Category Archives: Transhuman News

Three years ago, the Food and Drug Administration granted a landmark approval to the first gene therapy for an inherited disease, clearing a blindness treatment called Luxturna.

Since then, the regulator has approved one more gene therapy,the spinal muscular atrophy treatment Zolgensma, and given a green light for dozens of biotech and pharmaceutical companies to start clinical testing on others. Genetic medicines for a range of diseases, including hemophilia, sickle cell and several muscular dystrophies, appear in reach, and new science is galvanizing research.

But, entering 2021, the gene therapy field faces major questions after a series of regulatory and clinical setbacks have shaded optimism. "The ups and downs of adolescence are on full display" analysts at Piper Sandler wrote in September, summing up the state of gene therapy research.

Here are five questions facing scientists, drugmakers and investors this year. How they're answered will matter greatly to the patients and families holding out hope for one-time disease treatments.

The FDA was widely expected last year to approve a closely watched gene therapy for hemophilia A, the more common type of the blood disease. Instead, the agency in August surprisingly rejected the treatment, called Roctavian, and asked its developer, BioMarin Pharmaceutical, to gather more data.

The next day, Audentes Therapeutics reported news came a third clinical trial participant had died after receiving the biotech's experimental gene therapy for a rare neuromuscular disease. The tragedy brought flashbacks to past safety scares in gene therapy, although the current wave of treatments being tested have generally appeared safe.

A little less than five months later, the gene therapy field is grappling with two more setbacks. UniQure is exploring whether a study volunteer's liver cancer was caused by its gene therapy for hemophilia B. And Sarepta, one of the sector's top developers, faces significant doubts about its top treatment for Duchenne muscular dystrophy after disclosing a key study missed one of its main goals.

In each case, the drugmakers involved offered explanations and reasons for optimism. BioMarin still expects to obtain an approval; Audentes' trial is now cleared by the FDA to resume testing; UniQure thinks it's unlikely the cancer case is linked to treatment; and Sarepta argued its negative data were the product of unlucky study design.

But taken together, the developments are powerful reminders of both the stakes and uncertainty still facing gene therapy.

All four events also highlighted lingering worries about one-time genetic treatment. In rejecting Roctavian, for example, the FDA seemed to be concerned the impressive benefit hemophilia patients initially experienced may wane over time. The deaths in Audentes' study, meanwhile,renewed warnings about extremely high doses of gene therapy. Researchers have long watched for evidence that replacing or altering genes may cause cancer to develop in rare instances, particularly after four infants developed leukemia in a gene therapy study in the early 2000s.And Sarepta's negative findings were surprising because early signs of dramatic biological benefit that didn't seem to translate into clear-cut functional gains for all patients.

Experts are still confident gene therapy can deliver on its promise. Bu recent events suggest getting there may take a bit longer than some expected.

"The process is the product," is an often-used cliche about gene therapy, which are complex treatments with exacting manufacturing standards.

Most of the roughly 60,000 pages in Spark Therapeutics' application for approval of Luxturna, for instance, involved what's known in the industry as "chemistry, manufacturing and controls."

The therapeutic basis for gene therapy, by contrast, is much clearer for many of the rare, monogenic diseases that developers are targeting. If mutations in a single gene lead to disease, replacing or otherwise fixing that gene should have a large benefit.

"Genetic medicine is not industrialized serendipity," said Gbola Amusa, an analyst at Chardan, contrasting gene therapy with chemical-based drugs."It often is an engineering question."

In 2020, the FDA gave ample notice that it's watching gene (and cell) therapy manufacturing closely.Sarepta,Voyager Therapeutics,Iovance Biotherapeuticsand Bluebird biowere all forced to revise their development timelines after the agency asked for new details about production processes.

"The FDA is saying to companies that you've got to up your standards," Amusa added.

For their part, FDA officials have indicated the spate of data requests are a product of the sharply higher numbers of companies advancing through clinical testing.

While setbacks have piled up for therapies that seek to replace genes, 2020 was a "transformative year" for therapies designed to edit them, according to Geulah Livshits, an analyst at Chardan.

CRISPR gene editing, already widely recognized as a scientific breakthrough, gained further prestige with the awarding of the Nobel Prize in Chemistry to two early pioneers, Jennifer Doudna and Emmanuelle Charpentier.

But the year also brought important progress from early biotech adopters.Editas Medicine and Intellia Therapeutics, for example, notched CRISPR firsts with use of the editing technology inside the human body.

And CRISPR Therapeutics and partner Vertex showed their experimental therapy, which uses CRISPR to edit stem cells, worked exceptionally well in the first 10 patients with either sickle cell disease or beta thalassemia treated in two early studies.

The data are the most concrete sign yet that CRISPR's clinical use can live up to its laboratory promise. While all three companies' therapies are still in early stages, their advances have ginned up substantial investor enthusiasm.

Together, the market value of CRISPR Therapeutics, Editas and Intellia totals nearly $25 billion. Beam Therapeutics, a startup that uses a more precise form of gene editing, is worth nearly $6 billion.

"Gene therapy will have a big role to play," said John Evans, Beam's CEO. "But I do think in the last year or so there's a growing realization that, when possible, you'd probably rather edit than add an extra gene."

Clinical tests will prove that out but, until then, the large upswing in share price for gene editing companies may not be sustainable as valuations creep higher and higher. Some of the recent run-up, for instance,appears driven by money flowing from generalist investors through exchange-trade funds, rather than from investors experienced in handicapping preclinical- or early clinical-stage companies.

"They're overdue for some type of rationalization," predicted Brad Loncar, CEO of Loncar Investments, adding that many companies are targeting similar diseases, most commonly sickle cell and beta thalassemia.

Tasked with replacing faulty genes with functional ones, scientists for the most part have turned to two types of viruses to safely shuttle genetic instructions into cells. Adeno-associated viruses, or AAVs,are typically used for infused treatments, while researchers working on cells extracted from patients generally opt for lentiviruses.

Each virus class has advantages, but also notable drawbacks. AAVs, for instance, can trigger pre-existing immune defenses in some people, making those individuals ineligible or poor candidates for gene therapy. Lentiviruses, by contrast, are known to integrate their DNA directly into the genomes of cells they infect a useful attribute in some regards but limiting in others.

Over decades of gene therapy research, scientists have found ways to tweak and modify these viral vectors to better suit their needs, but the basic tools are the same. Jim Wilson, a gene therapy pioneer who ran the study that led to the death of teenager Jesse Gelsinger in 1999, told attendees at a STAT conference last fall that he's "somewhat disappointed" by slow progress in viral vector research.

And as more and more gene therapies enter clinical testing, the limitations of current viral vectors have become more apparent.

The pace of research might be picking up, however. Recently, a number of companies aiming to build better delivery tools have launched, including Harvard University spinout Dyno Therapeutics and 4D Molecular Therapeutics, which recently raised $222 million in an initial public offering.

Larger companies are interested, too. Roche, Sarepta and Novartis have all partnered with Dyno, for example.

In gene editing, meanwhile, researchers are developing new ways to cut DNA, while Beam and others are advancing different editing approaches altogether.

Billions of dollars have flowed from pharmaceutical companies into gene therapy over the past few years, leaving few large multinational drugmakers without a research presence.

2020 was no different, with sizable acquisitions inked by Bayer and Eli Lilly, as well as an array of smaller investments from Pfizer, Novartis, Johnson & Johnson, Biogen,and UCB. And CSL Behring, best known for its blood plasma products, spent nearly half a billion dollars to buy UniQure's most advanced gene therapy, a treatment for hemophilia B.

