Sodium Selenite Improves The Therapeutic Effect Of BMSCs Via Promoting | OTT – Dove Medical Press

Dongmei Yan,1,* Botao Tang,2,* Lixin Yan,3 Lei Zhang,1 Meijuan Miao,1 Xi Chen,4 Guangyi Sui,5 Qi Zhang,1 Daoyuan Liu,1 Hui Wang1

1Department of Blood Transfusion, The Second Affiliated Hospital of Harbin Medical University, Harbin, Peoples Republic of China; 2Department of Cardiology, Heilongjiang Red Cross Hospital, Harbin, Peoples Republic of China; 3Department of Laboratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Peoples Republic of China; 4Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Peoples Republic of China; 5Ethics Committee, The Tumor Hospital Affiliated to Harbin Medical University, Harbin, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Hui WangDepartment of Blood Transfusion, The Second Affiliated Hospital, Harbin Medical University, Xuefu Road No. 246, Nangang District, Harbin, Heilongjiang Province, Peoples Republic of ChinaTel +86-451-86605134Email wanghui@hrbmu.edu.cn

Purpose: Sodium selenite (Na2SeO3) has been known to restore the antioxidant capacity of bone marrow mesenchymal stem cells (BMSCs), reduce the production of reactive oxygen species (ROS) in the cells, and promote cell proliferation and inhibit cell apoptosis. However, it is still not clear whether selenium can mediate the differentiation and inhibit the induced hemagglutination of BMSCs. In this study, we attempted to explore the effect of Na2SeO3 on these aspects of BMSCs.Methods: We evaluated the fate of the MSCs isolated from the bone marrow of mice by studying their differentiation and proliferation after treatment with Na2SeO3. We also simultaneously evaluated the coagulation reaction induced by Na2SeO3-treated BMSCs in vitro.Results: While the mice-derived BMSCs expressed CD44, CD73, CD90, and CD105, they did not express CD45. The morphology of the derived cells was homogeneously elongated. These results showed that the isolated cells are indeed BMSCs. We found that 0.1 M and 1 M of Na2SeO3 promoted the proliferation and apoptosis of BMSCs, respectively. This showed that Na2SeO3 can be toxic and exert certain side effects on the BMSCs. The results of the osteogenic and adipogenic assay showed that 0.1 M Na2SeO3 could significantly promote the osteogenic and adipogenic differentiation of BMSCs by upregulating the lipid factors (LPL and PPRAG) and osteogenic factors, RUNX2, COL1, and BGP, in a concentration-dependent manner. Coagulation experiments in animals (mice and rats) revealed that Na2SeO3 can reduce the coagulation time of BMSCs in a concentration-dependent manner, which is related to the high expression of hematopoietic factors (SDF-1, GM-CSF, IL-7, IL-8, IL-11, and SCF).Conclusion: Na2SeO3 promotes the proliferation and differentiation as well as reduces the coagulation time of BMSCs, and this effect might enhance the therapeutic effect of BMSCs.

Keywords: sodium selenite, BMSCs, proliferation, differentiation, coagulation factors, clotting time

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Sodium Selenite Improves The Therapeutic Effect Of BMSCs Via Promoting | OTT - Dove Medical Press

US FDA Grants BeiGene’s BRUKINSA (zanubrutinib) Accelerated Approval to Treat Adult Patients with Mantle Cell Lymphoma Who Received at Least One Prior…

CAMBRIDGE, Mass. and BEIJING, China, Nov. 14, 2019 (GLOBE NEWSWIRE) -- BeiGene Co.,Ltd (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, today announced that BRUKINSA (zanubrutinib) has received accelerated approval from the United States Food and Drug Administration (FDA) as a treatment for mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy.1 BRUKINSA is the first BeiGene-discovered product to be approved, an important milestone toward the companys goal of transforming treatment for cancer patients around the world.

This accelerated approval is based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

We are working to improve outcomes for people with cancer worldwide and this approval brings us closer to realizing our mission of bringing the highest quality therapies to patients globally, said John V. Oyler, Chairman, Co-Founder, and CEO of BeiGene. Todays FDA approval of BRUKINSA, following the previously granted Breakthrough Therapy designation in this indication, validates it as an important treatment option for people with relapsed or refractory MCL. We hope this is the first of many approvals for BRUKINSA as we continue to evaluate its potential in other hematologic cancers.

BRUKINSA is a BTK inhibitor that was designed to maximize target occupancy and minimize off-target binding. It entered the clinic in 2014 and since that time our broad development program has enrolled more than 1,600 patients globally, said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. Todays accelerated approval is the culmination of many years of effort by the BeiGene team, the dedicated investigators involved in these trials and, most importantly, the patients who participated by enrolling in the clinical trials. We are humbled by the opportunity to develop this therapy and launch it as our first internally discovered and approved cancer treatment.

