A little more than a decade ago, seven patients with hemophilia Ba disease caused by a mutation on the F9 gene that prevents patients from forming crucial clotting proteinsvolunteered to be the first humans to receive a gene therapy delivered using an adeno-associated virus as a vector. This particular treatment didnt move past the Phase 1/2 trial because, while it was deemed safe, the patients did not sustain expression of the gene. But two other gene therapies based on an adeno-associated virus (AAV), Luxturna for rare forms of blindness and Zolgensma for spinal muscular atrophy, have since been approved by the US Food and Drug Administration (FDA), and several pharmaceutical companies are now pursuing regulatory approval of AAV-carried gene therapies for hemophilia B.

Recently, scientists followed up with four of those original patients. In a study published in Molecular Therapy in September, they report that the men are still free of any worrisome toxicities related to the treatment. The study wasnt all good news, though. The team also found that after all these years, the men still had elevated levels of AAV-neutralizing antibodies. That means that if an AAV gene therapy is approved to treat their illness, they likely wont be able to benefit from itthe antibodies would chew up the vector before it could insert the corrective gene.

Administration of an AAV gene therapy is essentially a vaccine against AAV, says Lindsey George, a hematologist at the Childrens Hospital of Philadelphia who led the research. Hers was not the first study to identify antibodies as a problem for those receiving AAV gene therapies, but it is the first to show that elevated titers can last this long. This role of AAV neutralizing antibodies is huge, says George, as it stands to undermine the effectiveness of gene therapies.

Because AAVs are viruses, the human immune system creates antibodies upon exposure that recognize and neutralize them in subsequent encounters. Sometimes patients have neutralizing antibodies in their blood before ever having received a gene therapy because theyre exposed to AAVs in the environment.

The ability to effectively modulate the antibody-mediated immune response could make AAV gene therapies far more effective for far more patients than they are now.

Along with high levels of antibodies to the specific AAV vector that theyd receivedAAV2the patients Georges team evaluated also had neutralizing antibodies to several other commonly used AAV vectors, namely, AAV5 and AAV8, she tells The Scientist.

Andrew Davidoff, a pediatric surgeon at St. Jude Childrens Research Hospital who studies AAV gene therapies but was not involved in the study, says, This paper suggests that not only will they not be able to receive a second dose of vector of the same [type of AAV], but potentially even other [types].

If scientists can prevent antibodies from neutralizing the AAV, they would not only give patients like these another opportunity to receive a more effective dose of gene therapy, but it will expand the patients that we can treat with the therapy to include the 3050 percent of patients who have already been exposed to AAVs in the environment, says Giuseppe Ronzitti, who heads a lab focused on gene therapy research at Genethon.

But, Davidoff says, nobody has found a suitable solution yet that is likely to be accepted by patients. The body has evolved over millions of years, this immune system that helps fight off infections. So to overcome that, even temporarily, is not an easy task.

Some immunosuppressant drugs wont work if the body has already developed specific antibodies to a particular pathogen, such as AAV. Scientists are therefore testing combinations of different types of immunosuppressants they hope will prevent the body from attacking AAVs, but these are likely to come with major risks, chiefly, susceptibility to infection.

Another option is plasmapheresisa process in which a persons blood is removed from the body and the cells separated from the plasma so that they can be reinfused without the antibodies found in the plasmabut, like immunosuppressant drugs, the technique is nonspecific and comes with similar risks. Its a matter of risk-benefit with the continued immunosuppression, says Ronzitti.

So scientists have been looking for other ways to control the bodys response to these gene therapy vectors.

Ronzitti and his team recently proposed a solution in Nature Medicine. The scientists used the imlifidase (IdeS) protein, conditionally approved by the European Commission, to degrade immunoglobulin G (IgG) antibodies that are developed after the body encounters a specific antigen so that it can remember and target that antigen in the future, and thus might cause a patient to reject a transplanted kidney. IgG antibodies are responsible for the immune systems response to AAVs. Its a newer, less invasive alternative to plasmapheresis, Ronzitti tells The Scientist in an email.

The team injected monkeys with the IdeS protein before administering a dose of gene therapy targeting the liver. The treatment appeared safe, the monkeys levels of preexisting AAV antibodies went down, and the AAV vector successfully made its way to the liver. To model a scenario in which a patient would need more than one dose of gene therapy, the scientists administered an AAV gene therapy to another group of monkeys before giving them the IdeS protein to degrade the antibodies theyd developed in response, then readministered the gene therapy. Again, AAV antibodies diminished after the IdeS treatment and the second gene therapy dose was successfully delivered.

One drawback to the approach is that IgGs are the most prevalent type of antibody found in the blood, and destroying all of them may have undesirable side effects. In an attempt to develop a more targeted therapy, one group published a study in January demonstrating that a specialized version of plasmapheresis could reduce the levels of antibodies against human AAVs in mice to the point where a new gene therapy should be effective, without depleting all other immunoglobulins that formed in response to infections.

More recently, a team of researchers at the University of Pittsburgh Medical Center made use of CRISPR-Cas9 to increase the efficacy of AAV gene therapy in mice. Pathologist Samira Kiani and her team werent looking for ways to improve gene therapy, but instead were seeking to temporarily modulate immunity in hopes of changing the course of diseases such as septicemia, a precursor to sepsis that occurs when an infection makes its way to the blood. The researchers aimed to temporarily downregulate the Myeloid differentiation primary response 88(Myd88) gene, which would briefly dampen the immune response, and then remove the brakes.

