Category Archives: Gene Medicine

A model incorporating gene expression and clinical factors predicts response to anti-tumor necrosis factor (TNF) therapy in patients with rheumatoid arthritis (RA), according to study results published in Network and Systems Medicine.

Rheumatoid arthritis is a complex disease and the molecular factors that predict response to treatment are poorly understood. Using gene expression data from patients receiving anti-TNF therapy, investigators aimed to build a biomarker panel, which predicts response to anti-TNF therapies in patients with RA.

Using publicly available data, a comprehensive map of the human protein-protein interactome was generated and used to identify an RA disease module, which contained approximately 200 proteins. Within this module, 66% of the proteins had been previously linked to RA in genome-wide association studies, and the remaining were significantly enriched in similar Gene Ontology biological processes.

Microarray data were obtained from the Gene Expression Omnibus database for 58 women receiving anti-TNF therapy. Using a random forest machine-learning algorithm, the data were used to identify genes for which expression was predictive of response and nonresponse to therapy. Based on the microarray profile and the RA disease module, 37 genes were identified as discriminatory biomarkers for anti-TNF response.

In addition, RNA sequencing (RNAseq) data were obtained for 143 patients with RA from the Comparative Effectiveness Registry to Study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) study. In addition to gene expression, RNAseq data enabled the identification of single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms) that were associated with treatment response. An additional 22 SNVs, which were associated with the RA disease model, were identified that were linked to response to anti-TNF therapy.

With the inclusion of clinical factors, a total of 70 biomarkers were identified and used to train a machine-learning algorithm to predict response to anti-TNF therapy. The final model generated, which predicted nonresponse to anti-TNF therapy, consisted of 10 SNPs, 8 gene transcripts, 2 laboratory tests, and 3 clinical measures.

To confirm that the model was broadly generalizable, data from an independent group of 175 patients from the CERTAIN study were used for a validation trial. Patients who were identified by the model as being nonresponders to anti-TNF therapy were 6.57-times more likely to be a true nonresponder than a responder (95% CI, 2.75-15.70). The model predicted nonresponse to therapy with a positive predictive value of 89.7% (95% CI, 79.0-95.7%), a specificity of 86.8% (95% CI, 72.4-94.1%), and a sensitivity of 50.0% (95% CI, 40.8-58.7%). There was no significant difference observed in the predictive power of the model based on ethnicity.

When the relevant gene transcripts and SNVs were mapped to the human interactome, they were all within close proximity to the RA disease module as well as established RA drug targets, including Janus kinase and TNF-. Pathway enrichment identified genes involved in T-cell signaling as the most enriched pathway in the biomarkers associated with a therapeutic response.

Customization of treatment regimens to match the individualized disease biology of each patient is a goal of modern medicine, the researchers concluded. Development and validation of a drug response algorithm that predicts nonresponse to a targeted therapy using this machine-learning and network medicine approach show great promise for advancing precision medicine in the treatment of RA and other complex autoimmune diseases where costly therapeutic interventions are met with inadequate patient response.

Disclosure: This study was supported by Scipher Medicine Corporation. Please see the original reference for a full list of authors disclosures.

Mellors T, Withers JB, Ameli A, et al. Clinical validation of a blood-based predictive test for stratification of response to tumor necrosis factor inhibitor therapies in rheumatoid arthritis patients. Network and Systems Medicine. 2020;3(1):91-104.

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Clinically Validated Blood-Based Test Predicts Response to Anti-TNF Therapies in RA - Rheumatology Advisor

MedicalResearch.com Interview with:

Caspar van der Made, MDResident in Internal Medicine, PhD-studentAlexander Hoischen, PhDGeneticist, Assistant professor,Departments of Human Genetics and Internal Medicine

Radboud University Medical enterNijmegen, The Netherlands

First author Caspar van der Made is a resident in Internal Medicine and PhD-student on the topic of immunogenomics.Alexander Hoischen is geneticist with a special focus on the application of genomic technologies in primary immunodeficiencies and last author of this study.

MedicalResearch.com: What is the background for this study?