BTK inhibition is an established mode of treatment for patients with MCL, but many patients treated with previously approved BTK inhibitors do not fully respond to BTK therapy or are forced to discontinue treatment early due to side effects. Today we have a new option for our adult patients who have received one prior systemic or targeted therapy and are living with MCL, an aggressive blood cancer thats often diagnosed at a more advanced stage, said Luhua (Michael) Wang, M.D., Professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, and clinical trial investigator.

The approval of BRUKINSA as a second line therapy represents an important advancement for the treatment of mantle cell lymphoma, said Meghan Gutierrez, Chief Executive Officer for the Lymphoma Research Foundation. Expanded treatment options can transform the patient experience and provide hope to people living with a mantle cell diagnosis.

The FDAs approval of BRUKINSA is based on efficacy results from two single-arm clinical trials, with independent review committee (IRC)-assessed ORR per 2014 Lugano Classification as the primary endpoint. Across both trials, BRUKINSA achieved an ORR, which is the sum of complete responses and partial responses, of 84%.

In the multicenter Phase 2 trial of zanubrutinib in patients with relapsed or refractory (R/R) MCL BGB-3111-206 (NCT03206970), the ORR was 84% (95% CI: 74%, 91%), including 59% complete response (FDG-PET scan required) and 24% partial response. In this study, the median duration of response (DOR) was 19.5 months (95%CI: 16.6, NE) and median follow-up time on study was 18.4 months. In the global Phase 1/2 trial BGB-3111-AU-003 (NCT02343120), the ORR was 84% (95% CI: 67%, 95%), including 22% complete response (FDG-PET scan not required) and 62% partial response. In this study, the median DOR was 18.5 months1 (95% CI:12.6, NE) and median follow-up time on study was 18.8 months.

The most common adverse reactions (> 10%) with BRUKINSA were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, cough, musculoskeletal pain, pneumonia, urinary tract infection, blood in the urine (hematuria), fatigue, constipation, and hemorrhage. The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Of the 118 patients with MCL treated with BRUKINSA, eight (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

The recommended dose of BRUKINSA is 320 mg, taken orally 160 mg twice daily or 320 mg once daily with or without food. The dose may be adjusted for adverse reactions, and reduced for patients with severe hepatic impairment and certain drug interactions.1

BRUKINSA is expected to be available to people in the United States in the coming weeks.

myBeiGene Patient Support Program

BeiGene is committed to ensuring that people have access to the medicine and the support needed to have the best possible outcomes and experiences. Coinciding with todays approval, BeiGene is launching myBeiGene in the United States to support patients, caregivers, and healthcare providers with access to BRUKINSA. The myBeiGene program goes beyond financial assistance support to provide patients and caregivers with education about their disease and treatment with BRUKINSA, as well provide practical and emotional support by connecting them to third-party resources that can address their individual unique needs. For more information on myBeiGene, please call 1-833-234-4363 or visit BRUKINSA.com.

About Mantle Cell Lymphoma (MCL)

Lymphoma is a diverse group of cancers that originate from B-, T- or NK- cells. MCL is typically an aggressive form of non-Hodgkins lymphoma (NHL) that arises from B-cells originating in the mantle zone.2 Inthe United States, about 74,200 people will be diagnosed with NHLin 2019,3 with MCL representing about six percent (about 4,452 cases) of all new cases ofNHL.2 MCL usually has a poor prognosis, with a median survival of three to four years,4 and it often diagnosed at a later stage of disease.

About BRUKINSA (zanubrutinib)

BRUKINSA is a small molecule inhibitor of Brutons tyrosine kinase (BTK), discovered by BeiGene scientists, that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. BRUKINSA was approved by the U.S. FDA to treat adult patients with MCL who have received at least one prior therapy on November 14, 2019.

New Drug Applications (NDAs) in China for relapsed refractory (R/R) MCL and R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been accepted by the China National Medical Products Administration (NMPA) and granted priority review and are pending approval.

BRUKINSA is not approved for use outside the United States.

IMPORTANT SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%) and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Drug Interactions

CYP3A Inhibitors:When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers:Avoid coadministration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

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

Please see fullPrescribing Information at beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at beigene.com/PDF/BRUKINSAUSPPI.pdf

About the Zanubrutinib Clinical Trial Program

Clinical trials of zanubrutinib include:

About BeiGene

BeiGene is a global, commercial-stage, research-based biotechnology company focused on molecularly-targeted and immuno-oncology cancer therapeutics. With a team of over 3,000 employees in the United States, China, Australia, and Europe; BeiGene is advancing a pipeline consisting of novel oral small molecules and monoclonal antibodies for cancer. BeiGene is also working to create combination solutions aimed to have both a meaningful and lasting impact on cancer patients. In the United States, BeiGene markets and distributes BRUKINSA (zanubrutinib) and in China, the Company markets ABRAXANE (nanoparticle albuminbound paclitaxel), REVLIMID (lenalidomide), and VIDAZA (azacitidine) under a license from Celgene Corporation.5

