Xie.

This study was approved by the Ethics Committee of Beijing Friendship hospital, Capital Medical University (20210208). Adult patients wrote the informed consent and a parent or legal guidance of patients under 18 years of age provided informed consent prior to the experiment described below. This study was conducted in accordance with the Declaration of Helsinki.

We thank Wei-dong Qian from Shaanxi University of Science and Technology providing the experimental consults.

This work was supported by the National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology (YFC1702605).

The authors declare no conflicts of interest for this study.

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In vitro antimicrobial activity and mechanism of berberine | IDR - Dove Medical Press

The National Comprehensive Cancer Network has announced their recommendation for the use of pacritinib in the first line and second line setting for treating patients with myeloproliferative neoplasms.

The novel kinase inhibitor pacritinib (Vonjo) was added to the latest National Comprehensive Cancer Network (NCCN) guidelines as a recommended treatment for patients with myeloproliferative neoplasms (MPN), according to a press release.1

"We are grateful that the NCCN acted quickly to include (pacritinib) with a Category 2A designation in its Clinical Practice Guidelines in Oncology as a first line treatment for high-risk patients with myelofibrosis with platelet counts less than 50 x 109/L who are not candidates for transplant, said Adam R. Craig, MD, PhD, president, and chief executive officer of CTI BioPharma, in a statement. This therapeutic option helps address an unmet medical need for patients who previously have no other treatment options. There is no other FDA-approved first line treatment for these patients with a 2A designation within the NCCN guidelines.

Pacritinib was approved by the FDA earlier this year for the treatment of patients with myelofibrosis and severe thrombocytopenia, defined as a platelet count less than 50x109/L. In addition to this designation from the FDA, the NCCN has recommended pacritinib as a second-line treatment in low-risk and high-risk patients with myelofibrosis who have a platelet count greater than 50 x 109/L who are also not candidates for transplant. According to Craig, this will allow for even more treatment options in patients with MPNs.

The JAK family of enzymes promotes normal blood cell growth in patients because JAK is central component in signal transaction pathways, meaning that there is a direct relationship between mutations in these pathways and the development of hematological cancers like MPNs. Thus, allowing pacritinib to impact the development of the disease.

In the US, there are approximately 21,000 patients with myelofibrosis, two-thirds of which have cytopenias (thrombocytopenia or anemia), commonly resulting from the toxicity of other approved therapies, Craig said in a press release when announcing the FDA approval of pacritinib.2 Severe thrombocytopenia, defined as a blood platelet count below 50 109/L, occurs in one-third of the overall myelofibrosis population, and has a particularly poor prognosis.

Results from the phase 3 PERSIST-1 (NCT01773187), phase 3 PERSIST-2 (NCT02055781), and phase2 dose-finding PAC203 trial led to the initial approval, and now recommendation by the NCCN, for the use of pacritinib in multiple lines of therapy for patients with MPNs. These findings demonstrated that the kinase inhibitor, with specificity for inhibiting JAK2 and IRAK1 without inhibiting JAK1, was associated with better outcomes in patients in comparison to the best available therapy.

After the PERSIST-1 trial met its primary endpoint at week 24 of the study when 19% of patients on pacritinib had a spleen reduction size by 35% or more compared to 5% in the control group, 311 patients enrolled in the PERSIST-2 trial saw better results on pacritinib given twice a day.3 Eighteen percent of patients in the twice daily pacritinib arm of the trial had a spleen reduction of 35% or greater vs 3% in the best available therapy arm.4

The most common adverse events (AEs) observed on twice-daily pacritinib at 200 mg, seen in 20% or more of paitents, was diarrhea, thrombocytopenia, nausea, anemia and peripheral edema. Serious AEs seen in 3% or more of patients on the same regimen were anemia, thrombocytopenia, pneumonia, cardiac failure, disease progression, pyrexia, and squamous cell carcinoma of skin.

The approval of pacritinib establishes a new standard of care for myelofibrosis patients suffering from cytopenic myelofibrosis," said John Mascarenhas, MD, associate professor, Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, in a press release on the approval of the drug. "Myelofibrosis with severe thrombocytopenia, defined as blood platelet counts below 50 109/L, has been shown to result in poor survival outcomes coupled with debilitating symptoms. Limited treatment options have rendered this disease an area of urgent unmet medical need."