The gene that we chose to target is known to a be a central gene for innate and adaptive immunity, says Kiani. It controls the production of IgG antibodies in response to AAV exposure, which provided a simple way to measure whether the strategy was effective. If the team administered an AAV to an animal shortly after it had received the CRISPR-Cas9 treatment, it should have a substantially lower antibody response to the virus.

First, they administered the CRISPR to tamp down Myd88 activity and measured a reduction in the expression of the Myd88 gene, as theyd expected. Then, the team used the technique to treat mice just before giving them a dose of AAV-based gene therapy that was designed to lower their cholesterol.

Weeks later, the researchers administered a second dose of the same AAV vector to determine if the temporary immunosuppression during the first dose had prevented the mice from making enough antibodies to thwart a second dose. The mice that were pretreated with the immune-modulating CRISPR showed lower levels of AAV-neutralizing antibodies and more dramatic responses to the cholesterol-lowering AAV treatment. The study was published in NatureCell Biologyin September.

If given prior to the administration of an AAV gene therapy, this approach would prevent the formation of new antibodies, so the patient could receive a second dose later, if needed, says Kiani. Given that the CRISPR treatment only prevents the development of antibodies temporarily, it shouldnt cause any long-term suppression of the rest of the immune system. On the flip side, because it doesnt clear existing antibodies, if the patients have already pre-existing antibodies [from natural exposure] this approach might not be the best approach.

All of the potential solutions have a long way to go, including still needing to be tested in human patients, but the ability to effectively modulate the antibody-mediated immune response could make AAV gene therapies far more effective for far more patients than they are now, says Ronzitti. The immune response to these vectors is quite a complex story, he says. But we are solving the issues one by one.

L. George et al., Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B,Molecular Therapy,doi:10.1016/j.ymthe.2020.06.001, 2020.

F. Moghadam et al., Synthetic immunomodulation with a CRISPR super-repressor in vivo,Nature Cell Biology,doi:10.1038/s41556-020-0563-3, 2020.

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Thwarting AAV-Neutralizing Antibodies Could Improve Gene Therapy - The Scientist

There are no Food and Drug Administration (FDA)-approved treatments for COVID-19, the pandemic infection caused by a novel coronavirus. While several therapies are being tested in clinical trials, current standard of care involves providing patients with fluids and fever-reducing medications. To speed the search for new COVID-19 therapies, researchers are testing repurposed drugs medicines already known to be safe for human use because they are FDA-approved for other conditions for their abilities to mitigate the virus.

UC San Diego Health researchers recently reported that statins widely used cholesterol-lowering medications are associated with reduced risk of developing severe COVID-19 disease, as well as faster recovery times. A second research team at UC San Diego School of Medicine has uncovered evidence that helps explains why: In short, removing cholesterol from cell membranes prevents the coronavirus from getting in.

SARS-CoV-2 infection (green, left) is inhibited by 25HC treatment (right).

The clinical study, published September 15, 2020 in American Journal of Cardiology, was led by Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health, and Karen Messer, PhD, professor and chief of the Division of Biostatics and Bioinformatics in the Department of Family Medicine and Public Health.

The mechanistic study, published September 18, 2020 in The EMBO Journal, was led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center.

A molecule known as ACE2 sits like a doorknob on the outer surfaces of many human cells, where it helps regulate and lower blood pressure. ACE2 can be affected by prescription statins and other medications used for cardiovascular disease.

But, in January 2020, researchers discovered a new role for ACE2: SARS-CoV-2, the coronavirus that causes COVID-19, primarily uses the receptor to enter lung cells and establish respiratory infections.

When faced with this novel virus at the beginning of the pandemic, there was a lot of speculation surrounding certain medications that affect ACE2, including statins, and if they may influence COVID-19 risk, Daniels said. We needed to confirm whether or not the use of statins has an impact on a persons severity of SARS-CoV-2 infection and determine if it was safe for our patients to continue with their medications.

Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health.

To do this, Daniels, Messer and team retrospectively analyzed the electronic medical records of 170 patients with COVID-19 and 5,281 COVID-negative control patients hospitalized at UC San Diego Health between February and June 2020. They collected anonymized data that included the patients disease severity, length of hospital stay, outcome, and use of statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) within 30 days prior to hospital admission.

Among the patients with COVID-19, 27 percent were actively taking statins on admission, while 21 percent were on an ACE inhibitor and 12 percent on an ARB. The median length of hospital stay was 9.7 days for patients with COVID-19.

The researchers found that statin use prior to hospital admission for COVID-19 was associated with a more than 50 percent reduction in risk of developing severe COVID-19, compared to those with COVID-19 but not taking statins. Patients with COVID-19 who were taking statins prior to hospitalization also recovered faster than those not taking the cholesterol-lowering medication.

We found that statins are not only safe but potentially protective against a severe COVID-19 infection, said Daniels. Statins specifically may inhibit SARS-CoV-2 infection through its known anti-inflammatory effects and binding capabilities as that could potentially stop progression of the virus.

This initial study was relatively small and focused on a single health system. Moving forward, Daniels is partnering with the American Heart Association to analyze thousands of patients all over the country to corroborate the data shes developed locally.

I tell my patients who are on statins, ACE inhibitors or other ARBs to keep taking them, she said. Fears of COVID-19 should not be a reason to stop, if anything our research findings should be incentive to continue with their medication.

Statins werent yet on Ranas radar when they began their EMBO Journal study approximately six months ago. At first, his team was simply curious to see which genes are switched on in human lung cells in response to SARS-CoV-2 infection.