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding BeiGenes plans and expectations for the commercialization of BRUKINSA, the potential implications of clinical data for patients, BeiGenes further advancement of, and anticipated clinical development, regulatory milestones and commercialization of BRUKINSA. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeiGene's ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; BeiGene's ability to achieve commercial success for its marketed products and drug candidates, if approved; BeiGene's ability to obtain and maintain protection of intellectual property for its technology and drugs; BeiGene's reliance on third parties to conduct drug development, manufacturing and other services; BeiGenes limited operating history and BeiGene's ability to obtain additional funding for operations and to complete the development and commercialization of its drug candidates, as well as those risks more fully discussed in the section entitled Risk Factors in BeiGenes most recent quarterly report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in BeiGene's subsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeiGene undertakes no duty to update such information unless required by law.

Investor Contact

Craig West

+1 857-302-5189

ir@beigene.com

Media Contact

Liza Heapes or Vivian Ni

+1 857-302-5663 or +1 857-302-7596

media@beigene.com

_________________________________________

1 BRUKINSA (zanubrutinib) Prescribing Information. beigene.com/PDF/BRUKINSAUSPI.pdf. BeiGene, Ltd; November 14, 2019.

2 https://www.lls.org/sites/default/files/file_assets/FS4_MCL_Facts_2018-final.pdf

3 https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html

4 Philip J. Bierman,James O. Armitage, in Goldman'sCecil Medicine(Twenty Fourth Edition), 2012.

5 ABRAXANE, REVLIMID and VIDAZA are registered trademarks of Celgene Corporation.

Photos accompanying this announcement are available at:

https://www.globenewswire.com/NewsRoom/AttachmentNg/f728ceea-0c2b-4042-a937-e6b1638b4323

https://www.globenewswire.com/NewsRoom/AttachmentNg/5e5fe145-2754-4389-b9b9-b23a3731d03e

PDFsaccompanying this announcement are available at:

http://ml.globenewswire.com/Resource/Download/aca04555-626d-4c35-821b-957abaab640c

http://ml.globenewswire.com/Resource/Download/c47ea153-ba25-4dd1-8155-937b64fdf4b7

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US FDA Grants BeiGene's BRUKINSA (zanubrutinib) Accelerated Approval to Treat Adult Patients with Mantle Cell Lymphoma Who Received at Least One Prior...

CRISPR’s unwanted anniversary – Science Magazine

PHOTO: BARBARA RIES FOR UCSF

There are key moments in the history of every disruptive technology that can make or break its public perception and acceptance. For CRISPR-based genome editing, such a moment occurred 1 year agoan unsettling push into an era that will test how society decides to use this revolutionary technology.

In November 2018, at the Second International Summit on Human Genome Editing in Hong Kong, scientist He Jiankui announced that he had broken the basic medical mantra of do no harm by using CRISPR-Cas9 to edit the genomes of two human embryos in the hope of protecting the twin girls from HIV. His risky and medically unnecessary work stunned the world and defied prior calls by my colleagues and me, and by the U.S. National Academies of Sciences and of Medicine, for an effective moratorium on human germline editing. It was a shocking reminder of the scientific and ethical challenges raised by this powerful technology. Once the details of He's work were revealed, it became clear that although human embryo editing is relatively easy to achieve, it is difficult to do well and with responsibility for lifelong health outcomes.

It is encouraging that scientists around the globe responded by opening a deeper public conversation about how to establish stronger safeguards and build a viable path toward transparency and responsible use of CRISPR technology. In the year since He's announcement, some scientists have called for a global but temporary moratorium on heritable human genome editing. However, I believe that moratoria are no longer strong enough countermeasures and instead, stakeholders must engage in thoughtfully crafting regulations of the technology without stifling it. In this vein, the World Health Organization (WHO) is pushing government regulators to engage, lead, and act. In July, WHO issued a statement requesting that regulatory agencies in all countries disallow any human germline editing experiments in the clinic and in August, announced the first steps in establishing a registry for future such studies. These directives from a global health authority now make it difficult for anyone to claim that they did not know or were somehow operating within published guidelines. On the heels of WHO, an International Commission on the Clinical Use of Human Germline Genome Editing convened its first meeting to identify the scientific, medical, and ethical requirements to consider when assessing potential clinical applications of human germline genome editing. The U.S. National Academy of Medicine, the U.S. National Academy of Sciences, and the Royal Society of the United Kingdom lead this commission, with the participation of science and medical academies from around the world. Already this week, the commission held a follow-up meeting, reflecting the urgent nature of their mission.