Over the past three years, there's been at least $30 billion spent on biotechs involved in gene or cell therapy. (Four deals account for the majority of that value.)

All of that dealmaking, while following promising and compelling science, is ultimately a bet that one-time genetic treatments can be scaled up and commercialized into a lucrative business.

Many of the acquired companies are working on therapies for very rare disorders affecting hundreds or thousands of people. A handful, however, are taking aim at more prevalent conditions, starting with still relatively uncommon diseases like hemophilia to ones affecting millions of people like Parkinson's.

"For gene therapy to meet our lofty expectations not just for investors, but for society it has to make the leap from these ultra-rare diseases," said Loncar.

Commercially, the track record for the few therapies on the market in the U.S. is mixed.Luxturna, now owned by Roche, is a niche product.Zolgensma has broader use and earned Novartis about $1 billion in the year and a half it's been commercially available.

Two cell therapies from Novartis and Gilead, meanwhile, have struggled to gain traction.

Gene therapy's biggest commercial test yet was supposed to come this year, with the expected approval of BioMarin's Roctavian in hemophilia A. The FDA's surprise rejection could mean a yearslong delay in the U.S., but the challenges of pricing, reimbursement and patient access in gene therapy remain dauntingly large.

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5 questions facing gene therapy in 2021 - BioPharma Dive

WALTHAM, Mass., Jan. 11, 2021 /PRNewswire/ --Fresenius Medical Care, the world's leading provider of products and services for people with chronic kidney failure,announced today that the company's Frenova division has enrolled the first participants in its new initiative to develop the largest renal-focused genomic registry in the world.

Along with this key milestone, the company also announced that Ali Gharavi, MD, Chief of the Division of Nephrology at Columbia University Irving Medical Center and Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons, will lead the project and provide scientific guidance as Principal Investigator.

As a contract clinical development services company dedicated exclusively to medicines and medical products in renal research, Frenova orchestrates studies within the clinical footprint of Fresenius Medical Care, which provides dialysis treatments to about 350,000 patients around the globe. The renal-focused genomic registry represents a new business line within Frenova, which is based in Fresenius Medical Care's Global Medical Office.

As part of its growth strategy 2025, Fresenius Medical Care is using digital technologies and the capability to analyze huge amounts of data to develop new forms of renal therapy.

Nephrology has been under-represented in clinical research, even as rapid progress in gene sequencing and analysis has led to advances in precision medicine and individualized care in oncology, cardiology and other medical areas. Frenova's new genomic registry will contain genetic sequencing data from chronic kidney disease patients worldwide, which will be used by researchers to improve the understanding of kidney disease. Frenova developed the registry after researchers identified the lack of a large-scale, renal-focused registry of genomic and clinical data as a major impediment to kidney disease research.

"The new Frenova registry will close this gap by generating data that adds a clinical and genetic backbone to help support and fuel scientific innovation," said Franklin W. Maddux, MD, Global Chief Medical Officer of Fresenius Medical Care. "Theevidence for genetic drivers in kidney diseases is substantial, but much larger data sets will be needed to untangle the complex interactions that lead to kidney injury. By combining clinical and genetic sequencing datafrom ethnically and pathologically diverse participants, this genomicand phenotypic research resource will help scientists better understand how genetic variations in patients can lead to more precise diagnoses and therapies that help improve outcomes by individualizing care."

"Our renal-focused genomic registry will be a sustainable and comprehensive tool for kidney-focused research," said Kurt Mussina, President of Frenova. "It will bring patients, their families, patient advocacy groups, physicians and researchers together in the common cause of improving the lives of people living with kidney disease."

Learn more about Frenova Renal Research at https://www.frenova.com/

Fresenius Medical Care is the world's leading provider of products and services for individuals with renal diseases of which around 3.5 million patients worldwide regularly undergo dialysis treatment. Through its network of 4,073 dialysis clinics, Fresenius Medical Care provides dialysis treatments for 349,167 patients around the globe. Fresenius Medical Care is also the leading provider of dialysis products such as dialysis machines or dialyzers. Along with the core business, the company focuses on expanding the range of related medical services in the field of Care Coordination. Fresenius Medical Care is listed on the Frankfurt Stock Exchange (FME) and on the New York Stock Exchange (FMS).

For more information visit the Company's website at http://www.freseniusmedicalcare.com.

DisclaimerThis release contains forward-looking statements that are subject to various risks and uncertainties. Actual results could differ materially from those described in these forward-looking statements due to various factors, including, but not limited to, changes in business, economic and competitive conditions, legal changes, regulatory approvals, results of clinical studies, foreign exchange rate fluctuations, uncertainties in litigation or investigative proceedings, and the availability of financing. These and other risks and uncertainties are detailed in Fresenius Medical Care AG & Co. KGaA's reports filed with the U.S. Securities and Exchange Commission. Fresenius Medical Care AG & Co. KGaA does not undertake any responsibility to update the forward-looking statements in this release.

Media ContactsMichael GavinT +49 6172 608-2978[emailprotected]

Brad PufferT +1 781 699-3331[emailprotected]

Contact for analysts and investorsDr. Dominik HegerT +49 6172 609-2601[emailprotected]www.freseniusmedicalcare.com

SOURCE Fresenius Medical Care Holdings, Inc.

https://fmcna.com/

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Fresenius Medical Care's Frenova enrolls patients in initiative to build world's largest genomic registry targeting kidney disease - PRNewswire

Preparations on Track for First Half 2021 Commercial Launch of Libmeldy (OTL-200), the First Approved Product for Metachromatic Leukodystrophy (MLD) in the EU

Filing Strategy for OTL-200 Biologics License Application (BLA) in MLD in the U.S. to be Communicated by Mid-2021 Following Additional Regulatory Interactions

Marketing Authorization Application (MAA) Filing for OTL-103 in Wiskott-Aldrich Syndrome (WAS) on Track for Year End 2021 in the EU; Followed by BLA Filing in 2022 in the U.S.

New Clinical Data for OTL-203 (for MPS-I) and OTL-201 (for MPS-IIIA) Accepted for Oral Presentation at February 2021 WORLD Symposium; Preclinical Data from Research Programs in Larger Indications Expected in 2021

$192M in Cash and Investments to Support Strategic Execution into the First Half of 2022

BOSTONandLONDON, Jan. 11, 2021 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today outlined the companys 2021 strategic priorities in advance of its attendance at the virtual 39thAnnual J.P. Morgan Healthcare Conference. These priorities support the companys plan of building a successful commercial business in HSC gene therapy and advancing its portfolio of investigational medicines for high-value, high-need indications.

In a year that challenged how we live and work, Im extremely proud of Orchards achievements in 2020, said Bobby Gaspar, M.D., Ph.D., chief executive officer, Orchard Therapeutics. Our accomplishments were a direct result of the drive and innovation that fuels our commitment to bring our potentially life-saving HSC therapies to patients, including Libmeldy, which is the first product approved for the treatment of eligible patients with early-onset MLD in the EU. With the HSC approach to gene therapy as our scientific foundation, we are focused on the capabilities that can deliver our therapies on a global commercial scale and support our ability to also treat larger indications over time. It has been a privilege to be a pioneer in changing the way medicine is practiced in these conditions, and we look forward to another year of continued execution and scientific progress.

2021 Corporate PrioritiesOrchard has outlined the following key corporate objectives and expected milestones for 2021:

In preparation for a European launch, Orchard has put in place the commercial infrastructure to support Libmeldy as well as future product launches. The company is qualifying five treatment centers in the UK, Germany, Italy, France and the Netherlands with specialized expertise in transplant and disease area knowledge. In addition, the company expects to leverage cross-border and treatment abroad reimbursement pathways in both Europe and markets such as the Middle East and Turkey. Activities are also underway to drive timely MLD patient identification and access, including disease awareness, genetic testing and newborn screening studies, which have started or are on track to initiate in five countries in 2021.