A gene called CH25H was blazing hot, Rana said. CH25H encodes an enzyme that modifies cholesterol. I got excited because with HIV, Zika, and a few others, we know that CH25H blocks the virus ability to enter human cells.

Heres whats happening inside our cells: CH25Hs enzymatic activity produces a modified form of cholesterol called 25-hydroxycholesterol (25HC). In turn, 25HC activates another enzyme called ACAT, found inside cells in the endoplasmic reticulum. ACAT then depletes accessible cholesterol on the cells membrane. Its a normally occurring process that gets kicked into high gear during some viral infections.

The team quickly got to work examining 25HC in the context of SARS-CoV-2 from several angles. They explored what happens to human lung cells in the lab with and without 25HC treatment when they are exposed to first a noninfectious virus that carries the SARS-CoV-2 spike protein (its key to cell entry) or to live SARS-CoV-2 virus itself.

No matter which way they came at it, added 25HC inhibited the ability of the virus to enter cells blocking infection almost completely.

The difference between untreated cells and those treated with 25HC was like day and night, Rana said.

While SARS-CoV-2 uses the ACE2 receptor to initially dock on a cell, Ranas study suggests that the virus also needs cholesterol (normally found in cell membranes) in order to fuse with and enter the cell. 25HC takes away a lot of that membrane cholesterol, preventing viral entry.

In a similar way, statins are likely beneficial in preventing or reducing the severity of SARS-CoV-2 infection because, while intended to remove cholesterol from blood vessels, they are also removing cholesterol from cell membranes. As a result, the coronavirus cant get in.

This is already happening in our bodies on a regular basis, so perhaps we just need to give it a boost, with statins or by other means, to better resist some viruses, Rana said. Its not unlike cancer immunotherapy the idea that sometimes instead of attacking a tumor directly, its better to arm a patients immune system to do a better job of clearing away tumors on its own.

If it can be developed into a therapeutic, 25HC might work even better as an antiviral than statins, Rana said. Thats because it works specifically on cholesterol in cell membranes, rather than cholesterol throughout the body. Like all medications, statins can cause negative side effects, including digestive problems and muscle pains, and may not be an option for many people with COVID-19. Whats more, while some previous studies suggested statins may also elevate ACE2 levels, which could allow more viral entry, Ranas team did not see an increase in the receptor in response to 25HC.

Statins are FDA-approved for human use, but 25HC is a natural product currently available only for laboratory work. Rana and team plan to continue optimizing 25HC as a potential antiviral agent. Many steps remain before it might be tested in human clinical trials.

Co-authors of the American Journal of Cardiology study also include: Christopher Longhurst, Amy Sitapati, Jing Zhang, Jingjing Zou, Quan Bui, Junting Ren, Michael Criqui, all at UC San Diego.

Funding for this research came, in part, from the University of California Office of the President (grant R00RG24990).

Co-authors of The EMBO Journal study also include: Shaobo Wang, Wanyu Li, Hui Hui, Shashi Kant Tiwari, Qiong Zhang, Ben A. Croker, Stephen Rawlings, Davey Smith and Aaron F. Carlin, all at UC San Diego.

Funding for this research came, in part, from National Institutes of Health (grants CA177322, DA039562, DA049524 and AI125103), Burroughs Wellcome Fund and John and Mary Tu Foundation.

Disclosure: Tariq Rana is a founder of ViRx Pharmaceuticals and has an equity interest in the company. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

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Statins Reduce COVID-19 Severity, Likely by Removing Cholesterol That Virus Uses to Infect - UC San Diego Health

Having demonstrated the ability to offer improved treatment related outcomes and also enhance the quality of lives of patients suffering from a diverse range of clinical conditions, the demand for cell therapies is anticipated to increase in the near future

Roots Analysis has announced the addition of Cell Therapy Manufacturing Market (2nd Edition), 2018 2030 report to its list of offerings.

Given the commercial success of multiple cell therapies, such as RECELL (Avita Medical) and YESCARTA (Gilead Sciences), and an evolving clinical pipeline, the opportunity for contract development and manufacturing organizations (CDMOs) is anticipated to grow significantly. Over the years, many service providers have begun automating their operations, in order to eliminate chances of human error during manufacturing.

To order this 400+ page report, which features 125+ figures and 175+ tables, please visit this link.

Key Market Insights

Over 145 companies / organizations are actively involved in manufacturing cell-based therapiesThe market landscape is currently dominated by the presence of industry players, which represent more than 55% of the total number of players. Amongst these, over 45 are large or mid-sized firms (having more than 50 employees). It is also worth noting that this field has witnessed the entry of several start-ups.

50+ organizations claim to possess commercial manufacturing capabilities for cell therapiesAs most of the cell therapy products are under clinical evaluation, majority of the manufacturing facilities currently have the capacity to support clinical scale production requirements. At the same time, it is worth noting that several players (over 35%) have already developed / are developing commercial scale capacity for cell therapies.

Europe has emerged as a key region for the production of cell therapies with more than 40% of manufacturing facilitiesGlobally, 195 facilities have been established by various players for the manufacturing of the cell therapies; of these, 41% are located in Europe, followed by those based in North America (38%). Other emerging regions include Australia, China, Japan, Singapore, South Korea and Israel.

Close to 15 companies are presently offering automated solutions to cell therapy developersOver the years, automation has emerged as a key enabler of cell therapy manufacturing. Players that claim to offer consultancy services related to automation include (in alphabetical order) these include (in alphabetical order) Berkeley Lights, Cesca Therapeutics, Ferrologix, FluDesign Sonics, GE Healthcare and Terumo BCT. Further, we identified five players, namely (in alphabetical order) Fraunhofer Institute for Manufacturing Engineering and Automation IPA, Invetech, KMC Systems, Mayo Clinic Center for Regenerative Medicine and RoosterBio, that offer consultancy solutions related to automation.