Where is CRISPR technology headed? Since 2012, it has transformed basic research, drug development, diagnostics, agriculture, and synthetic biology. Future CRISPR-based discoveries will depend on increased knowledge of genomes and safe and effective methods of CRISPR delivery into cells. There needs to be more discussion about prioritizing where the technology will have the most impact as well as equitable, affordable access to its products. As for medical breakthroughs, clinical trials using CRISPR are already underway for patients with cancer, sickle cell disease, and eye diseases. These and many other future uses of genome editing will involve somatic changes in individuals, not heritable changes that are transmissible. But the rapidly advancing genome editing toolbox will soon make it possible to introduce virtually any change to any genome with precision, and the temptation to tinker with the human germ line is not going away.

The CRISPR babies saga should motivate active discussion and debate about human germline editing. With a new such study under consideration in Russia, appropriate regulation is urgently needed. Consequences for defying established restrictions should include, at a minimum, loss of funding and publication privileges. Ensuring responsible use of genome editing will enable CRISPR technology to improve the well-being of millions of people and fulfill its revolutionary potential.

* J.D. is a cofounder of Caribou Biosciences, Editas Medicine, Scribe Therapeutics, and Mammoth Biosciences; scientific advisory board member of Caribou Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics, Mammoth Biosciences, Synthego, and Inari; and director at Johnson & Johnson. Her lab has research projects sponsored by Biogen and Pfizer.

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CRISPR's unwanted anniversary - Science Magazine

Vertex Confirms Wales Offer Accepted for Access to All Licensed Cystic Fibrosis Medicines – Business Wire

LONDON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today confirms that NHS Wales has accepted an offer for all currently licensed Vertex cystic fibrosis (CF) medicines and any future indications of these medicines under the same terms as the recently announced agreement with NHS England.

This means that once the contract is finalized, patients with CF in Wales ages 2 years and older who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can access ORKAMBI (lumacaftor/ivacaftor) and CF patients ages 12 years and older who either have two copies of the F508del mutation or one copy of the F508del mutation and a copy of one of the other 14 licensed mutations can access SYMKEVI (tezacaftor/ivacaftor) in combination with ivacaftor in the coming weeks.

The agreement also offers expanded access to KALYDECO (ivacaftor) to include those patients ages 12 months and older who have one of the nine licensed gating mutations.

Todays announcement is good news for the approximately 270 eligible cystic fibrosis patients in Wales who will soon have access to CFTR modulators to treat the underlying cause of their disease, said Ludovic Fenaux, Senior Vice President, Vertex International. We thank the authorities in Wales for their collaboration in accepting this offer under the same terms as were recently announced in England.

About CF in the UKOver 10,000 people in the UK have CF the second highest number in the world. Over 430 people in Wales have CF. CF is a debilitating, life-shortening inherited condition that causes progressive damage to organs across the body from birth. Currently, there is no cure for CF and half of people in the UK with CF die before they are 32. The daily impact of treatment is significant. It can take up to four or more hours, involving nebulizers, physiotherapy and up to 70 tablets a day. CF accounts for 9,500 hospital admissions and over 100,000 hospital bed days a year. A third of these are used by children under 15.

About ORKAMBI (lumacaftor/ivacaftor) and the F508del mutationIn people with two copies of the F508del mutation, the CFTR protein is not processed and trafficked normally within the cell, resulting in little-to-no CFTR protein at the cell surface. Patients with two copies of the F508del mutation are easily identified by a simple genetic test.

Lumacaftor/ivacaftor is a combination of lumacaftor, which is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del-CFTR protein, and ivacaftor, which is designed to enhance the function of the CFTR protein once it reaches the cell surface.

For complete product information, please see the Summary of Product Characteristics that can be found on http://www.ema.europa.eu.

About SYMKEVI (tezacaftor/ivacaftor) in combination with ivacaftorSome mutations result in CFTR protein that is not processed or folded normally within the cell, and that generally does not reach the cell surface. Tezacaftor is designed to address the trafficking and processing defect of the CFTR protein to enable it to reach the cell surface and ivacaftor is designed to enhance the function of the CFTR protein once it reaches the cell surface.

SYMKEVI is indicated for people with CF ages 12 and older who either have two copies of the F508del mutation or one copy of the F508del mutation and have one of the following 14 mutations in which the CFTR protein shows residual function: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3AG, S945L, S977F, R1070W, D1152H, 2789+5GA, 3272-26AG, or 3849+10kbCT.

For complete product information, please see the Summary of Product Characteristics that can be found on http://www.ema.europa.eu.