Response: This study was initiated to investigate the presence of monogenic factors that predispose young individuals to develop a severe form of COVID-19. It has become clear that several general risk factors such as obesity, hypertension and diabetes mellitus increase the risk of developing severe coronavirus disease. However, even though differences in interindividual genetic make-up are thought to influence the immune response to SARS-CoV-2, such specific genetic risk factors had not yet been identified.

We therefore chose to study young brother pairs (sharing half of their genomes) without any general risk factors that nevertheless contracted severe COVID-19.

We hypothesized these highly selected case series may offer the most optimal chance of identifying a (possible X-linked) primary immunodeficiency specific to COVID-19.

MedicalResearch.com: What are the main findings?

Response: In this case series, two young brother pairs of which all four individuals with a mean age of 26 years required mechanical ventilation at the ICU were enrolled and studied. We performed rapid clinical whole-exome sequencing of the patients and segregation in available family members to identify loss-of-function variants of the X-chromosomal TLR7. This gene encodes the toll-like receptor 7 protein that plays a critical role in the innate immune response against coronaviruses, predominantly by mediating the production of type I interferons. Especially in SARS-CoV-2 infections this response is crucial, as the virus has evasive mechanisms to disrupt a proper type I interferon response. In primary peripheral blood mononuclear cells extracted from the patients, we have shown that the transcription of type I-interferon genes was lower in patients upon stimulation with the TLR7 agonist imiquimod, as compared to controls. Furthermore, the production of the type II interferon IFNg was also decreased in patients.

MedicalResearch.com: What should readers take away from your report?

Response: To our knowledge this is the first report that proposes a specific monogenic factor to develop severe COVID-19. We aim to highlight the important contribution of genetics in the susceptibility to develop COVID-19 and hope to create awareness among physicians to consider genetic evaluation of young patients with unexplained severe COVID-19.

The finding of TLR7 deficiency in these patients furthermore underlines the importance of an intact type I and II interferon response to fight off SARS-CoV-2 and provides insight in the timing of possible treatment options.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: While the TLR7 deficiency is most likely a rare phenomenon, with an estimate of 1:10,000 TLR7 mutation carriers in the general population; our findings shall be replicated and expanded by others. Similar to other rare disease genetic studies, this shall allow additional insides into disease pathogenesis in general. Further research should focus on the elucidation of the exact role of TLR7-signaling in the pathogenesis of SARS-CoV-2 and ultimately the exploration of rational treatment options.

Also, these findings may provide part of the explanation for the male sex bias observed in COVID-19, which should be addressed more in-depth. More generally, we encourage further studies towards the identification of other genetic risk factors and applaud the efforts already undertaken by other large consortia.

MedicalResearch.com: Is there anything else you would like to add?

Response: We are very grateful to the families that participated in this study, and would like to acknowledge our interdisciplinary team of collaborators.

Any disclosures?

No relevant conflict of interest for any of the authors.

Citation:

van der Made CI, Simons A, Schuurs-Hoeijmakers J, et al. Presence of Genetic Variants Among Young Men With Severe COVID-19.JAMA.Published online July 24, 2020. doi:10.1001/jama.2020.13719

https://jamanetwork.com/journals/jama/fullarticle/2768926

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Genetic Change Detected in Brothers Helps Explain Why COVID-19 More Severe in Men - MedicalResearch.com

Inherited mutations in a gene that keeps nerve cells intact was shown, for the first time, to be a driver of a neuropathy known as Charcot-Marie-Tooth (CMT) disease. This finding is detailed in a study led by researchers in the Perelman School of Medicine, which published inNeurologyGenetics, an official journal of the American Academy of Neurology.

The findings, thanks to siblings treated at Penn since the late 1980s, present a clearer picture of the diseases genetic underpinnings that could inform the development of gene therapies to correct it.

The mutations in the gene known as dystonin (DST) add to a growing list of malfunctions found to cause their type of CMT, known as CMT2, which is defined by the loss of the nerve fibers, or axons, in the peripheral nerve cells. The researchers also showed that these mutations affect two key protein isoforms, BPAG1-a2 and BPAG1-b2, that are involved in nerve fiber function. Mutations in other isoforms of the same protein were previously tied to a blistering skin disease.

There are more than 100 mutations found to be associated with CMT, with likely many more out there.Past studies from Penn researchers haveidentified some of these mutations by studying patients treated at Penn Medicine.