150+ partnerships were inked between 2014 and 2018Of these, 32% were observed to be focused on the supply of cell-based therapy products for clinical trials. Other popular types of collaboration models implemented in this domain include additional services agreements (24%), joint ventures (9%) and acquisitions (3%).

North America anticipated to capture 50% of the cell therapy manufacturing market by 2030Owing to high venture capital funding and drug development activity, North America is anticipated to capture close to 50% of the total market share by 2030. It is also important to highlight that financial resources, technical expertise and established infrastructure is likely to drive cell therapy manufacturing market in Europe to grow at a CAGR of over 18%.

To request a sample copy / brochure of this report, please visit this link

Key Questions Answered

The USD 10+ billion (by 2030) financial opportunity within the cell therapy manufacturing market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom manufacturing of cell therapies is largely being outsourced due to the exorbitant costs associated with setting-up in-house facilities. The report includes detailed transcripts of discussions held with the following experts:

The research covers profiles of key players (industry and non-industry) that offer contract manufacturing services for cell-based therapies, featuring an overview of the company, information on its manufacturing facilities, and recent collaborations.

For additional details, please visithttps://www.rootsanalysis.com/reports/view_document/cell-therapy-manufacturing-market-2nd-edition-2018-2030/209.html

or email [emailprotected]

Contact:Gaurav Chaudhary+1 (415) 800 3415+44 (122) 391 1091[emailprotected]

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cell therapy manufacturing market is projected to reach close to USD 11 Billion by 2030, growing at an annualized rate of 14.9% - The Daily Chronicle

DURHAM, N.C., Sept. 25, 2020 /PRNewswire/ -- Predigen Inc., a privately held diagnostic company and emerging leader in precision medicine, spun-out from Duke University, announced today a study published in The Lancet Infectious Diseases identifying biomarkers that detect viral infections before clinical disease develops. These findings, stemming from work performed by Duke Health scientists, could form the basis of novel approaches for early diagnosis, treatment and management of emerging viral outbreaks and pandemics.

"The study is exciting because, currently, there is no reliable way to identify pre-symptomatic patients," said Ephraim Tsalik, M.D., Ph.D., Predigen's chief science officer and co-founder, and a clinical investigator of this study. "Early diagnosis can lead to earlier, more effective therapy as well as quarantine before someone can spread the infection to others. Predigen's team of physician-scientists at Duke University used machine learning to discover these molecular signatures, representing a more rapid and accurate means to predict, diagnose and manage disease. Especially in light of the challenges posed by COVID-19, these results offer hope for new solutions."

According to the authors of this five-year study involving 1465 participants, these findings arethe first to validate, in a real-world setting, that a blood-based, host gene expression test can accurately predict respiratory viral infection before typical symptoms are present.

For years, Tsalik and colleagues in the Duke Center for Applied Genomics and Precision Medicine have focused on developing innovative tests to diagnose infectious diseases such as sepsis, fungal infection, and most notably, to distinguish between viral and bacterial infections. The ability to discriminate these various causes of illness can help reduce the unnecessary use of antibiotics, a major cause of antibiotic resistance. Predigen has licensed the intellectual property for the company's viral signature, referred to as HR-PreV (Host Response PreViral).

With testing solutions that assess the immune response to stress and disease, Predigen is collaborating with Biomeme, Inc. to deliver host response tests to the point-of-need. Applying Predigen's tests to Biomeme's "PCR anywhere" platform will deliver a better diagnostic methodology (host response signatures) for use in a wide variety of settings that are more accessible to patients.

About the SciencePredigen's scientists from Duke University focused on gene expression, which is a measure of how active or inactive a gene may be in a given situation. By looking at the expression of tens of thousands of genes, the team used machine learning to discover patterns (or signatures) in that data. They found a gene expression signature indicating the presence of a bacterial infection and another signature for viral infection. However, there were no readily available technologies that could measure these biomarkers in a simple and rapid format. To address this need, Predigen formed a partnership with Biomeme, tapping into their 27-target, multiplex, quantitative, RT-PCR assay, which delivers results in about 60 minutes. The signatures and interpretive algorithms have been combined into a point-of-need prototype utilizing Biomeme's Franklin thermocycler and its companion mobile app.

"Predigen's tests focus on the host response, which is itself a molecular measurement of health and disease," said Tsalik. "As such, our tests have been shown to be very accurate and have potential to provide valuable information to inform healthcare providers' management of patients. It has long been clear that tests to reliably distinguish bacterial and viral infections simply don't exist on the market. Moving forward, Predigen will focus on translating its successful research to real-world utilization of its tests by physicians, delivering innovative testing solutions to the point of need."

About PredigenPredigen, Inc. is a global leader in the development of host gene expression signatures for use as prognostic, diagnostic, and therapeutic monitoring tools. Predigen is devoted to advancing the diagnostics field in areas of high unmet need, including infectious disease, cardiovascular disease, autoimmune and inflammatory disease, cancer and drug response. For more information on Predigen, please visit the company's website atwww.predigen.com.