The company also provided an update concerning the impact of the COVID-19 pandemic on certain development activities. These include restrictions to laboratory access at Orchard and third-party service providers, which is impacting the timeline to develop a specific functional potency assay for OTL-103 in WAS, as requested by the FDA. As a result, the company now expects to file a BLA for OTL-103 in the U.S. in 2022. Orchard is utilizing the benefits provided under OTL-103s RMAT designation and plans to continue interacting with the FDA in 2021 to confirm the data package for the BLA filing. In addition, with several of the follow-up visits associated with the companys active clinical trials impacted by COVID-19 travel restrictions and other trial site limitations, Orchard is using alternative data collection approaches to capture the necessary data to support future regulatory filings.

Frank Thomas, president and chief operating officer continued, Starting 2021 with a clear set of strategic priorities is crucial to our ability to effectively manage the business while fueling Orchards continued growth. Our launch preparations for Libmeldy not only mark our evolution towards a fully integrated company but establish a common manufacturing, commercial and operational infrastructure to support multiple future potential products. This work is complemented by our exciting proof-of-concept and research pipeline that we look forward to advancing internally or in partnership.

Key 2020 AchievementsOrchards key 2020 achievements are highlighted below.

Cash GuidanceThe company ended 2020 with approximately $192 million of cash and investments. The company expects that its cash, cash equivalents and marketable securities as of December 31, 2020 will enable the funding of its currently anticipated operating expenses and capital expenditure requirements into the first half of 2022. This excludes the $50 million expected to be available under the companys credit facility and any non-dilutive capital received from potential future partnerships or priority review vouchers.

About Libmeldy / OTL-200

Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), also known as OTL-200, has been approved by the European Commission for the treatment of MLD in eligible early-onset patients characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For more information about Libmeldy, please see the Summary of Product Characteristics (SmPC) available on the EMA website.

Libmeldy is not approved outside of the European Union, UK, Iceland, Liechtenstein and Norway. OTL-200 is an investigational therapy in the US.

Libmeldy was developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy.

About Orchard

Orchard Therapeuticsis a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Ourex vivoautologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and theSan Raffaele Telethon Institute for Gene Therapy inMilan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S.headquarters inBoston. For more information, please visitwww.orchard-tx.com, and follow us on TwitterandLinkedIn.

Availability of Other Information About Orchard

Investors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (TwitterandLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Forward-Looking Statements

This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, including its plans and expectations for the commercialization of Libmeldy, the therapeutic potential of Libmeldy (OTL-200) and Orchards product candidates, including the product candidates referred to in this release, Orchards expectations regarding its ongoing preclinical and clinical trials, including the timing of enrollment for clinical trials and release of additional preclinical and clinical data, the likelihood that data from clinical trials will be positive and support further clinical development and regulatory approval of Orchard's product candidates, and Orchards financial condition and cash runway into the first half of 2022. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials of Libmeldy will not continue or be repeated in our ongoing or planned clinical trials of Libmeldy, will be insufficient to support regulatory submissions or marketing approval in the US or to maintain marketing approval in the EU, or that long-term adverse safety findings may be discovered; the risk that any one or more of Orchards product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk of cessation or delay of any of Orchards ongoing or planned clinical trials; the risk that Orchard may not successfully recruit or enroll a sufficient number of patients for its clinical trials; the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates; the delay of any of Orchards regulatory submissions; the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates or the receipt of restricted marketing approvals; the inability or risk of delays in Orchards ability to commercialize its product candidates, if approved, or Libmeldy, including the risk that Orchard may not secure adequate pricing or reimbursement to support continued development or commercialization of Libmeldy; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2020, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaChristine HarrisonVice President, Corporate Affairs+1 202-415-0137media@orchard-tx.com

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Orchard Therapeutics Announces 2021 Corporate Priorities Supporting the Build-out of its Commercial Business in Hematopoietic Stem Cell (HSC) Gene...

Dive Brief:

Biogen is at a crossroads, awaiting a regulatory decision on the Alzheimer's drug aducanumab by early March that will have wide-ranging implications for the biotech's future.

But while aducanumab's fate hangs in the balance, Biogen has been stocking up on other early-stage assets, aiming to diversify its portfolio beyond risky neuroscience bets. Company executives in 2019 said they were putting more emphasis on ophthalmology and immunology, for instance, and that same year, the company spent $800 million on an acquisition of the eye gene therapy company Nightstar Therapeutics.

ViGeneron offers a novel technology for harnessing adeno-associated virus vectors to treat eye disease. Its vgAAV vectors are designed to get around some of the limits of the standard gene therapy delivery tools and target a variety of different cell types. The two companies noted the technology's potential to more efficiently transduce retinal cells via eye injections, which in theory could lead to more potent treatments.

The company is still fairly new, however, having being spun off in 2017 by Ludwig-Maximilians University in Munich. Its investors include WuXi AppTec and Sequoia Capital China. None of its experimental treatments, led by a gene therapy for retinitis pigmentosa, are in human testing.

The deal is another bet by Biogen on genetic medicine. Earlier this year, the biotech formed a gene editing alliance with Sangamo Therapeutics that could be worth billions of dollars.

Still, investors at the moment are most focused on aducanumab. The roller coaster ride for the drug began in March 2019, when the drug appeared to have failed two clinical trials. Seven months later, however, the company said a further analysis showed significant benefits for a high dose in one clinical trial, and the Food and Drug Administration agreed to review the medicine.

In November 2020, the FDA convened a panel of outside experts, whose review was overwhelmingly negative. Panelists criticized the agency for being too optimistic about Biogen's data and voted near-unanimously against approving the drug.

The committee's vote isn't binding for the FDA, though the agency typically follows its advice. Regulators are due to make their final decision on aducanumab by March 7.

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Biogen pushes further into eye gene therapy with new deal - BioPharma Dive

January 11, 2021 -Researchers from the Johns Hopkins departments of oncology and pathology, the Johns Hopkins Kimmel Cancer Center, the Johns Hopkins University (JHU) School of Medicine, and 18 other organizations around the US and Poland have compiled a database of head and neck cancers to speed the development of precision medicine therapies.

The database is believed to be the most comprehensive molecular characterization to date of the most common type of head and neck cancer. With the database, researchers clarified the contribution of key cancer-associated genes, proteins, and signaling pathways in these cancers, as well as proposed possible new treatment avenues.

In a study published in Cancer Cell, researchers noted that head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignancy worldwide. HNSCCs arise in the cells that line the upper aerodigestive tract, including the lips, mouth, tongue, nose, throat, vocal chords, and part of the esophagus and windpipe.

HNSCCs can be classified into HPV-associated and HPV-negative subtypes. About 75 percent of all HNSCCs are HPV-negative, meaning they have distinct molecular profiles and significantly worse prognoses.

Most patients are treated with surgery, chemotherapy, and radiation. While targeted agents like an epidermal growth factor receptor (EGFR) monoclonal antibody inhibitor and two PD-1 immune checkpoint inhibitors have been approved by the FDA, overall response rates have been moderate.

Until now, researchers have lacked a complete understanding of how genetic aberrations drive tumor types. Experts have also had limited ability to translate genomic and transcriptomic findings into improved HNSCC treatment.