We are determined to fill in the blanks of this giant jigsaw puzzle, says senior authorSteven S. Scherer, a professor of neurology. This latest paper is but one of many examples of where breakthroughs have happened between patients and the doctors at Penn and the support of different organizations and institutions to bring it all together."

Read more at Penn Medicine News.

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New genetic cause of an inherited neuropathy discovered | Penn Today - Penn Today

Dimitri Maamari1 ,* Habib El-Khoury1 ,* Omran Saifi,1 Samar A Muwakkit,2 Nathalie K Zgheib3

1Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 2Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 3Department of Pharmacology and Toxicology, American University of Beirut, Faculty of Medicine, Beirut, Lebanon

*These authors contributed equally to this work

Correspondence: Samar A Muwakkit; Nathalie K Zgheib Email sm03@aub.edu.lb; nk16@aub.edu.lb

Abstract: Despite major advances in the management and high cure rates of childhood acute lymphoblastic leukemia (ALL), patients still suffer from many drug-induced toxicities, sometimes necessitating dose reduction, or halting of cytotoxic drugs with a secondary risk of disease relapse. In addition, investigators have noted significant inter-individual variability in drug toxicities and disease outcomes, hence the role of pharmacogenetics (PGx) in elucidating genetic polymorphisms in candidate genes for the optimization of disease management. In this review, we present the PGx data in association with main toxicities seen in children treated for ALL in addition to efficacy, with a focus on the most plausible germline PGx variants. We then follow with a summary of the highest evidence drug-gene annotations with suggestions to move forward in implementing preemptive PGx for the individualization of treatment regimens for children with ALL.

Keywords: pharmacogenetics, childhood ALL, implementation

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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Implementation of Pharmacogenetics to Individualize Treatment Regimens | PGPM - Dove Medical Press

$26.5 million total near-term payments to BridgeBio, plus participation in long-term value creation of up to $505 million in milestone payments, tiered double-digit royalty payments and an equity interest in LianBio.

BridgeBio CEO and founder Neil Kumar, Ph.D., has been appointed to LianBios board of directors.

PALO ALTO, Calif., Aug. 11, 2020 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. (NASDAQ: BBIO), a clinical-stage biopharmaceutical company focused on genetic diseases and cancers with clear genetic drivers, today announced that it is partnering with Shanghai-based LianBio, a new company founded by Perceptive Advisors, to expand its global reach into China, the second-largest pharmaceutical market in the world. The partnership marks the first major expansion of BridgeBios pipeline into Asian markets.

This strategic relationship will initially focus on two of BridgeBios targeted oncology drug candidates, FGFR inhibitor infigratinib, currently in Phase 3 development for FGFR-driven tumors and Phase 1-ready SHP2 inhibitor BBP-398, for tumors driven by RAS and receptor tyrosine kinase mutations. The agreement also provides LianBio with preferential future access in the territory to more than 20 drug development candidates currently owned or controlled by BridgeBio. This collaboration is designed to advance and accelerate BridgeBios programs in China and other major Asian markets, allowing BridgeBio to quickly bring innovation to large numbers of patients with high unmet need.

Tremendous patient need and a fast-developing healthcare infrastructure make China a strategic priority. We are eager to not only expand late-stage therapies to the broader patient population there, but also to accelerate our clinical development efforts in Asia and better understand and address the needs of patients there early. We are grateful to be deepening our relationship with Perceptive Advisors through this agreement with LianBio and look forward to a lasting partnership focused on expanding our reach to patients, said BridgeBio CEO and founder Neil Kumar, Ph.D.

We value our relationship with BridgeBio and are happy to be enabling the entry of important programs to LianBios territories, said Adam Stone, CIO of Perceptive Advisors. BridgeBio and its affiliate companies exemplify the commitment to science-driven, precision medicine that we believe is a key driver to innovation in healthcare. We are excited about this opportunity to leverage their promising pipeline and LianBios local expertise to accelerate both global development and local access to leading edge therapeutics.