Media Contact:Betsy Levy | Phone: (415) 377-3112 | Email: [emailprotected] | http://predigen.com

SOURCE Predigen

http://www.predigen.com

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Study Reveals Blood-Based Host Response Test Can Accurately Predict Respiratory Viral Infection in Pre-Symptomatic Patients - PRNewswire

- Fetal Hemoglobin expression in human cellular models increased up to ~30% by FTX-6058 for the potential treatment of sickle-cell disease

- Company plans to initiate Phase 1 trial in healthy volunteers by year-end

- Non-provisional composition of matter patent application covering FTX-6058 published

CAMBRIDGE,Mass., Sept. 25, 2020 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.(Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases, today announced preclinical proof-of-concept data supporting the development of FTX-6058 to treat sickle cell disease and beta-thalassemia. FTX-6058, a small molecule designed to increase expression of fetal hemoglobin, demonstrated target engagement and good tolerability in multiple preclinical rodent models with once-a-day oral dosing. The Company presented these data today at the 14th Annual Sickle Cell Disease Research & Educational Symposium and 43rd National Sickle Cell Disease Scientific Meeting being held virtually. Slides from the presentation will be available on Fulcrums website at ir.fulcrumtx.com/events-and-presentations.

Despite newly approved therapies for sickle cell disease, a significant unmet need remains, saidMartin H. Steinberg, MD, Professor of Medicine at Boston University School of Medicine. An orally available small molecule therapeutic acting through a novel mechanism to induce increased pancellular HbF should be an important disease-modifying agent.

Fetal Hemoglobin (HbF) is a key modulator of sickle cell disease. Increasing HbF levels has the potential to prevent or reduce disease-related pathophysiology, resulting in reduction of recurring events such as vaso-occlusive crises (VOCs) and hemolysis. In some cases, sickle cell patients with high HbF levels have asymptomatic disease, underscoring the protective effect of HbF. Fulcrum has identified FTX-6058, a highly potent small molecule inhibitor of Embryonic Ectoderm Development (EED) capable of inducing robust HbF protein expression in cell and murine models. Additionally, Fulcrum believes that pharmacokinetics and human dose simulations support FTX-6058 may be given as a once daily oral compound.

The validation of EED as a target for sickle cell disease and the discovery of FTX-6058 as a novel HbF-inducing small molecule were conducted using Fulcrums Product Engine. Through inhibition of EED, Fulcrum has demonstrated the ability to modulate the activity of the Polycomb Repressive Complex 2 (PRC2), a key regulator of HbF expression, in preclinical studies. Fulcrum validated the role between EED binding/PRC2 modulation and HbF induction utilizing its proprietary CRISPR and chemical probe screening platform. Treatment of human CD34+-derived erythroid cells from healthy and sickle cell disease donors with FTX-6058 resulted in clinically desirable fetal hemoglobin levels (up to ~30% of total hemoglobin), demonstrating a superior globin profile relative to hydroxyurea and other small molecule compounds or mechanisms currently under development. In these preclinical studies, FTX-6058 also induced pancellular distribution of HbF similar to hereditary persistence of fetal hemoglobin.

In vivo preclinical studies showed elevation of HbF at the mRNA and protein levels at plasma concentrations predicted by Fulcrum to be achievable in patients. FTX-6058 treatment led to, elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. In a head-to-head in-vivo preclinical study, FTX-6058 demonstrated superior HbF induction over hydroxyurea in the Townes SCD mouse model.

We continue to demonstrate important progress with our Product Engine, developing a robust pipeline focused on treatments for rare diseases and areas of significant unmet need, said Owen Wallace, Fulcrums chief scientific officer. We are very encouraged by these in vitro and in vivo findings, as the preclinical data support our novel approach to treating hemoglobinopathies, such as sickle cell disease and beta-thalassemia. In addition to achieving robust fetal hemoglobin levels in cell and murine models, an extensive nonclinical safety package and off-target profile has been established for FTX-6058. We believe FTX-6058 has the potential to offer a durable and transformative therapy for people living with sickle cell disease.

Fulcrum completed a comprehensive IND-enabling package, including preclinical safety studies and up to 28-day Good Laboratory Practices (GLP) toxicology studies, as well as Good Manufacturing Practices (GMP) material scale-up for its planned Phase 1 clinical trial. The Company remains on track to initiate a Phase 1 clinical trial by year-end. In addition, Fulcrums non-provisional composition of matter patent application covering FTX-6058 and related structures has published.

About Sickle Cell DiseaseSickle cell disease (SCD) is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. SCD patients typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease and reduced life expectancy.

About Fulcrum TherapeuticsFulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrums proprietary product engine identifies drug targets which can modulate gene expression to treat the known root cause of gene mis-expression. The company has advanced losmapimod to Phase 2 clinical development for the treatment of facioscapulohumeral muscular dystrophy (FSHD) and has advanced losmapimod to Phase 3 for the treatment of COVID-19. Fulcrum also anticipates filing an IND in the third quarter with initiation of a clinical trial in the fourth quarter of 2020 with FTX-6058 for the treatment of sickle cell disease.

Please visit http://www.fulcrumtx.com.

Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the development status of the Companys product candidates, including the timing of initiation of a Phase 1 clinical trial for FTX-6058, and the potential advantages and therapeutic potential of our product candidates. All statements, other than statements of historical facts, contained in this press release, including statements regarding the Companys strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, should, target, will, would and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrums ability to obtain and maintain necessary approvals from the FDA and other regulatory authorities; continue to advance its product candidates in clinical trials; initiate and enroll clinical trials on the timeline expected or at all; correctly estimate the potential patient population and/or market for the Companys product candidates; replicate in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of losmapimod and its other product candidates; advance the development of its product candidates under the timelines it anticipates in current and future clinical trials; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys actual results to differ from those contained in the forward-looking statements, see the Risk Factors section, as well as discussions of potential risks, uncertainties and other important factors, in the Companys most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent the Companys views as of the date hereof and should not be relied upon as representing the Companys views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Companys views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so.

