Monthly Archives: June 2020

In its rather short life, the gene therapy field has been on a rollercoaster of experiences. While the initial hype was dampened by failures in clinical trials, the field is now experiencing a strong comeback. What was once seen as a hope, is now becoming a reality. But producing viral vectors, the essential delivery vehicles of gene therapies, remains challenging. CEVEC Pharmaceuticals has found a solution and developed a platform that can produce adeno-associated viral vectors (AAVs) as easily as if they were monoclonal antibodies.

As the gene therapy field grows, drug developers are confronted with the fact that most gene therapy products cant be produced at the scale needed to meet growing demands. The reason: lack of adequate viral vector production technologies. What gene therapy developers desperately need is a production platform that can produce viral vectors simply, with no variations, avoiding cumbersome processes, and at reasonable costs.

I have spoken to Nicole Faust, CEO at CEVEC Pharmaceuticals about the challenges in viral vector production, how these are addressed with the companys brand new production platform for AAVs, ELEVECTA, and what it has in common with standardized production platforms that already exist for monoclonal antibodies.

The great thing about gene therapy is that you can, in many cases, tackle the underlying cause of the disease. A lot of diseases today are just treated symptomatically, but with gene therapy, if the underlying cause is a gene defect, you can bring an intact copy of the gene into the patient or even repair the gene using genome editing tools like CRISPR-Cas.

To be able to do so, you need vehicles to deliver the gene. In most cases, although there are a number of non-viral approaches out there, the researchers use viral vectors. This makes a lot of sense because thats what a virus does it delivers genes to cells. Were exploiting that feature of the virus, replacing the viral genes with the therapeutic gene, and using that viral vector to deliver the therapeutic gene to the target cells.

At the moment, there are three different viral vector types mainly used for gene-therapy approaches. One of them is the lentiviral vector, which has the advantage of integrating the gene into the cells, so it will stay there permanently. But lentiviral vectors also bear some risks because they can integrate into an unwanted position in the genome.

At the moment, lentiviral vectors are mainly used for ex-vivo therapies, in particular, because they are very good for transducing hematopoietic cells. Novartis Kymriah, for example, is a CAR-T therapy that uses a lentiviral vector to deliver the Chimeric Antigen Receptor (CAR) to T-cells outside of the patient. Then the modified cells are given back to the patient.

Second, there are adenoviral vectors, which were basically used when gene therapy started more than 20 years ago. They are still being used, but mainly for vaccination approaches. For example, there are some SARS-CoV-2 vaccines being developed at the moment with adenoviral vectors.

When we talk about in vivo gene therapies actually delivering the therapeutic gene to the target cells inside the patient then nearly always AAVs are used. The reason is that AAVs are non-pathogenic and the virus always needs the presence of a helper virus to replicate, and this makes it a lot safer than other viral vectors.

AAV is also a very interesting virus because it comes in a lot of different serotypes different species of AAV. These serotypes correspond to distinctive structures on the surface of the virus, and that means that different tissues can be targeted. If you want to target neural tissue, for example, youll use a different AAV serotype than if you target the liver or muscles.

Another advantage of the AAV is that the particles themselves are very robust and very stable. They are easy to purify and once youve purified them, you can store them for a very long time without losing activity. All that makes them a nearly perfect tool for gene therapy.

Upscaling is one of the biggest challenges in AAV production. The reason is that most of these therapies come out of universities, which means the first viral vectors were produced in a research lab by a method that would yield just enough vector material to do lab experiments. These methods work very well at this level, but they are not really scalable.

Also, in many cases, the viral vector production is based on adherently growing cells, so the cells need a substrate to adhere to in order to survive and divide. That means you cant just use a huge 2000 L bioreactor, but you really have to provide the cells with a substrate and this is difficult at a large scale.Also, adherent cells are not a good solution for scalability because, very often, they still require animal-derived serum to grow, which presents a potential safety issue.

So instead, more and more suspension cell lines are being developed. But these cells still share one problem with adherent cells: Production of AAVs relies on a method called transient transfection.

What does that mean? To make an AAV, you have to bring into the cell different genetic elements. You need one plasmid that carries the rep and cap genes for the AAV life cycle and for producing the capsid; you need a second plasmid with the adenoviral helper gene; and a third plasmid with the therapeutic gene of interest, which is flanked by the recognition sequences that will allow the gene of interest to be packaged into the AAV vector.

So, you can imagine, transient transfection is convenient if you do it at a small scale in a lab,but its a challenge if you need to do it at several hundred liters. Its not only a challenge with respect to the complexity of the process, but it also means you have to provide a lot of plasmid material.