Researchers analyzed tumors from 108 patients who had not yet received cancer treatment, as well as 66 samples of healthy tissue surrounding the tumors. The team aimed to systematically catalogue HPV-negative HNSCC-associated proteins, phosphosites (areas where they are modified by phosphate groups) and signaling pathways, finding three distinct subtypes of HNSCCs.

The first subtype researchers identified, called CIN, showed the worst prognosis. This subtype was associated with the larynx, a strong history of smoking and high instability of chromosomes. Because this subtype was associated with frequent aberrations of the CCND1 and CDKN2A genes, and high activity of the enzymes CDK4 and CDK6, this type of cancer may respond best to anti-cancer drugs called CDK4/6 inhibitors.

The second subtype, called Basal, showed protein elevations of several basal factors, the most basic set of proteins needed to activate gene transcription. Researchers characterized this subtype by high activity in a signaling pathway called EGFR and high expression of molecules called AREG and TNFA, which attach to the EGFR tumor protein.

The team concluded that these cancers may respond best to anti-cancer drugs called monoclonal antibodies that are aimed at EGFR.

The third subtype, called Immune, was discovered among tumors in people who did not smoke and showed high expression of multiple immune checkpoint proteins. Researchers believe that these tumors may respond to anti-cancer drugs called immune checkpoint inhibitors. Overall, 32 percent of CIN tumors, 62 percent of Basal tumors, and 83 percent of Immune tumors had high potential for the suggested treatments.

The team also found two modes of activation of EGFR, suggesting a new strategy to stratify HNSCCs based on the number of molecules bound to EGFR, for effective treatment with monoclonal antibody drugs that enlist the natural immune system to fight cancer.

The group also noted that widespread deletion of immune modulatory genes among these cancers accounts for a loss of ability to produce an immune response.

This study extends our biological understanding of HPV-negative HNSCCs and generates therapeutic hypotheses that may serve as the basis for future studies and clinical trials toward molecularly guided precision medicine treatment of this aggressive cancer type, saidDaniel Chan, PhD, principal investigator, a professor of pathology and oncology, and director of theCenter for Biomarker Discovery and Translationat JHU School of Medicine.

These findings have critical implications for head and neck cancer precision medicine treatments. The research team plans to uncover the properties of HPV-positive HNSCCs.

Previously, patients would be treated using different options, but there was no systematic way to know which treatment would be the best option for certain patients, said Hui Zhang, PhD, co-principal investigator of the study, professor of pathology and oncology, and director of theMass Spectrometry Core facilityat JHU School of Medicine.

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Cancer Database Paves the Way for Precision Medicine Therapies - HealthITAnalytics.com

Full-Year 2020 Galafold Revenue of~$261M Exceeds Guidance

Strengthened Galafold IP Portfolio Now Includes 24 Issued Patents Including 13 Patents through 2038

Pompe Phase 3 PROPEL Study Last Patient, Last Visit Complete with Data Expected in 1Q2021

AT-GAA Pompe Clinical and CMC Milestones On-Track to Support 2021 BLA and MAA

Multiple Data and Manufacturing Updates and Advancements Planned Across Industry-Leading Rare Disease Gene Therapy Portfolio

Cash Position Sufficient to Achieve Self-Sustainability

CRANBURY, N.J., Jan. 11, 2021 (GLOBE NEWSWIRE) -- Amicus Therapeutics (Nasdaq: FOLD), a patient-dedicated global biotechnology company focused on discovering, developing and delivering novel medicines for rare diseases, today provided preliminary, unaudited Galafold revenue for the full-year 2020 and introduced its full-year 2021 strategic outlook and financial guidance.

Over the previous year, Amicus substantially met or exceeded its strategic priorities, highlighted by:

John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, Inc., stated, During 2020, Amicus remained steadfast on our journey to becoming a leading global rare disease biotechnology company. Despite the extraordinary challenges of COVID, Amicus emerged from 2020 a better and stronger company organizationally, strategically, scientifically and financially. Following continued momentum and strong adoption across the globe for our Fabry precision medicine Galafold, we have again for 2020 exceeded our annual revenue guidance. We are eagerly looking ahead to our Phase 3 readout of AT-GAA in Pompe disease this quarter with high expectations that this novel medicine has the potential to become the new standard of care in Pompe disease treatment. And finally, our world leading gene therapy pipeline gives us tremendous promise in the ability to develop next-generation gene therapies to treat many devastating rare diseases. Amicus is in a stronger position than ever and remains focused on transforming the lives of people living with these rare, life-threatening conditions and creating significant value for our shareholders.

Amicus is focused on the following five key strategic priorities in 2021:

1 Guidance range to be provided on full-year earnings call.

Mr. Crowley will discuss Amicus' corporate objectives and key milestones in a presentation at the 39th Annual J.P. Morgan Healthcare Conference on Tuesday, January 12, 2021, at 8:20 a.m. ET. A live webcast of the presentation can be accessed through the Investors section of the Amicus Therapeutics corporate web site at http://ir.amicusrx.com/events.cfm, and will be archived for 90 days.

Full-Year 2020 Galafold Summary and 2021 Guidance

Global revenue for Galafold in full-year 2020 was approximately $261 million, preliminary and unaudited, representing a year-over-year increase of 43% from total revenue of $182 million in 2019, and exceeded the Companys 2020 guidance of $250 million to $260 million despite worsening of the COVID-19 pandemic towards the end of the year. Full-year revenue benefited from a positive currency impact of approximately $2 million. Fourth quarter Galafold revenue was approximately $70 million, preliminary and unaudited. While we observed increased lag times between patient identification and Galafold initiation due to the resurgence of COVID in the fourth quarter, demand for Galafold for Fabry patients with amenable variants worldwide remained strong with queues of potential new Galafold patients in multiple geographies. We also continue to see 90%+ compliance rates among already treated Galafold patients.

For the full-year 2021, the Company anticipates total Galafold of revenue at least $300 million+. Double-digit revenue growth in 2021 is expected to be driven by continued operational growth and commercial execution across all major markets, including the U.S., EU, U.K. and Japan. Non-GAAP operating expense guidance in 2021 is expected to remain flat at $410 million to $420 million, driven by continued investment in the global Galafold launch, AT-GAA clinical studies and advancing the gene therapy pipeline. The current cash position is sufficient to achieve self-sustainability without the need for future dilutive financing.

Updates and Anticipated 2021 Milestones by Program

Galafold (migalastat) Oral Precision Medicine for People Living with Fabry Disease and have an Amenable Variant

AT-GAA For Pompe Disease

Gene Therapy Pipeline

About GalafoldGalafold(migalastat) 123 mg capsules is an oral pharmacological chaperone of alpha-Galactosidase A (alpha-Gal A) for the treatment of Fabry disease in adults who have amenableGLAvariants. In these patients, Galafold works by stabilizing the bodys own dysfunctional enzyme so that it can clear the accumulation of disease substrate. Globally, Amicus Therapeutics estimates that approximately 35 to 50 percent of Fabry patients may have amenableGLAvariants, though amenability rates within this range vary by geography. Galafold is approved in over 40 countries around the world, including the U.S., EU, U.K., Japan and others.

U.S. INDICATIONS AND USAGEGalafold is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based oninvitroassay data.

This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

U.S. IMPORTANT SAFETY INFORMATION

ADVERSE REACTIONSThe most common adverse reactions reported with Galafold (10%) were headache, nasopharyngitis, urinary tract infection, nausea and pyrexia.

USE IN SPECIFIC POPULATIONSThere is insufficient clinical data on Galafold use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

It is not known if Galafold is present in human milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Galafold and any potential adverse effects on the breastfed child from Galafold or from the underlying maternal condition.