Contact:

Investors:Christi WaarichDirector, Investor Relations andCorporate Communicationscwaarich@fulcrumtx.com 617-651-8664

Stephanie AscherStern Investor Relations, Inc.stephanie.ascher@sternir.com 212-362-1200

Media:Kaitlin GallagherBerry & Company Public Relationskgallagher@berrypr.com212-253-8881

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Fulcrum Therapeutics Announces Preclinical Proof-of-Concept Data for FTX-6058 at the Virtual 14th Annual Sickle Cell Disease Research &...

Newswise DALLAS Sept. 24, 2020 Two studies led by UT Southwestern researchers shed light on the biology and potential vulnerabilities of schistosomes parasitic flatworms that cause the little-known tropical disease schistosomiasis. The findings, published online today in Science, could change the course of this disease that kills up to 250,000 people a year.

About 240 million people around the world have schistosomiasis mostly children in Africa, Asia, and South America in populations that represent the poorest of the poor, says study leader James J. Collins III, Ph.D., associate professor in UTSWs department of pharmacology.

Most of those infected survive, but those who die often suffer organ failure or parasite-induced cancer. Symptoms can be serious enough to keep people from living productive lives, Collins says.

The parasite that causes this disease has a complicated life cycle that involves stages in both freshwater snails and mammals. Dwelling in mammalian hosts circulatory systems, schistosomes feed on blood and lay copious numbers of eggs, all while causing an array of symptoms including abdominal pain, diarrhea, bloody stool, or blood in the urine. Larval worms are released from snails into water, where the flatworms then may infect humans by penetrating the skin. Schistosomiasis may become a chronic disease that affects the person for years.

Only one drug, praziquantel, is available to treat this condition. However, Collins explains, it is of limited use it doesnt kill all intramammalian stages of the schistosome life cycle, and it has a variable cure rate in some endemic settings. Theres been little interest by pharmaceutical companies in developing new drugs for this disease, he adds, because there is no monetary incentive to do so. Consequently, relatively few studies have been devoted to understanding schistosomes basic biology, which might reveal inherent weaknesses that could serve as targets for new drugs.

To that end, Collins and his colleagues embarked upon two separate studies one at the cellular level and another at the molecular level to better understand these organisms.

In the first study, the researchers delved into the cell types that make up these flatworms. Although the worms are multicellular organisms composed of a variety of unique tissue types, researchers knew little about the different cell populations in these parasites.

With a goal to create an atlas of cell types in Schistosoma mansoni one of the schistosome species that commonly causes schistosomiasis Collins and his team used a technique called single-cell RNA sequencing that distinguishes individual cell types based on their unique gene expression patterns. With this method, they identified 68 molecularly unique clusters of cells, including a population of stem cells that form the gut. When the researchers used a targeted approach called RNA interference (RNAi) to shut down the activation of a key gene in these cells, the resulting worms couldnt digest red blood cells a key to their growth and a pivotal part of the pathology they cause.

In the second study, the researchers used RNAi to sort out the function of about 20 percent of S. mansonis protein coding genes 2,216 in total. Previously, only a handful of genes in these organisms had been assessed.

By deactivating the genes one by one, Collins and his colleagues identified more than 250 genes crucial for survival. Using a database of pharmacological compounds, the researchers then searched for drugs that had the potential to act on proteins produced by these genes, identifying several compounds with activity on worms. The team also uncovered two protein kinases a group of proteins renowned for their ability to be targeted by drugs that are essential for muscle function. When these kinases were inhibited, the worms became paralyzed and eventually died, suggesting that drugs targeting these proteins could eventually treat people with schistosomiasis. A next step in the research will be to search for inhibitors of these proteins.

Collins notes that these strides in understanding the basic biology of schistosomes could eventually lead to new treatments to save untold lives in places where schistosomiasis is endemic.

This is a very important disease that most people have never heard of, he says. We need to invest and invigorate research on these parasites.

UTSW researchers who contributed to the first study include George Wendt, Lu Zhao, Rui Chen, and Michael L. Reese. UTSW researchers who contributed to the second study include Jipeng Wang, Carlos Paz, Irina Gradinaru, and Julie N. R. Collins.

The first study was supported by grants from the National Institutes of Health (R01 R01AI121037, R01 R01AI150715, R21 R21AI133393, and F30 1F30AI131509-01A1, the Welch Foundation (I-1948-20180324 and I-1936-20170325), the National Science Foundation (MCB1553334), the Burroughs Wellcome Fund, the Wellcome Trust (107475/Z/15/Z), and the Bill and Melinda Gates Foundation (OPP1171488).

The second study was supported by grants from the National Institutes of Health (R01AI121037), the Welch Foundation (I-1948-20180324), the Burroughs Wellcome Fund, and the Wellcome Trust (107475/Z/15/Z and 206194).

James Collins is Rita C. and William P. Clements, Jr. Scholar in Biomedical Research.

About UTSouthwestern Medical Center

UTSouthwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

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Finding The Achilles Heel of A Killer Parasite - Newswise

BOSTON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that data from the companys portfolio of cystic fibrosis (CF) medicines will be presented at the 43rd European Cystic Fibrosis Digital Conference (ECFS) held September 24-25, 2020 and the 2020 North American Cystic Fibrosis Virtual Conference (NACFC) taking place October 7-23, 2020. An oral presentation at the ECFS Digital Conference will highlight, for the first time, interim results from the TRIKAFTA open-label extension study, which showed safety and efficacy consistent with the results of the Phase 3 pivotal studies in patients with CF ages 12 and older with F508del/Minimal Function (F/MF) or F508del/F508del (F/F) genotypes. Four additional scientific abstracts for ORKAMBI and TRIKAFTA were published in the Journal of Cystic Fibrosis as part of the ECFS conference. In addition, six scientific presentations will occur at NACFC regarding KALYDECO, ORKAMBI and TRIKAFTA, including new data from KALYDECO in infants ages 4 to less than 6 months old.