About KALYDECO (ivacaftor)KALYDECO (ivacaftor) is the first medicine to treat the underlying cause of CF in people with specific mutations in the CFTR gene. Known as a CFTR potentiator, ivacaftor is an oral medicine designed to keep CFTR proteins at the cell surface open longer to improve the transport of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

KALYDECO is indicated in people ages 12 months and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R. KALYDECO is also indicated for the treatment of patients with CF ages 18 years and older who have an R117H mutation in the CFTR gene.

For complete product information, please see the Summary of Product Characteristics that can be found on http://www.ema.europa.eu.

About VertexVertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has four approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational medicines in other serious diseases where it has deep insight into causal human biology, such as sickle cell disease, beta thalassemia, pain, alpha-1 antitrypsin deficiency, Duchenne muscular dystrophy and APOL1-mediated kidney diseases.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London, UK. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 10 consecutive years on Science magazine's Top Employers list and top five on the 2019 Best Employers for Diversity list by Forbes.

Special Note Regarding Forward-looking StatementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, the statements by Mr. Fenaux in the fourth paragraph of this press release, statements regarding our expectations for the patient populations that will be able to access Vertexs medicines and the timing of such access, and statements about our expectations regarding a formal agreement in Northern Ireland. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under Risk Factors in Vertex's annual report and subsequent quarterly reports filed with the Securities and Exchange Commission and available through the company's website at http://www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

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Vertex Confirms Wales Offer Accepted for Access to All Licensed Cystic Fibrosis Medicines - Business Wire

FETROJA (cefiderocol) Approved by the FDA for Treatment of Complicated Urinary Tract Infections (cUTI) in Adult Patients with Limited or No…

OSAKA, Japan & FLORHAM PARK, N.J.--(BUSINESS WIRE)--Shionogi & Co., Ltd. (hereafter Shionogi) today announced the U.S. Food and Drug Administration (FDA) has approved FETROJA (cefiderocol) for patients 18 years of age or older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following: susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. Approval of this indication is based on limited clinical safety and efficacy data for FETROJA.

FETROJA will fill a very important unmet medical need because of its unique method of penetrating the cell wall of Gram-negative bacteria and its ability to overcome many of the resistance mechanisms that bacteria employ against antibiotics. Todays approval represents Shionogis ongoing commitment to develop medicines that help fight these life-threatening infections in patients for whom limited or no alternative treatment options exist, said Isao Teshirogi, Ph.D., president and CEO at Shionogi.

The approval of FETROJA is based on data from the pivotal APEKS-cUTI study, a multinational, multicenter, double-blind clinical trial that evaluated the efficacy and safety of FETROJA versus imipenem/cilastatin (IPM/CS) in patients with cUTI. Study results showed the response rates for the composite endpoint of microbiological eradication and clinical response at the test of cure (TOC) were significantly higher in the FETROJA arm compared to the IPM/CS arm. In the study, 72.6% (183/252) of patients in the FETROJA arm met the primary endpoint versus 54.6% (65/119) in the IPM/CS arm at TOC. The adjusted difference between the groups was 18.58% (95% CI: 8.2%, 28.2%). Clinical response rates at the TOC visit were similar between FETROJA and IPM/CS.

Serious adverse events were reported for 4.7% (14/300) of patients who received FETROJA and 8.1% (12/148) of patients who received IPM/CS. The most frequently occurring adverse reactions in greater than or equal to 2% of patients treated with FETROJA were diarrhea, infusion site reactions, constipation, rash, candidiasis, cough, elevations in liver tests, headache, hypokalemia, nausea, and vomiting. Please see Important Safety Information, Indications and Usage below.

In the pivotal study, cefiderocol achieved a higher response rate compared to imipenem/cilastatin, said George H. Karam, M.D., MACP, Paula Garvey Manship Chair of Medicine at the Louisiana State University School of Medicine. With todays approval of cefiderocol, the infectious disease community now has a new type of antibiotic with a unique mechanism of cell entry to add to their toolkit to assist in the complexity of treating highly resistant pathogens that are occurring with increasing frequency in life-threatening infections.

FETROJA was designated a Qualified Infectious Disease Product (QIDP) by the FDA, providing Fast Track designation and Priority Review. Shionogi anticipates making FETROJA commercially available in early 2020.