Galafold is not recommended for use in patients with severe renal impairment or end-stage renal disease requiring dialysis.

The safety and effectiveness of Galafold have not been established in pediatric patients.

To report Suspected Adverse Reactions, contact Amicus Therapeutics at 1-877-4AMICUS or FDA at1-800-FDA-1088 orwww.fda.gov/medwatch.

For additional information about Galafold, including the full U.S. Prescribing Information, please visithttps://www.amicusrx.com/pi/Galafold.pdf.

EU Important Safety InformationTreatment with Galafold should be initiated and supervised by specialists experienced in the diagnosis and treatment of Fabry disease. Galafold is not recommended for use in patients with a nonamenable mutation.

For further important safety information for Galafold, including posology and method of administration, special warnings, drug interactions and adverse drug reactions, please see the European SmPC for Galafold available from the EMA website at http://www.ema.europa.eu.

About Fabry DiseaseFabry disease is an inherited lysosomal disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A), which results from mutations in the GLA gene. The primary biological function of alpha-Gal A is to degrade specific lipids in lysosomes, including globotriaosylceramide (referred to here as GL-3 and also known as Gb3). Lipids that can be degraded by the action of alpha-Gal A are called "substrates" of the enzyme. Reduced or absent levels of alpha-Gal A activity lead to the accumulation of GL-3 in the affected tissues, including heart, kidneys, and skin. Accumulation of GL-3 and progressive deterioration of organ function is believed to lead to the morbidity and mortality of Fabry disease. The symptoms can be severe, differ from person to person, and begin at an early age.

AboutAmicus TherapeuticsAmicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the companys website at http://www.amicusrx.com, and follow us onTwitterandLinkedIn.

Forward Looking StatementThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 relating to preclinical and clinical development of our product candidates, the timing and reporting of results from preclinical studies and clinical trials, the prospects and timing of the potential regulatory approval of our product candidates, commercialization plans, manufacturing and supply plans, financing plans, and the projected revenues and cash position for the Company. The inclusion of forward-looking statements should not be regarded as a representation by us that any of our plans will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong and can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding the goals, progress, timing, and outcomes of discussions with regulatory authorities, and in particular the potential goals, progress, timing, and results of preclinical studies and clinical trials, including as they are impacted by COVID-19 related disruption, are based on current information. The potential impact on operations from the COVID-19 pandemic is inherently unknown and cannot be predicted with confidence and may cause actual results and performance to differ materially from the statements in this release, including without limitation, because of the impact on general political and economic conditions, including as a result of efforts by governmental authorities to mitigate COVID-19, such as travel bans, shelter in place orders and third-party business closures and resource allocations, manufacturing and supply chain disruptions and limitations on patient access to commercial or clinical product. In addition to the impact of the COVID-19 pandemic, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in our business, including, without limitation: the potential that results of clinical or preclinical studies indicate that the product candidates are unsafe or ineffective; the potential that it may be difficult to enroll patients in our clinical trials; the potential that regulatory authorities, including the FDA, EMA, and PMDA, may not grant or may delay approval for our product candidates; the potential that we may not be successful in commercializing Galafold in Europe, Japan, the US and other geographies or our other product candidates if and when approved; the potential that preclinical and clinical studies could be delayed because we identify serious side effects or other safety issues; the potential that we may not be able to manufacture or supply sufficient clinical or commercial products; and the potential that we will need additional funding to complete all of our studies and manufacturing. Further, the results of earlier preclinical studies and/or clinical trials may not be predictive of future results. Statements regarding corporate financial guidance and financial goals and the attainment of such goals. With respect to statements regarding projections of the Company's revenue and cash position, actual results may differ based on market factors and the Company's ability to execute its operational and budget plans. In addition, all forward-looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended December 31, 2019 and the Quarterly Report filed on Form 10-Q for the quarter ended September 30, 2020. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and we undertake no obligation to revise or update this news release to reflect events or circumstances after the date hereof.

Non-GAAP Financial MeasuresIn addition to financial information prepared in accordance with U.S. GAAP, this presentation also contains adjusted financial measures that we believe provide investors and management with supplemental information relating to operating performance and trends that facilitate comparisons between periods and with respect to projected information. These adjusted financial measures are non-GAAP measures and should be considered in addition to, but not as a substitute for, the information prepared in accordance with U.S. GAAP. We typically exclude certain GAAP items that management does not believe affect our basic operations and that do not meet the GAAP definition of unusual or non-recurring items. Other companies may define these measures in different ways. When we provide our expectation for non-GAAP operating expenses on a forward-looking basis, a reconciliation of the differences between the non-GAAP expectation and the corresponding GAAP measure generally is not available without unreasonable effort due to potentially high variability, complexity and low visibility as to the items that would be excluded from the GAAP measure in the relevant future period, such as unusual gains or losses. The variability of the excluded items may have a significant, and potentially unpredictable, impact on our future GAAP results.

CONTACT:

Investors: Amicus Therapeutics Andrew FaughnanDirector, Investor Relationsafaughnan@amicusrx.com(609) 662-3809

Media: Amicus Therapeutics Diana Moore Head of Global Corporate Communicationsdmoore@amicusrx.com(609) 662-5079

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Amicus Therapeutics Reports Preliminary 2020 Revenue and Provides 2021 Outlook - GlobeNewswire

No! The doctor snapped. Look at me!

I had been staring her in the eyes, as she had ordered, but when a doctor on my other side began jabbing me with a needle, I started to turn my head. Dont look at it, the first doctor said. I obeyed.

This was in early August in New Orleans, where I had signed up to be a participant in the clinical trial for the Pfizer-BioNTech COVID-19 vaccine. It was a blind study, which meant I was not supposed to know whether I had gotten the placebo or the real vaccine. I asked the doctor if I would really been able to tell by looking at the syringe. Probably not, she answered, but we want to be careful. This is very important to get right.

I became a vaccine guinea pig because, in addition to wanting to be useful, I had a deep interest in the wondrous new roles now being played by RNA, the genetic material that is at the heart of new types of vaccines, cancer treatments and gene-editing tools. I was writing a book on the Berkeley biochemist Jennifer Doudna. She was a pioneer in determining the structure of RNA, which helped her and her doctoral adviser figure out how it could be the origin of all life on this planet. Then she and a colleague invented an RNA-guided gene-editing tool, which won them the 2020 Nobel Prize in Chemistry.

The tool is based on a system that bacteria use to fight viruses. Bacteria develop clustered repeated sequences in their DNA, known as CRISPRs, that can remember dangerous viruses and then deploy RNA-guided scissors to destroy them. In other words, its an immune system that can adapt itself to fight each new wave of virusesjust what we humans need. Now, with the recently approved Pfizer-BioNTech vaccine and a similar one from Moderna being slowly rolled out across the U.S. and Europe, RNA has been deployed to make a whole new type of vaccine that will, when it reaches enough people, change the course of the pandemic.

Drs. Ugur Sahin and Ozlem Tureci, Co-founders, BioNTech. In January 2020, before many in the Western world were paying attention to a new virus spreading in China, Dr. Ugur Sahin was convinced it would spur a pandemic. Sahin, who in 2008 co-founded the German biotech company BioNTech with his wife Dr. Ozlem Tureci, went to work on a vaccine and by March called his contact at Pfizer, a much larger pharmaceutical company with which BioNTech had previously worked on an influenza vaccine using mRNA. Less than a year later, the Pfizer-BioNTech COVID-19 vaccine became the first ever mRNA vaccine available for widespread use. Even so, Sahin, BioNTechs CEO, and Tureci, its chief medical officer, maintain that BioNTech is not an mRNA company but rather an immunotherapy company. Much of the couples workboth at BioNTech and at their previous venture, Ganymedhas focused on treating cancer. But it is mRNA, and the COVID-19 vaccine made possible by the technology, that has pushed the famously hardworking couple into the limelightand helped them become one of the richest pairs in Germany, though they reportedly still bicycle to work and live in a modest apartment near their office.