As we continue to reach additional people with CF with our medicines, gaining a better understanding of their long-term and real-world impact becomes even more important, said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex. We are pleased to report the first longer-term data for TRIKAFTA which show the significant benefits seen early are maintained through one year of treatment.

Data highlighting interim results from the ongoing TRIKAFTA open-label extension (OLE) study to evaluate long-term safety and efficacy in people with CF ages 12 and older with F508del/Minimal Function (F/MF) or F508del/F508del (F/F) genotypes who completed pivotal studies will be presented at the ECFS Digital Conference. In the interim analysis, TRIKAFTA was generally well-tolerated, with no new safety concerns. The data show that the marked improvements observed in the prior pivotal studies across multiple efficacy endpoints, including, percent predicted forced expiratory volume in 1 second (ppFEV1), sweat chloride (SwCl), Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score, and body mass index (BMI), were sustained with continued treatment with TRIKAFTA.

A full listing of Vertex scientific presentations at ECFS and NACFC are below:

Abstract Title

PresentationType

PresentingAuthor

Date/ Time

ELX/TEZ/IVA

A phase 3, open-label extension study of elexacaftor/tezacaftor/ivacaftor: interim analysis of safety and efficacy in people with cystic fibrosis and F508del/minimal function or F508del/F508del genotypes

ECFS Oral Presentation

Professor Griese

September 24, 2020

11:21-11:45 a.m. CET

Impact of elexacaftor/tezacaftor/ivacaftor triple combination therapy on health-related quality of life in people with cystic fibrosis heterozygous for F508del and a minimal function mutation: results from a phase 3 clinical study

ECFS published abstract: Journal of Cystic Fibrosis 19S2 (2020) S55S168, P221

NACFC Poster Presentation #447

Professor Fajac

Oct 7 Oct 23, 2020

Impact of elexacaftor/tezacaftor/ivacaftor triple combination therapy on health-related quality of life in people with cystic fibrosis homozygous for F508del: results from a phase 3 clinical study

ECFS published abstract: Journal of Cystic Fibrosis 19S2 (2020) S1S36, WS19.6

NACFC Poster Presentation #478

Professor Majoor

Oct 7 Oct 23, 2020

IVA

An observational study of ivacaftor in people with cystic fibrosis and selected non-G551D gating mutations: outcomes from the third interim analysis of the VOCAL study

NACFC Poster Presentation

#466

Professor Kors van der Ent

Oct 7 Oct 23, 2020

Ivacaftor in 4 to < 6-month-old infants with a gating mutation: results of a 2-part, single-arm, phase 3 study

NACFC Poster Presentation

#415

Dr. Rosenfeld

Oct 7 Oct 23, 2020

Real-world outcomes in children aged 2-5 with CF treated with ivacaftor

NACFC Poster Presentation

#141

Dr. Volkova

Oct 7 Oct 23, 2020

LUM/IVA

Long-term safety of lumacaftor/ivacaftor in persons with cystic fibrosis aged 2-5 years homozygous for the F508del-CFTR mutation (F/F)

ECFS Published abstract:

Journal of Cystic Fibrosis 19S2 (2020) S1S36, WS19.2

Disease progression in F508del homozygous (F/F) persons with cystic fibrosis treated with lumacaftor/ivacaftor (LUM/IVA): interim results of a long-term safety study using data from the US Cystic Fibrosis Foundation Patient Registry (CFFPR)

ECFS Published abstract:

Journal of Cystic Fibrosis 19S2 (2020) S1S36, WS13.1

NACFC Poster Presentation

#190

Dr. Bower

Oct 7 Oct 23, 2020

About Cystic Fibrosis

Cystic Fibrosis (CF) is a rare, life-shortening genetic disease affecting approximately 75,000 people worldwide. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF. While there are many different types of CFTR mutations that can cause the disease, the vast majority of all people with CF have at least one F508del mutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR KALYDECO (ivacaftor), TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor), and ORKAMBI (lumacaftor/ivacaftor)

What is KALYDECO?KALYDECO is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 6 months and older who have at least one mutation in their CF gene that is responsive to KALYDECO. Patients should talk to their doctor to learn if they have an indicated CF gene mutation. It is not known if KALYDECO is safe and effective in children under 6 months of age.

What is TRIKAFTA?TRIKAFTA is a prescription medicine used for the treatment of CF in patients aged 12 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients should talk to their doctor to learn if they have an indicated CF gene mutation. It is not known if TRIKAFTA is safe and effective in children under 12 years of age.

What is ORKAMBI?ORKAMBI is a prescription medicine used for the treatment of CF in patients age 2 years and older who have two copies of the F508del mutation (F508del/F508del) in their CFTR gene. ORKAMBI should only be used in these patients. It is not known if ORKAMBI is safe and effective in patients under 2 years of age.

Patients should not take KALYDECO or TRIKAFTA if they take certain medicines or herbal supplements, such as: the antibiotics rifampin or rifabutin; seizure medicines such as phenobarbital, carbamazepine, or phenytoin; or St. Johns wort.