About Gram-negative InfectionsThe increasing resistance of many infections caused by Gram-negative bacteria to existing therapies, including carbapenem-resistant Enterobacteriaceae and non-fermenting species such as Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii (A. baumannii), and Stenotrophomonas maltophilia (S. maltophilia), poses a serious health challenge.1-5 There is an increasing number of Gram-negative pathogens resistant to multiple antibiotics, making them difficult to treat and resulting in high mortality rates.6 In the U.S., More than 2.8 million antibiotic-resistant infections occur in the United States each year, and more than 35,000 people die as a result.7 In the EU, about 25,000 patients die from an infection with the selected multidrug-resistant bacteria.8 The World Health Organization and the Centers for Disease Control and Prevention have identified carbapenem-resistant strains of Enterobacteriaceae, P. aeruginosa, and A.baumannii as the top priority in the research and development of new antibiotics.2,7

About FETROJA (cefiderocol) for injectionFETROJA (cefiderocol) is a cephalosporin antibiotic with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, FETROJA binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which function to incorporate this essential nutrient for bacteria.13 These mechanisms allow cefiderocol to achieve higher concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells.13 FETROJA has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases.13 Data from multinational surveillance studies for FETROJA demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii (A. baumannii), Pseudomonas aeruginosa (P. aeruginosa), Enterobacteriaceae, and Stenotrophomonas maltophilia (S. maltophilia).1 The clinical significance of the in vitro data is unknown. FETROJA has poor in vitro activity against Gram-positive or anaerobic bacteria.

Shionogi also submitted a marketing authorization application for cefiderocol to the European Medicines Agency and it was accepted in March 2019.10

Important Safety Information

ContraindicationsFETROJA (cefiderocol) is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA.

Warnings and Precautions

Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial InfectionsAn increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of one-to-three antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including nonfermenters such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. The safety and efficacy of FETROJA has not been established for the treatment of nosocomial pneumonia, bloodstream infections, or sepsis.

Reserve FETROJA for use in patients who have limited or no alternative treatment options for the treatment of cUTI. Closely monitor the clinical response to therapy in patients with cUTI.

Hypersensitivity ReactionsSerious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in FETROJA clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue FETROJA if an allergic reaction occurs.

Clostridium difficile-Associated Diarrhea (CDAD)Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Seizures and Other Central Nervous System (CNS) Adverse ReactionsCephalosporins, including FETROJA, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust FETROJA dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued.

Development of Drug-Resistant BacteriaPrescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and may increase the risk for development of drug-resistant bacteria.

Adverse ReactionsThe most common adverse reactions occurring in (>2%) of patients receiving FETROJA compared to imipenem/cilastatin in clinical trials were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%).

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Shionogi Inc. at 1-800-849-9707.

Indications and Usage

Indication

FETROJA (cefiderocol) is indicated in patients 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

Approval of this indication is based on limited clinical safety and efficacy data for FETROJA.

UsageTo reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

For full Prescribing Information, please visit Shionogi.com.

About ShionogiShionogi & Co., Ltd. is a Japanese major research-driven pharmaceutical company dedicated to bringing benefits to patients based on its corporate philosophy of supplying the best possible medicine to protect the health and wellbeing of the patients we serve. The company currently markets products in several therapeutic areas including anti-infectives, pain, cardiovascular diseases, and gastroenterology. Our pipeline is focused on infectious disease, pain, CNS, and oncology. For more information on Shionogi & Co., Ltd., visit http://www.shionogi.co.jp/en. Shionogi Inc. is the U.S. subsidiary of Shionogi & Co., Ltd. based in N.J. For more information on Shionogi Inc., please visit https://www.shionogi.com/.

Forward-Looking StatementsThis announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also, for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, unavailability of raw materials, and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events, or otherwise.

References

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FETROJA (cefiderocol) Approved by the FDA for Treatment of Complicated Urinary Tract Infections (cUTI) in Adult Patients with Limited or No...

Todos and Amarantus JV Announces Full Enrollment for Clinical Trial of LymPro Alzheimer’s Blood Test Relationship with Amyloid PET – GlobeNewswire

REHOVOT, Israel and NEW YORK, Nov. 14, 2019 (GLOBE NEWSWIRE) -- Todos Medical Ltd. (OTCQB: TOMDF), a clinical-stage in-vitro diagnostics company focused on the development of blood tests for the early detection of cancer and neurodegenerative disorders, and Amarantus Bioscience Holdings, Inc. a US-based JLABS-alumnus biotechnology holding company developing proprietary orphan neurologic, regenerative medicine and ophthalmic therapies and diagnostics through its subsidiaries, today announced that their joint venture company, Breakthrough Diagnostics, Inc. has completed enrollment of its ongoing clinical trial evaluating the relationship of Alzheimers blood diagnostic Lymphocyte Proliferation Test (LymPro Test) with amyloid PET neuroimaging at Leipzig University in Germany (the LymPro PET 2). Topline results are expected before the end of the first quarter of 2020.

Breakthrough completed a 20-subject clinical study (LymPro PET 1) in 2018 evaluating the correlation between LymPro scores and the diagnosis of Alzheimers disease, as confirmed with amyloid PET neuroimaging and other Alzheimers disease biomarkers. LymPro measures cell cycle dysregulation in peripheral lymphocytes. The top-line data, announced in July 2019, revealed a strong and statistically significant correlation between LymPro scores and amyloid PET neuroimaging cSUVR scores (r = -0.849; p = 0.00000216). Breakthroughs academic collaborators at the Leipzig University then expanded enrollment of that study to include an additional cohort of 20 subjects (LymPro PET 2) to confirm the strong relationship seen from LymPro PET 1. The data from both LymPro 1 and LymPro 2 will be published together in a peer-reviewed journal in 2020.