References

1. NCCN Guidelines Recommend VONJO (pacritinib) for the Treatment of Myeloproliferative Neoplasms. CTI BioPharma Corp. News release. April 14, 2022. Accessed April 14, 2022. https://prn.to/3EiDaN0

2. CTI BioPharma announces FDA accelerated approval of VONJO (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. CTI BioPharma Corp. News release. February 28, 2022. Accessed April 14, 2022. https://bit.ly/3vsDPsO

3. Mesa R, Vannuchhi A, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. The Lan. Hem. Published: March 20, 2017. doi: https://doi.org/10.1016/S2352-3026(17)30027-3

4. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2018;4(5):652659. doi:10.1001/jamaoncol.2017.5818

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Pacritinib Added to NCCN Recommendation for Treatment in MPNs - Targeted Oncology

The study, published in the journal Nature Aging, lays the ground for research that explores the possibility of translating the findings into humans.

People have traditionally thought of aging as an inevitable part of life. But since the seminal work of Cynthia Kenyon in the 90s, researchers have also become aware that aging is under genetic control.

Scientists continue to be interested in finding out whether the negative effects of aging can be reduced or reversed entirely.

Currently, 16% of the United States population is 65 years or older. By 2050 this is expected to reach 22%.

The Centers for Disease Control and Prevention (CDC) note that aging increases a persons risk of various serious chronic illnesses, such as cancer, dementia, type 2 diabetes, and heart disease.

The National Institute on Aging points out that there are various things a person can do to help reduce the effects of aging.

These include staying physically active, eating a healthy diet with lots of vegetables, fruit, and whole grains, getting a good amount of quality sleep, avoiding smoking and drinking alcohol, and regularly seeing a doctor.

In 2020 the World Health Organization (WHO) published a baseline report for the Decade of Healthy Ageing, highlighting how countries can go about ensuring health and well-being as people age.

Dr. Tedros Adhanom Ghebreyesus, WHO Director-General, says that humans now live longer than at any time in history. But adding more years to life can be a mixed blessing if it is not accompanied by adding more life to years.

The Baseline Report for the Decade of Healthy Ageing has the potential to transform the way policy-makers and multiple service providers engage with older adults. We have to work together, to foster the abilities and well-being of our older generations, who continue to give us so much.

As well as lifestyle and policy changes, scientists are also exploring whether new types of medical interventions could reduce the physiological effects of aging.

The authors behind the present study have previously found that epigenetic markers in mice could be reprogrammed using the molecules Oct4, Sox2, Klf4, and cMyc. These molecules, known as Yamanaka factors, increased the lifespan and reduced the effects of aging in mice with premature aging.

Medical News Today spoke with Prof. Juan Carlos Izpisua Belmonte, of the Gene Expression Laboratory at the Salk Institute for Biological Studies, San Diego, CA, and a corresponding author of the present study.

In the 2016 paper, we developed a protocol and showed for the first time that Yamanaka factors could be expressed in mice safely without generating cancer. Moreover, in our previous study, we used a premature aging mouse model to demonstrate that Yamanaka factors can extend the lifespan of these mice by preventing the accumulation of aging phenotypes in cells and tissues.

However, we did not know if expressing the Yamanaka factors for an extended period of time in animals without any preexisting pathologies will work and whether it would be safe. The goal of the current study was to establish whether long-term partial reprogramming would have a positive or negative impact on a wild-type animals health, said Prof. Izpisua Belmonte.

To do this, Prof. Izpisua Belmonte and his colleagues split the mice into three groups. The first group received Yamanaka factors from 15 to 22 months or around 50 to 70 years in human terms.

The second group received the Yamanaka factors from 12 to 22 months or 35 to 70 in human years.

The third group was treated for a single month at 25 months or 80 years in human terms.

The researchers found that compared with mice that acted as a control, the mice who received the Yamanaka factors did not develop cancer or see any blood cell or neurological changes.

Further, the mice that received the Yamanaka factors for a number of months showed various reversals in the effects of aging.

The kidneys and skin of the mice resembled those of younger mice, their skin healed from wounds without producing as much scarring, and the scientists did not observe the usual metabolic changes in the blood typically seen in older animals.

The animals treated for just a single month late in life did not see these effects.

Prof. Izpisua Belmonte said there were still necessary steps before the research could be tested in humans.

The translation of our approach to humans requires developing ways to deliver the factors and controlling the levels and how long the factors are expressed. These steps will allow [us] to demonstrate the safe delivery of the factors, a critical aspect before we could start thinking in clinical trials.

Nonetheless, the findings provide exciting evidence that the technique could have benefits far beyond the reversal of the effects of aging.

After our initial 2016 study, our lab, as well as several other laboratories around the world, have used the same approach to demonstrate improvement in the regeneration of different tissues in mice and rejuvenation of human cells.

All these studies further prove that the controlled expression of Yamanaka factors for cell reprogramming could benefit diverse conditions and might be a general medicine approach in the future for various complications that arise during life, said Prof. Izpisua Belmonte.

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