Patients should not take ORKAMBI if they take certain medicines or herbal supplements, such as: the antibiotics rifampin or rifabutin; the seizure medicines phenobarbital, carbamazepine, or phenytoin; the sedatives and anti-anxiety medicines triazolam or midazolam; the immunosuppressant medicines cyclosporine, everolimus, sirolimus, or tacrolimus; or St. Johns wort.

Before taking KALYDECO, TRIKAFTA, or ORKAMBI, patients should tell their doctor about all of their medical conditions, including if they: have or have had liver problems; have kidney problems; have had an organ transplant; are pregnant or plan to become pregnant because it is not known if KALYDECO, TRIKAFTA, or ORKAMBI will harm an unborn baby; or are breastfeeding or planning to breastfeed because it is not known if KALYDECO, TRIKAFTA, or ORKAMBI passes into breast milk. Before taking ORKAMBI, patients should tell their doctor if they are using birth control as hormonal contraceptives, including oral, injectable, transdermal, or implantable forms should not be used as a method of birth control when taking ORKAMBI.

KALYDECO, TRIKAFTA, or ORKAMBI may affect the way other medicines work, and other medicines may affect how KALYDECO, TRIKAFTA, or ORKAMBI work. Therefore, the dose of KALYDECO, TRIKAFTA, or ORKAMBI may need to be adjusted when taken with certain medications. Patients should especially tell their doctor if they take antifungal medications such as ketoconazole, itraconazole, posaconazole, voriconazole, or fluconazole; or antibiotics such as telithromycin, clarithromycin, or erythromycin.

KALYDECO or TRIKAFTA can cause dizziness in some people who take it. Patients should not drive a car, use machinery, or do anything that needs them to be alert until they know how KALYDECO or TRIKAFTA affects them.

When taking ORKAMBI, patients should tell their doctor if they stop taking ORKAMBI for more than 1 week as their doctor may need to change the dose of ORKAMBI or other medicines the patient is taking.

Patients should avoid food or drink containing grapefruit or Seville oranges while taking KALYDECO. Patients should avoid food or drink containing grapefruit while taking TRIKAFTA.

KALYDECO, TRIKAFTA, and ORKAMBI can cause serious side effects, such as:

High liver enzymes in the blood have been reported in patients receiving KALYDECO, TRIKAFTA, or ORKAMBI. The patient's doctor will do blood tests to check their liver before starting treatment with KALYDECO, TRIKAFTA, or ORKAMBI; every 3 months during the first year of treatment; and every year while on treatment. For patients who have had high liver enzymes in the past, the doctor may do blood tests to check the liver more often. Patients should call their doctor right away if they have any of the following symptoms of liver problems: pain or discomfort in the upper right stomach (abdominal) area; yellowing of their skin or the white part of their eyes; loss of appetite; nausea or vomiting; or dark, amber-colored urine.

Breathing problems such as shortness of breath or chest tightness in patients when starting ORKAMBI, especially in patients who have poor lung function. If a patient has poor lung function, their doctor may monitor them more closely when starting ORKAMBI.

An increase in blood pressure in some people receiving ORKAMBI. The patients doctor should monitor their blood pressure during treatment with ORKAMBI.

Abnormality of the eye lens (cataract) in some children and adolescents treated with KALYDECO, TRIKAFTA, or ORKAMBI. If the patient is a child or adolescent, their doctor should perform eye examinations before and during treatment with KALYDECO, TRIKAFTA, or ORKAMBI to look for cataracts.

The most common side effects of KALYDECO include headache; upper respiratory tract infection (common cold), which includes sore throat, nasal or sinus congestion, and runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness.

The most common side effects of TRIKAFTA include headache, diarrhea, upper respiratory tract infection (common cold) including stuffy and runny nose, stomach (abdominal) pain, inflamed sinuses, increase in liver enzymes, increase in a certain blood enzyme called creatine phosphokinase, rash, flu (influenza), and increase in blood bilirubin.

The most common side effects of ORKAMBI include breathing problems, such as shortness of breath and chest tightness; nausea; diarrhea; fatigue; increase in a certain blood enzyme called creatinine phosphokinase; rash; gas; common cold, including sore throat, stuffy or runny nose; flu or flu-like symptoms; and irregular, missed, or abnormal periods (menses) and increase in the amount of menstrual bleeding. Additional side effects seen in children include: cough with sputum, stuffy nose, headache, stomach pain, and increase in sputum.

These are not all the possible side effects of KALYDECO, TRIKAFTA, or ORKAMBI. Please click product link to see the full Prescribing Information for KALYDECO, TRIKAFTA, or ORKAMBI.

About Vertex

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

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London, UK. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 10 consecutive years on Science magazine's Top Employers list and top five on the 2019 Best Employers for Diversity list by Forbes. For company updates and to learn more about Vertex's history of innovation, visit http://www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.

Special Note Regarding Forward-looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Dr. Carmen Bozic in this press release, statements regarding the potential benefits, safety and efficacy of TRIKAFTA, KALYDECO and ORKAMBI, and our plans to present data at the ECFS and the NACFC, including data from our TRIKAFA open-label extension study, scientific abstracts for ORKAMBI and TRIKAFTA, and scientific presentations regarding KALYDECO, ORKAMBI and TRIKAFTA. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration, approval or further development of its compounds due to safety, efficacy or other reasons, risks related to approval and commercialization of our medicines, and other risks listed under Risk Factors in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

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Vertex to Present New Data at European and North American Virtual Cystic Fibrosis Conferences Highlighting Long-Term Use of CFTR Modulators - Business...