Under the terms of the agreements, LianBio will receive commercial rights in China and selected Asian markets and participate in clinical development activities for infigratinib (housed in BridgeBio affiliate QED) and BBP-398 (housed in BridgeBio affiliate Navire). BridgeBios near-term economics includes a total of $26.5 million in upfront and milestone payments. BridgeBio will receive up to $505 million in future milestone payments, tiered royalty payments from single- to double-digits on net sales of both products in licensed territories. Additionally, BridgeBio will increase its equity interest via investment in LianBio and BridgeBio CEO Neil Kumar has been appointed to the LianBio board of directors.

LianBio is participating in the ongoing Phase 3 study of infigratinib in first line cholangiocarcinoma (PROOF) in mainland China and further plans to initiate a Phase 2a study of infigratinib in gastric cancer and other FGFR-driven tumors. Additionally, LianBio will contribute to clinical development of BBP-398 in combination with various agents in solid tumors such as non-small cell lung cancer (NSCLC), colorectal and pancreatic cancer, in mainland China and other major Asian markets.

About BridgeBio PharmaBridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBios pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development. For more information, please visitwww.bridgebio.com.

About LianBio

LianBios mission is to catalyze the development and accelerate availability of paradigm-shifting medicines to patients in China and major Asian markets through partnerships that provide access to the best science-driven therapeutic discoveries. LianBio collaborates with world-class partners across a diverse array of therapeutic and geographic areas to build out a pipeline based on disease relevance and the ability to impact patients with transformative mechanisms and precision-based therapeutics. For more information, please visit http://www.lianbio.com.

About Perceptive Advisors

Founded in 1999, Perceptive Advisors is a leading life sciences focused investment firm with over $7billion of regulatory assets under management as of June 30, 2020. Since inception, Perceptive Advisors has focused on supporting progress in the life sciences industry by identifying opportunities and directing financial resources toward the most promising technologies in modern healthcare. For more information, please visitwww.perceptivelife.com.

About QED Therapeutics

QED Therapeutics, an affiliate of BridgeBio Pharma, is a biotechnology company focused on precision medicine for FGFR-driven diseases. Its lead investigational candidate is infigratinib (BGJ398), an orally administered, FGFR1-3 selective tyrosine kinase inhibitor that has shown activity that it believes to be meaningful in clinical measures, such as overall response rate, in patients with chemotherapy-refractory cholangiocarcinoma with FGFR2 fusions and advanced urothelial carcinoma with FGFR3 genomic alterations. QED intends to submit a New Drug Application (NDA) with the United States Food and Drug Administration for second and later-line cholangiocarcinoma in 2020. QED Therapeutics is also evaluating infigratinib in clinical studies for the treatment of achondroplasia. QED plans to conduct further clinical trials to evaluate the potential for infigratinib to treat patients with other FGFR-driven tumor types and rare disorders. For more information, please visit http://www.qedtx.com.

About Navire Pharma

Navire Pharma, an affiliate of BridgeBio Pharma, and in collaboration with the Institute for Applied Cancer Science at MD Anderson, is developing inhibitors of SHP2 as targeted therapeutics for the treatment of multiple cancers. Together with patients and physicians, the company aims to bring safe, effective treatments to market as quickly as possible. For more information, please visit http://www.navirepharma.com.

BridgeBio Pharma Forward-Looking Statements

This press release contains forward-looking statements. Statements we make in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act), which are usually identified by the use of words such as anticipates, believes, estimates, expects, intends, may, plans, projects, seeks, should, will, and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to BridgeBios anticipated receipt of future milestone and/or royalty payments from LianBio, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to, the success of clinical trials, regulatory filings, approvals and/or sales of infigratinib and BBP-398 in China and other major Asian markets, as well as those risks set forth in the Risk Factors section of BridgeBio Pharmas most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q and BridgeBio Pharmas other SEC filings. Moreover, BridgeBio Pharma operates in a very competitive and rapidly changing environment in which new risks emerge from time to time. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

Contact:Grace RauhBridgeBio Pharma, Inc.Grace.rauh@bridgebio.com(917) 232-5478

Source: BridgeBio Pharma, Inc.

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BridgeBio Pharma Expands Reach Into China and Other Major Asian Markets Through Strategic Collaboration With Perceptive Advisors-Founded Company,...