Dina LitovskyRedux for TIME

Up until last year, vaccines had not changed very much, at least in concept, for more than two centuries. Most have been modeled on the discovery made in 1796 by the English doctor Edward Jenner, who noticed that many milkmaids were immune to smallpox. They had all been infected by a form of pox that afflicts cows but is relatively harmless to humans, and Jenner surmised that the cowpox had given them immunity to smallpox. So he took some pus from a cowpox blister, rubbed it into scratches he made in the arm of his gardeners 8-year-old son and then (this was in the days before bioethics panels) exposed the kid to smallpox. He didnt become ill.

Before then, inoculations were done by giving patients a small dose of the actual smallpox virus, hoping that they would get a mild case and then be immune. Jenners great advance was to use a related but relatively harmless virus. Ever since, vaccinations have been based on the idea of exposing a patient to a safe facsimile of a dangerous virus or other germ. This is intended to kick the persons adaptive immune system into gear. When it works, the body produces antibodies that will, sometimes for many years, fend off any infection if the real germ attacks.

One approach is to inject a safely weakened version of the virus. These can be good teachers, because they look very much like the real thing. The body responds by making antibodies for fighting them, and the immunity can last a lifetime. Albert Sabin used this approach for the oral polio vaccine in the 1950s, and thats the way we now fend off measles, mumps, rubella and chicken pox.

At the same time Sabin was trying to develop a vaccine based on a weakened polio virus, Jonas Salk succeeded with a safer approach: using a killed or inactivated virus. This type of vaccine can still teach a persons immune system how to fight off the live virus but is less likely to cause serious side effects. Two Chinese companies, Sinopharm and Sinovac, have used this approach to develop vaccines for COVID-19 that are now in limited use in China, the UAE and Indonesia.

Another traditional approach is to inject a subunit of the virus, such as one of the proteins that are on the viruss coat. The immune system will then remember these, allowing the body to mount a quick and robust response when it encounters the actual virus. The vaccine against the hepatitis B virus, for example, works this way. Using only a fragment of the virus means that they are safer to inject into a patient and easier to produce, but they are often not as good at producing long-term immunity. The Maryland-based biotech Novavax is in late-stage clinical trials for a COVID-19 vaccine using this approach, and it is the basis for one of the two vaccines already being rolled out in Russia.

The plague year of 2020 will be remembered as the time when these traditional vaccines were supplanted by something fundamentally new: genetic vaccines, which deliver a gene or piece of genetic code into human cells. The genetic instructions then cause the cells to produce, on their own, safe components of the target virus in order to stimulate the patients immune system.

For SARS-CoV-2the virus that causes COVID-19the target component is its spike protein, which studs the outer envelope of the virus and enables it to infiltrate human cells. One method for doing this is by inserting the desired gene, using a technique known as recombinant DNA, into a harmless virus that can deliver the gene into human cells. To make a COVID vaccine, a gene that contains instructions for building part of a coronavirus spike protein is edited into the DNA of a weakened virus like an adenovirus, which can cause the common cold. The idea is that the re-engineered adenovirus will worm its way into human cells, where the new gene will cause the cells to make lots of these spike proteins. As a result, the persons immune system will be primed to respond rapidly if the real coronavirus strikes.

This approach led to one of the earliest COVID vaccine candidates, developed at the aptly named Jenner Institute of the University of Oxford. Scientists there engineered the spike-protein gene into an adenovirus that causes the common cold in chimpanzees, but is relatively harmless in humans.

The lead researcher at Oxford is Sarah Gilbert. She worked on developing a vaccine for Middle East respiratory syndrome (MERS) using the same chimp adenovirus. That epidemic waned before her vaccine could be deployed, but it gave her a head start when COVID-19 struck. She already knew that the chimp adenovirus had successfully delivered into humans the gene for the spike protein of MERS. As soon as the Chinese published the genetic sequence of the new coronavirus in January 2020, she began engineering its spike-protein gene into the chimp virus, waking each day at 4 a.m.

Her 21-year-old triplets, all of whom were studying biochemistry, volunteered to be early testers, getting the vaccine and seeing if they developed the desired antibodies. (They did.) Trials in monkeys conducted at a Montana primate center in March also produced promising results.

Bill Gates, whose foundation provided much of the funding, pushed Oxford to team up with a major company that could test, manufacture and distribute the vaccine. So Oxford forged a partnership with AstraZeneca, the British-Swedish pharmaceutical company. Unfortunately, the clinical trials turned out to be sloppy, with the wrong doses given to some participants, which led to delays. Britain authorized it for emergency use at the end of December, and the U.S. is likely to do so in the next two months.

Johnson & Johnson is testing a similar vaccine that uses a human adenovirus, rather than a chimpanzee one, as the delivery mechanism to carry a gene that codes for making part of the spike protein. Its a method that has shown promise in the past, but it could have the disadvantage that humans who have already been exposed to that adenovirus may have some immunity to it. Results from its clinical trial are expected later this month.

In addition, two other vaccines based on genetically engineered adenoviruses are now in limited distribution: one made by CanSino Biologics and being used on the military in China and another named Sputnik V from the Russian ministry of health.

There is another way to get genetic material into a human cell and cause it to produce the components of a dangerous virus, such as the spike proteins, that can stimulate the immune system. Instead of engineering the gene for the component into an adenovirus, you can simply inject the genetic code for the component into humans as DNA or RNA.

Lets start with DNA vaccines. Researchers at Inovio Pharmaceuticals and a handful of other companies in 2020 created a little circle of DNA that coded for parts of the coronavirus spike protein. The idea was that if it could get inside the nucleus of a cell, the DNA could very efficiently churn out instructions for the production of the spike-protein parts, which serve to train the immune system to react to the real thing.

The big challenge facing a DNA vaccine is delivery. How can you get the little ring of DNA not only into a human cell but into the nucleus of the cell? Injecting a lot of the DNA vaccine into a patients arm will cause some of the DNA to get into cells, but its not very efficient.

Some of the developers of DNA vaccines, including Inovio, tried to facilitate the delivery into human cells through a method called electroporation, which delivers electrical shock pulses to the patient at the site of the injection. That opens pores in the cell membranes and allows the DNA to get in. The electric pulse guns have lots of tiny needles and are unnerving to behold. Its not hard to see why this technique is unpopular, especially with those on the receiving end. So far, no easy and reliable delivery mechanism has been developed for getting DNA vaccines into the nucleus of human cells.

That leads us to the molecule that has proven victorious in the COVID vaccine race and deserves the title of TIME magazines Molecule of the Year: RNA. Its sibling DNA is more famous. But like many famous siblings, DNA doesnt do much work. It mainly stays bunkered down in the nucleus of our cells, protecting the information it encodes. RNA, on the other hand, actually goes out and gets things done. The genes encoded by our DNA are transcribed into snippets of RNA that venture out from the nucleus of our cells into the protein-manufacturing region. There, this messenger RNA (mRNA) oversees the assembly of the specified protein. In other words, instead of just sitting at home curating information, it makes real products.