LymPro is a unique immune system-based Alzheimers blood test, said Dr. Herman Weiss, President & CEO of Todos. LymPro could prove to be a major breakthrough for Alzheimers disease diagnosis by measuring cell cycle dysregulation and amyloid, together, conveniently as part of a blood workup in routine clinical practice. The therapeutic field in Alzheimers has begun to see some renewed hope based upon recent Aducanumab data announced by Biogen that is directly related to the amyloid hypothesis, as well as conditional approval by the National Medical Products Administration in China for the first new Alzheimers drug in over 20 years, called Oligomannate from Shanghai Green Valley Pharmaceuticals, that is based on gut-brain biology of the microbiome and its effects on the immune system. We believe this renewed optimism and broadening of pathophysiological hypotheses relevant to Alzheimers disease being evaluated in the clinic significantly increases the scope for LymPro pharma services collaborations and begins to refine LymPros clinical utility profile for primary care physicians as strategies to correct cell cycle dysregulation emerge.

About Alzheimer's DiseaseAccording to the Alzheimer's Association, it is estimated that over 5.4 million people in the United States suffer from Alzheimer's disease. Over 500,000 patients are diagnosed annually, with nearly one-in-eight older Americans affected by the disease. Alzheimer's disease is the third leading cause of death in the United States. The cost of unpaid care in the United States is estimated at over $210 billion annually.Total payments for care are estimated at over $200 billion annually, including $140 billion in cost to Medicare and Medicaid. Alzheimer's expenditures in the United States are expected to exceed $1.2 trillion by 2050. There is no cure or effective treatment for Alzheimer's disease. Worldwide, about 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer's by 2050.

About Dr. Arendt's Research at Leipzig UniversityDr. Thomas Arendt is Professor of Neuroscience at Leipzig University where he runs the Paul Flechsig Institute of Brain Research. He has a 30-year record in R&D of therapeutic and diagnostic strategies of neurodegenerative disorders and made several seminal contributions to therapeutic concepts of Alzheimer's disease, including stem cell therapy and modulating tumor suppressor genes. In the early 1980's, he was involved in identifying the degeneration of the cholinergic system in Alzheimer's disease laying the basis for today's only available treatment. He is one of the pioneers of the "cell-cycle theory" of Alzheimer's disease, which he developed towards a diagnostic and therapeutic concept.

About Breakthrough Diagnostics, Inc.Breakthrough Diagnostics, Inc. is a joint venture owned by Amarantus Bioscience Holdings, Inc. (OTCPK: AMBS) (80.01%) and Todos Medical Ltd. (19.99%). Breakthrough has been assigned the intellectual property and other rights to the LymPro Test, a diagnostic blood test for Alzheimers disease, as well as rights to other neurological diagnostics testing intellectual property. Todos Medical has provided Amarantus with notice of Todos decision to exercise its exclusive option to acquire the 80.01% of Breakthrough Diagnostics that it currently does not own.

The Lymphocyte Proliferation Test (LymPro Test) determines the ability of peripheral blood lymphocytes (PBLs) and monocytes to withstand an exogenous mitogenic stimulation that induces them to enter the cell cycle. It is believed that certain diseases, most notably Alzheimer's disease, are the result of compromised cellular machinery that leads to aberrant cell cycle re-entry by neurons, which then leads to apoptosis. LymPro is unique in the use of peripheral blood lymphocytes as surrogates for neuronal cell function, suggesting a common relationship between PBLs and neurons in the brain.

About Todos Medical Ltd.Todos Medical Ltd. is an in-vitro diagnostic company engaged in the development of blood tests for the early detection of a variety of cancers, and also has initiated the development of blood tests for neurodegenerative disorders such as Alzheimer's disease through Breakthrough Diagnostics, Inc., its joint venture with Amarantus Bioscience Holdings, Inc. Todos has developed two cancer screening tests based on TBIA (Todos Biochemical Infrared Analyses), a method for cancer screening using peripheral blood analysis. The TBIA screening method is based on the cancers influence on the immune system, which triggers biochemical changes in peripheral blood mononuclear cells and plasma. This proprietary and patented method incorporates biochemistry, physics and signal processing. The companys two cancer screening tests, TM-B1 and TM-B2, have received the CE mark. Breakthrough Diagnostics is developing the LymPro Test, a blood test for diagnosing Alzheimers disease.