Aug. 12, 2020 12:00 UTC

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Omega Therapeutics, a company pioneering a new category of genomic medicine through epigenomic programming, today announced the appointment of Dr. Roger Sawhney as Chief Financial Officer. Dr. Sawhney brings 25 years of financial and strategic expertise to Omega, with vast experience ranging from global investments in healthcare sectors to business and strategy development in the biopharma industry.

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Omega Therapeutics strengthens leadership team with appointment of Roger Sawhney, M.D. as Chief Financial Officer. (Photo: Business Wire)

Mahesh Karande, President and Chief Executive Officer of Omega Therapeutics remarked, The addition of Roger as Chief Financial Officer strengthens our leadership team and positions Omega for continued success in 2020 and beyond, particularly as we look to further developing our epigenomic programming platform, exploring partnerships, and readying our lead indications for clinical development in 2021. Rogers stellar background, and breadth and depth of industry expertise, combined with his strategic and transactional experience are invaluable attributes, and I am proud to welcome him to the team.

Most recently, Dr. Sawhney served at KKR & Co. as Director of its healthcare investment platform in the Americas, where his work focused on investments across private and growth equity in the healthcare sector. While at KKR & Co., he was responsible for deal sourcing, diligence, investing, corporate governance and portfolio value realization, and he ultimately helped lead and manage investments in over five portfolio companies across KKRs healthcare platform.

Earlier, he held the role of Senior Vice President and Head of Corporate Strategy for Novartis AG, as well as Senior Vice President of Corporate Strategy and Business Development for Outcome Health, a privately-funded leader in the digital health space. In these roles, Roger was progressively responsible for growth initiatives, M&A, business development and global strategic planning.

Dr. Sawhney commented, "Omega has a compelling story, breakthrough science and an ambitious mission, so I am excited to join Mahesh and the team in their efforts to deliver transformative genomic medicine to patients, forging a new future of disease management. Through pursuing strategic financial and operational initiatives, I aim to assist Omega in successfully capitalizing on opportunities and achieving its clinical, regulatory, and financial milestones."

We are thrilled to announce that Roger has joined the Omega leadership team as CFO, said Noubar Afeyan, Ph.D., Chief Executive Officer of Flagship Pioneering and Co-founder and Chairman of the Board for Omega Therapeutics. His impressive background bolsters Omegas strategic position, which is especially relevant during these uncertain times in the global markets. I look forward to his contributions in helping Omega capitalize on opportunities in what is certain to be an impactful year for the company.

Dr. Sawhney has also served as Partner with both Bain and Company and the Boston Consulting Group, where he led and managed numerous investments across the life sciences, med-tech and digital health sectors, as well as transformation engagements for the worlds leading global biopharma companies. He has particular depth in M&A, BD&L, portfolio strategy and growth strategy. He earned his M.D. degree from Harvard Medical School and also holds a BA in Economics from Stanford University.

About Omega Therapeutics

Omega Therapeutics is a genomic medicine company advancing novel engineered therapeutics, Omegas Epigenomic Controllers, enabling controllable epigenomic programming into clinical development for a broad range of indications. These therapeutics deliver Precision Genomic Control by controlling Insulated Genomic Domains (IGDs), the fundamental structural and functional units of genomic regulation, by modulating single and multiple gene expression through epigenomic programming. IGDs encompass single or multiple genes and their associated regulatory elements, and are correlated with diverse diseases, including cancer, autoimmune, inflammatory, regenerative, metabolic, neurological conditions and rare diseases. Omegas Epigenomic Controllers deliver the required potent and durable therapeutic effect by precisely modulating or tuning single or multiple genes, up or down, with high specificity to unleash the human genomes innate capacity to cure disease without altering native genomic nucleic acid codes. Omegas Epigenomic Controllers also allow repeat dosing with controllable durability.

Founded by Flagship Pioneering in 2017, with a long-term vision to create a programmable, epigenetic-based genomic medicine platform that would identify novel targets, as well as medicines, Omegas epigenomic programming platform has identified and mapped IGDs and their structure and function in both healthy and diseased states across cell types. This scientific insight drives the discovery and development of Omegas novel Epigenomic Controllers, intended for clinical development across a range of therapeutic indications. To learn more please visit http://www.omegatherapeutics.com.

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Omega Therapeutics Strengthens Leadership Team with Appointment of Roger Sawhney, MD as Chief Financial Officer - BioSpace