Scientists including Sydney Brenner at Cambridge and James Watson at Harvard first identified and isolated mRNA molecules in 1961. But it was hard to harness them to do our bidding, because the bodys immune system often destroyed the mRNA that researchers engineered and attempted to introduce into the body. Then in 2005, a pair of researchers at the University of Pennsylvania, Katalin Kariko and Drew Weissman, showed how to tweak a synthetic mRNA molecule so it could get into human cells without being attacked by the bodys immune system.

Stphane Bancel, CEO, Moderna. Modernas COVID-19 vaccine was first tested in humans less than three months after news of the novel virus broke. But that lightning-fast development process belies the years of work that got Moderna to where it is today. The startup was founded in 2010 with the belief that mRNA technology, then still fairly new, could help treat any number of ailments. CEO Stphane Bancel, pictured above, joined a year later. Moderna wasnt originally focused on vaccines, but over time, its scientists began working toward vaccines against several infectious diseases as well as some forms of cancer. That experience came in handy when the COVID-19 pandemic arrived, leaving the world clamoring for a vaccine that could fight the deadly virusand fast. Bancels company took the challenge in stride, using its mRNA platform to develop a vaccine around 95% effective at protecting against COVID-19 disease in less than a year.

Cody OLoughlinThe New York Times/Redux

When the COVID-19 pandemic hit a year ago, two innovative young pharmaceutical companies decided to try to harness this role played by messenger RNA: the German company BioNTech, which formed a partnership with the U.S. company Pfizer; and Moderna, based in Cambridge, Mass. Their mission was to engineer messenger RNA carrying the code letters to make part of the coronavirus spike proteina string that begins CCUCGGCGGGCA and to deploy it in human cells.

BioNTech was founded in 2008 by the husband-and-wife team of Ugur Sahin and Ozlem Tureci, who met when they were training to be doctors in Germany in the early 1990s. Both were from Turkish immigrant families, and they shared a passion for medical research, so much so that they spent part of their wedding day working in the lab. They founded BioNTech with the goal of creating therapies that stimulate the immune system to fight cancerous cells. It also soon became a leader in devising medicines that use mRNA in vaccines against viruses.

In January 2020, Sahin read an article in the medical journal Lancet about a new coronavirus in China. After discussing it with his wife over breakfast, he sent an email to the other members of the BioNTech board saying that it was wrong to believe that this virus would come and go as easily as MERS and SARS. This time it is different, he told them.

BioNTech launched a crash project to devise a vaccine based on RNA sequences, which Sahin was able to write within days, that would cause human cells to make versions of the coronaviruss spike protein. Once it looked promising, Sahin called Kathrin Jansen, the head of vaccine research and development at Pfizer. The two companies had been working together since 2018 to develop flu vaccines using mRNA technology, and he asked her whether Pfizer would want to enter a similar partnership for a COVID vaccine. I was just about to call you and propose the same thing, Jansen replied. The deal was signed in March.

By then, a similar mRNA vaccine was being developed by Moderna, a much smaller company with only 800 employees. Its chair and co-founder, Noubar Afeyan, a Beirut-born Armenian who immigrated to the U.S., had become fascinated by mRNA in 2010, when he heard a pitch from a group of Harvard and MIT researchers. Together they formed Moderna, which initially focused on using mRNA to try to develop personalized cancer treatments, but soon began experimenting with using the technique to make vaccines against viruses.

In January 2020, Afeyan took one of his daughters to a restaurant near his office in Cambridge to celebrate her birthday. In the middle of the meal, he got an urgent text message from the CEO of his company, Stphane Bancel, in Switzerland. So he rushed outside in the freezing temperature, forgetting to grab his coat, to call him back.

Bancel said that he wanted to launch a project to use mRNA to attempt a vaccine against the new coronavirus. At that point, Moderna had more than 20 drugs in development but none had even reached the final stage of clinical trials. Nevertheless, Afeyan instantly authorized him to start work. Dont worry about the board, he said. Just get moving. Lacking Pfizers resources, Moderna had to depend on funding from the U.S. government. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, was supportive. Go for it, he declared. Whatever it costs, dont worry about it.

It took Bancel and his Moderna team only two days to create the RNA sequences that would produce the spike protein, and 41 days later, it shipped the first box of vials to the National Institutes of Health to begin early trials. Afeyan keeps a picture of that box on his cell phone.

An mRNA vaccine has certain advantages over a DNA vaccine, which has to use a re-engineered virus or other delivery mechanism to make it through the membrane that protects the nucleus of a cell. The RNA does not need to get into the nucleus. It simply needs to be delivered into the more-accessible outer region of cells, the cytoplasm, which is where proteins are constructed.

The Pfizer-BioNTech and Moderna vaccines do so by encapsulating the mRNA in tiny oily capsules, known as lipid nanoparticles. Moderna had been working for 10 years to improve its nanoparticles. This gave it one advantage over Pfizer-BioNTech: its particles were more stable and did not have to be stored at extremely low temperatures.

Katalin Kariko, Senior vice president, BioNTech. In 1995, after years of struggle, Hungarian-born Katalin Kariko was pushed off the path to full professorship at the University of Pennsylvania. Her work on mRNA, molecules she believed could fundamentally change the way humans treat disease, had stalled. Then, in 1997, she met and began working with immunologist Drew Weissman. In 2005, they published a study describing a modified form of artificial mRNAa discovery, they argued, that opened the door to mRNAs use in vaccines and other therapies. Eventually, Kariko and Weissman licensed their technology to the German company BioNTech, where Kariko, shown here in a portrait shot by a photographer working remotely, is now a senior vice president. Her patience paid off this year. The mRNA-based Pfizer-BioNTech coronavirus vaccine, which Kariko helped develop, has been shown to be 95% effective at preventing COVID-19.

Dina LitovskyRedux for TIME

By November, the results of the Pfizer-BioNTech and Moderna late-stage trials came back with resounding findings: both vaccines were more than 90% effective. A few weeks later, with COVID-19 once again surging throughout much of the world, they received emergency authorization from the U.S. Food and Drug Administration and became the vanguard of the biotech effort to beat back the pandemic.

The ability to code messenger RNA to do our bidding will transform medicine. As with the COVID vaccines, we can instruct mRNA to cause our cells to make antigensmolecules that stimulate our immune systemthat could protect us against many viruses, bacteria, or other pathogens that cause infectious disease. In addition, mRNA could in the future be used, as BioNTech and Moderna are pioneering, to fight cancer. Harnessing a process called immunotherapy, the mRNA can be coded to produce molecules that will cause the bodys immune system to identify and kill cancer cells.

RNA can also be engineered, as Jennifer Doudna and others discovered, to target genes for editing. Using the CRISPR system adapted from bacteria, RNA can guide scissors-like enzymes to specific sequences of DNA in order to eliminate or edit a gene. This technique has already been used in trials to cure sickle cell anemia. Now it is also being used in the war against COVID. Doudna and others have created RNA-guided enzymes that can directly detect SARS-CoV-2 and eventually could be used to destroy it.

More controversially, CRISPR could be used to create designer babies with inheritable genetic changes. In 2018, a young Chinese doctor used CRISPR to engineer twin girls so they did not have the receptor for the virus that causes AIDS. There was an immediate outburst of awe and then shock. The doctor was denounced, and there were calls for an international moratorium on inheritable gene edits. But in the wake of the pandemic, RNA-guided genetic editing to make our species less receptive to viruses may someday begin to seem more acceptable.

Throughout human history, we have been subjected to wave after wave of viral and bacterial plagues. One of the earliest known was the Babylon flu epidemic around 1200 B.C. The plague of Athens in 429 B.C. killed close to 100,000 people, the Antonine plague in the 2nd century killed 5 million, the plague of Justinian in the 6th century killed 50 million, and the Black Death of the 14th century took almost 200 million lives, close to half of Europes population.