For more information, the content of which is not part of this press release, please visithttp://www.todosmedical.com

About Amarantus Bioscience Holdings, Inc.Amarantus Bioscience Holdings (AMBS) is a JLABS alumnus biotechnology company developing treatments and diagnostics for diseases in the areas of neurology, regenerative medicine and orphan diseases through its subsidiaries. The Companys 80.01%-owned subsidiaryBreakthrough Diagnostics, Inc.,currently a joint venture with Todos Medical, Ltd., has licensed intellectual property rights to the Alzheimers blood diagnostic LymPro Test from Leipzig University that was originally developed by Dr. Thomas Arendt, as well as certain rights to multiple sclerosis diagnostic MSPrecise and Parkinsons diagnostic NuroPro. Amarantus entered into a joint venture agreement withTodos Medical, Ltd. to advance diagnostic screening assets and Todos has exercised its exclusive option to acquire Amarantus remaining ownership in Breakthrough in exchange for approximately 50% ownership of Todos. The transaction is expected close before the end of the first quarter of 2020. Amarantus also owns approximately 30% of the common shares of Avant Diagnostics, Inc., a healthcare data-generating technology company that specializes in biomarker assay services that target multiple areas of oncology. Avant provides precision oncology data through its TheraLink assays to assist the biopharmaceutical industry and clinical oncologists in identifying likely responders, initially for breast cancer, to over 70 FDA-approved drug treatments.

AMBS 50%-owned subsidiaryElto Pharma, Inc. has development rights to eltoprazine, a Phase 2b-ready small molecule indicated for Parkinson's disease levodopa-induced dyskinesia, Alzheimers aggression and adult attention deficit hyperactivity disorder, commonly known as ADHD. AMBS acquiredCutanogen Corporationfrom Lonza Group in 2015. Cutanogen is preparing for pivotal studies with Engineered Skin Substitute (ESS) for the treatment of pediatric life-threatening severe burns. ESS is a regenerative medicine-based, autologous full-thickness skin graft technology originally developed by the Shriners Hospital that can be used to treat severe burns, as well as several other catastrophic and cosmetic dermatological indications. AMBS wholly-owned subsidiary,MANF Therapeutics Inc.owns key intellectual property rights and licenses from a number of prominent universities related to the development of the therapeutic protein known as mesencephalic astrocyte-derived neurotrophic factor (MANF). MANF Therapeutics is developing MANF-based products as treatments for ophthalmological disorders such as Wolfram Syndrome, Retinitis Pigmentosa and Glaucoma, as well as neurodegenerative diseases such as Parkinsons disease. MANF was discovered by the Companys Chief Scientific Officer John Commissiong, PhD. Dr. Commissiong discovered MANF from AMBS proprietary discovery engine PhenoGuard, and believes several other neurotrophic factors remain to be discovered. Amarantus has entered into a binding letter of intent to license the therapeutic assets from Elto Pharma, Cutanogen and MANF Therapeutics to Emerald Organic Products.

Forward-looking StatementsCertain statements contained in this press release may constitute forward-looking statements. For example, forward-looking statements are used when discussing our expected clinical development programs and clinical trials. These forward-looking statements are based only on current expectations of management, and are subject to significant risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements, including the risks and uncertainties related to the progress, timing, cost, and results of clinical trials and product development programs; difficulties or delays in obtaining regulatory approval or patent protection for product candidates; competition from other biotechnology companies; and our ability to obtain additional funding required to conduct our research, development and commercialization activities. In addition, the following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; delays or obstacles in launching our clinical trials; changes in legislation; inability to timely develop and introduce new technologies, products and applications; lack of validation of our technology as we progress further and lack of acceptance of our methods by the scientific community; inability to retain or attract key employees whose knowledge is essential to the development of our products; unforeseen scientific difficulties that may develop with our process; greater cost of final product than anticipated; loss of market share and pressure on pricing resulting from competition; and laboratory results that do not translate to equally good results in real settings, all of which could cause the actual results or performance to differ materially from those contemplated in such forward-looking statements. Except as otherwise required by law, Todos Medical does not undertake any obligation to publicly release any revisions to these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. For a more detailed description of the risks and uncertainties affecting Todos Medical, please refer to its reports filed from time to time with the U.S. Securities and Exchange Commission.

Todos Investor and Corporate Contact:Kim Sutton GolodetzLHA Investor RelationsSenior Vice President (212) 838-3777kgolodetz@lhai.com

Todos Corporate ContactDaniel HirschTodos MedicalInvestor RelationsEmail:Dan.h@todosmedical.comPhone: (347) 699-0029

Amarantus Investor and Media Contact:Gerald CommissiongPresident & CEOOffice: 650-862-5391Email: gerald@amarantus.com

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Todos and Amarantus JV Announces Full Enrollment for Clinical Trial of LymPro Alzheimer's Blood Test Relationship with Amyloid PET - GlobeNewswire