The common understanding is that plasmids used for transient transfection in vector manufacturing for use in humans need to fulfill good manufacturing practice (GMP) requirements, which makes them very expensive. The plasmid costs can make up one-third of the production cost of a batch. Thats obviously a huge cost factor. You also need a transfection reagent. Often, there are sourcing issues and it can sometimes take up to half a year until you finally get the plasmid you need for your GMP production round.

At the moment, were still talking about ultra-rare diseases where batch sizes arent large. But a lot of common diseases, like Alzheimers and Parkinsons, are currently in gene therapy trials. Once these trials are successful and they go into clinical phase III or even enter the market, then upscaling becomes a huge challenge. How will we produce sufficient amounts of the vectors in sufficient quantity and quality?

With ELEVECTA, our new scalable, stable producer cell line technology for AAV gene therapy vectors, we wanted to address all the challenges I just mentioned. First of all, we have eliminated the lengthy and complex transfection step. Our platform does not require any transfection for the actual production of the AAV vector, which also means it doesnt require any plasmid or transfection reagent. So, we dont need any of the expensive raw materials.

ELEVECTA is truly scalable because its basically made AAV production very similar to the well-established recombinant protein production methods. Using our platform, AAV production is very much like making a monoclonal antibody. With this, were addressing the major challenges that people are seeing for AAV production.

Weve been thinking about how people have mastered the production of other biotherapeutics like monoclonal antibodies and why their production is scalable, and the answer is relatively simple: because they are using true, stable producer cell lines. That means all the genetic information thats required to make the product is stably integrated into a producer cell.

Of course, we have to do cell line development in the beginning, but that only needs to be done once. Then, the producer cell line can be used for the production of the gene therapy vector for an unlimited period, as all the components are integrated into the cells genome.

I like making the comparison to monoclonal antibodies because making a monoclonal antibody used to be difficult, but its now become a common technology that can be outsourced to numerous service providers. We wanted to accomplish the same for AAVs. With our ELEVECTA producer cells, were now able to do so.

Developing the ELEVECTA technology was not trivial and we had to apply some tricks from the molecular biology toolbox, but we have been successful in the end. And we have very convincing data from true producer cells where we generated AAV vectors in large bioreactors with consistent productivity and quality.

One of the important quality measures is the full-versus-empty ratio because you always also generate empty particles that will not carry your gene of interest. Thats just inherent to AAVs. With our ELEVECTAplatform, we see a high ratio of full particles, which is what you are looking for, and its also consistent over different batches, making the process more robust and subsequent purification easier.

We want to make ELEVECTAwidely available and we want to see it in use for most of the future AAV gene therapy products. We will help interested parties make their specific producer cell lines with their specific gene of interest and their specific serotype

We are also supporting Pharma companies with a whole portfolio of products by offering a partner package and enabling them to do everything themselves, including cell line development.

But for most clients, we offer product-based projects. This means we generate stable producer cell lines as a service and then transfer those cells and the corresponding manufacturing processes to our clients who then use them under a technology license.

I believe that gene therapy has overcome the initial hurdles now and we will see many more products on the market in the future. But this also means that the therapy costs have to go down. At the moment, were talking about one million or two million for a treatment. Thats a big obstacle to making gene therapies commonly available. One important factor in addressing this issue is lowering production costs.

The standard size of a transient production run is about 200 L. With ELEVECTA, its not a problem to scale up to 2000 L and beyond. So, in addition to reducing the material costs, our clients can benefit significantly from the economy of scale while using standardized processes, equipment, and facilities as known from antibody production.

Are you struggling to find an upscaling solution for your gene therapy? Get in touch with the experts at CEVEC and visit their website for more information!

Images via Shutterstock.com and CEVEC

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How to Solve the Production Challenges of AAVs for Gene... - Labiotech.eu

PHILADELPHIA, June 01, 2020 (GLOBE NEWSWIRE) -- Spark Therapeutics, a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease, today announced the publication of new research in the journal Nature Medicine demonstrating that treatment with immunoglobulin G-degrading (IgG) enzyme of Streptococcus pyogenes (IdeS) resulted in rapid and transient reduction of neutralizing anti-adeno-associated virus (AAV) antibodies and restored gene therapy efficacy in controlled laboratory tests of animal models.

One of the main challenges associated with AAV-mediated gene therapy is neutralizing antibodies that can impact the ability to administer gene therapy, saidFederico Mingozzi, Ph.D., chief scientific officer atSpark Therapeutics. The IdeS technology has the potential to eliminate anti-AAV antibodies that allow for the extended use of gene therapy in a larger segment of candidates who may have been excluded due to pre-existing or developing neutralizing antibodies and also enable vector re-administration.

The study was conducted by an international collaboration of researchers from Spark Therapeutics in the U.S., and Genethon, the Centre de Recherche des Cordeliers (Inserm, Sorbonne Universit, Universit de Paris) and the National Centre for Scientific Research (CNRS) in France.