The COVID-19 pandemic that killed more than 1.8 million people in 2020 will not be the final plague. However, thanks to the new RNA technology, our defenses against most future plagues are likely to be immensely faster and more effective. As new viruses come along, or as the current coronavirus mutates, researchers can quickly recode a vaccines mRNA to target the new threats. It was a bad day for viruses, Modernas chair Afeyan says about the Sunday when he got the first word of his companys clinical trial results. There was a sudden shift in the evolutionary balance between what human technology can do and what viruses can do. We may never have a pandemic again.

The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes are transcribed into RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to destroy viruses. Great inventions come from understanding basic science. Nature is beautiful that way.

Isaacson, a former editor of TIME, is the author of The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race, to be published in March. After the Pfizer vaccine was approved, he opted to remain in the clinical trial and has not yet been unblinded.

This appears in the January 18, 2021 issue of TIME.

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mRNA Technology Gave Us the First COVID-19 Vaccines. It Could Also Upend the Drug Industry - TIME

LEVERKUSEN, Germany & SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Leaps by Bayer and Senti Biosciences, Inc., a leading gene circuit company, today announced a USD 105 million Series B financing round. The financing was led by Leaps by Bayer, the impact investment arm of Bayer AG. Additional investors included Matrix Partners China, Mirae Asset Capital, Ridgeback Capital and Intel Capital as well as existing investors, including New Enterprise Associates (NEA), 8VC, Amgen Ventures and Lux Capital.

Senti Bio is at the forefront of using synthetic biology to engineer gene circuits that improve cell and gene therapy products. A gene circuit is an assembly of multi-component genetic constructs specifically designed to program cells to interact with the bodys complex environment using logic to perform desired therapeutic functions. Senti Bio uses these gene circuits to create smarter cell and gene therapies with enhanced therapeutic properties that aim to increase efficacy, precision and control.

Senti Bio is applying its gene circuit technology platform to develop an internal therapeutic pipeline of allogeneic chimeric antigen receptor natural killer (CAR-NK) cells. Senti Bios lead development candidates include next-generation allogeneic CAR-NK cell therapies: SENTI-202 for acute myeloid leukemia (AML), SENTI-301 for hepatocellular carcinoma (HCC), and additional candidates for other undisclosed solid tumor targets.

Leaps by Bayers mission is to invest in breakthrough technologies that may transform the lives of millions of patients for the better, said Juergen Eckhardt, MD, Head of Leaps by Bayer. We believe that synthetic biology will become an important pillar in next-generation cell and gene therapy, and that Senti Bios leadership in designing and optimizing biological circuits fits precisely with our ambition to prevent and cure cancer and to regenerate lost tissue function.

In addition to potentially treating cancer with allogeneic CAR-NK cells, the Senti Bio gene circuit technology platform can be deployed into multiple other cell and gene therapy delivery modalities, across diverse therapeutic areas, such as immunology, neuroscience, cardiovascular disease, regenerative medicine and genetic diseases with the potential to move from treatment to cure.

We are grateful for the support of new and existing investors, including Leaps by Bayer, who believe in our mission of developing gene circuits to program smart cell and gene therapies to improve health outcomes for many people, said Tim Lu, MD, PhD, co-founder and chief executive officer of Senti Bio. Over the past two years, our team has designed, built and tested thousands of sophisticated gene circuits to drive a robust product pipeline, focused initially on allogeneic CAR-NK cell therapies for difficult-to-treat liquid and solid tumor indications. I look forward to continued platform and pipeline advancements, including starting IND-enabling studies in 2021.

Proceeds from the Series B financing will support development of preclinical oncology programs and expansion of the Senti Bio gene circuit technology platform across additional delivery modalities and therapeutic areas. Senti Bio also plans to scale up clinical manufacturing, including process development and design of a cGMP-compliant manufacturing facility for off-the-shelf allogeneic CAR-NK cell product candidates.

The Series B syndicate included existing and new investors as follows: 8VC, Alexandria Ventures Investments, Amgen Ventures, Gaingels, Intel Capital, KB Investment, Leaps by Bayer, LifeForce Capital, LifeSci Venture Partners, Lux Capital, Matrix Partners China, Menlo Ventures, Mirae Asset Capital, NEA, Nest.Bio, Noveus Capital, Pear VC, Ridgeback Capital and Smilegate Investment.

About the Senti Bio Gene Circuit Technology Platform

By combining disciplines from computer science and biology, Senti Bio has designed, built and tested thousands of sophisticated gene circuits that can be deployed into virtually any cell therapy or gene therapy modality. Senti Bios gene circuits are novel and proprietary combinations of DNA that enable cells to sense their environment, perform logic and instruct cells to produce therapeutic proteins for enhanced safety and efficacy. Senti Bio believes that its approach to programming gene circuits in living cells may enable drug developers to build optimal functionality into almost any cell- or gene-based medicine. Senti Bios proprietary platform includes specific gene circuit technologies such as logic gates, small-molecule regulators, combinatorial payloads and synthetic promoters that have the potential to confer greater efficacy, precision and control to cell and gene therapy products. By mixing and matching different gene circuits together, Senti Bio has the ability to create next-generation medicines with enhanced functionality to outsmart disease.

About Bayer and Leaps by Bayer

Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to benefit people by supporting efforts to overcome the major challenges presented by a growing and aging global population. At the same time, the Group aims to increase its earning power and create value through innovation and growth. Bayer is committed to the principles of sustainable development, and the Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2019, the Group employed around 104,000 people and had sales of 43.5 billion euros. Capital expenditures amounted to 2.9 billion euros, R&D expenses to 5.3 billion euros. For more information, go to http://www.bayer.com.

Leaps by Bayer, a unit of Bayer AG, leads impact investments into solutions to some of todays biggest challenges in health and agriculture. The investment portfolio includes more than 30 companies. They are all working on potentially breakthrough technologies to overcome some specific challenges such as, e.g. regenerating lost tissue function, reducing the environmental impact of agriculture, preventing or curing cancer, and others. For more information, go to leaps.bayer.com

About Senti Bio

Senti Bio is a next-generation therapeutics company that is developing gene circuits and programming cells for tremendous therapeutic value. Senti Bios mission is to outsmart complex diseases with more intelligent medicines to transform peoples lives. By programming cells to respond, adapt and make decisions, Senti Bio is creating smarter therapies with computer-like logic, enhanced functionality and greater therapeutic control.

Senti Bio is developing a wholly-owned, gene circuit pipeline focused on allogeneic CAR-NK cells to address major challenges in cancer treatment. Senti Bios lead product candidates include SENTI-202 and SENTI-301. SENTI-202 is a logic-gated allogeneic CAR-NK cell therapy for the potential treatment of acute myeloid leukemia (AML) that more precisely targets and eliminates cancer cells while sparing healthy tissues. SENTI-301 is a combinatorial payload-armed allogeneic CAR-NK cell therapy for the potential treatment of hepatocellular carcinoma. Beyond oncology, Senti Bio plans to leverage its gene circuit technology platform to build other cell and gene therapies that may be of interest to strategic partners across diverse therapeutic areas, such as immunology, neuroscience, cardiovascular disease, regenerative medicine and genetic diseases. For more information, please visit the Senti Bio website at https://www.sentibio.com.

Forward-Looking Statements

This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayers public reports which are available on the Bayer website at http://www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

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Leaps by Bayer Leads USD 105 Million Series B Financing in Senti Bio to Develop Next-Generation Cell and Gene Therapies Using Advanced Gene Circuit...