AAV-mediated gene therapy allows for the treatment of a growing number of diseases in patients today, however the presence of neutralizing anti-AAV antibodies can lead to limitations of this technology. Specifically, neutralizing anti-AAV IgG pre-exist in up to seventy percent of the population and block the entry of viral vector particles in a given target tissue. Furthermore, high-titer anti-AAV antibody levels usually develop following vector administration and persist long-term thereafter, preventing vector re-administration. To date, researchers have been limited in their ability to bypass the neutralizing activity of anti-AAV IgG.

Study FindingsThe study demonstrated that treatment with the IgG-degrading enzyme IdeS, an endopeptidase from Streptococcus pyogenes that specifically hydrolyses human IgG, resulted in a rapid and transient elimination of neutralizing anti-AAV IgG and restored gene therapy efficacy. IdeS is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients.

Researchers demonstrated efficacy in vivo using animal models of liver gene transfer, including hemophilia A and B. Hemophilia is a rare genetic bleeding disorder that causes a delay in clot formation as a result of a deficiency in coagulation factor VIII or IX for hemophilia A or B, respectively. In both mice and non-human primates with neutralizing anti-AAV IgG, IdeS treatment prior to the injection of AAV vectors eliminated neutralizing IgG and rescued the expression of the factor VIII or IX in hepatocytes.

Furthermore, administration of AAV vectors systematically induces a neutralizing anti-AAV immune response, making gene therapy inefficient upon subsequent injections of AAV vectors. The study also demonstrated that treatment with IdeS restores the efficacy of the re-administration of AAV vectors, allowing for efficient transgene expression in non-human primates. The research shows that IdeS allows the repeated administration of AAV vectors by blocking the neutralizing activity of anti-AAV IgG in small and large animal models.

Additional studies in the field of gene therapy have the potential to translate these findings to human trials, with the goal of opening a therapeutic window for patients with neutralizing anti-AAV antibodies. Spark will assess and investigate the potential impact of the IdeS technology on its current gene therapy programs and potential applications in the future.

About Spark Therapeutics AtSpark Therapeutics, a fully integrated, commercial company committed to discovering, developing and delivering gene therapies, we challengethe inevitability of genetic diseases,includingblindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases.We currently have four programs in clinical trials.At Spark, a member of the Roche Group, we see the path to a world where no life is limited by genetic disease. For more information, visit http://www.sparktx.com, and follow us on Twitter and LinkedIn.

Media Contact:Kevin Giordanocommunications@sparktx.com (215) 294-9942

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Study Demonstrating Role of IdeS in Enabling of Gene Therapy in the Presence of Neutralizing Anti-AAV Antibodies Published in Nature Medicine -...

Radiation, chemotherapy and surgery dont cut it against glioblastoma, an aggressive type of brain cancer that often recurs with a vengeance. Ziopharm is working on a remote-controlled gene therapy to buy these patients more timeand early data show it extended patients lives by more than a year.

The company tested the treatment, dubbed Controlled IL-12, in 95 patients as a monotherapy in two studies and in combination with a PD-1 inhibitor in a third study. After finding that the treatment worked best in six patients who took low doses of dexamethasonea steroid commonly prescribed after brain tumor removal surgeryZiopharm tested it in that exact patient population, adding 36 patients in an expansion study. The treatment helped those patients live a median of 16.2 months, an improvement on the 12.7-month survival rate from the main trial, which tested the treatment in 38 patients who took varying amounts of the steroid.

Sixteen months is very, very encouraging, Ziopharm CEO Laurence Cooper, M.D., Ph.D., told FierceBiotech. Those four months may not sound like a lot to me and you, but those four months might represent getting to a wedding or a graduation. Frankly, those four months are 30% more life, he added, referring to historical survival rates for glioblastoma, which top out at 12 months but could be as short as six months.

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A substudy testing Controlled IL-12 with Bristol Myers Squibbs Opdivo is still in its early days, but signs are encouraging, with half of the patients still alive an average of 8.3 months into treatment. And thats not allinvestigators found that one patient in each study had their tumors shrink, bringing the total partial responses across the three studies to five.

Observing responses in brain tumors in the setting of recurrence is unusual and highly encouraging, and, along with the survival data, highlight the potential of [Controlled IL-12] for the treatment of [recurrent glioblastoma], said Antonio Chiocca, M.D., Ph.D., a trial investigator and professor of neurosurgery at Harvard Medical School.

Some patients did exceptionally well, with one patient in the main study still responding after nearly two years and one patient from the expansion study still responding after 48 weeks. Cooper thinks the studies may turn up more exceptional responders, which could help the company figure out why some patients do better than others and, eventually, help itdevelop drugs that boost survival even more.

RELATED: Treating glioblastoma with a Ziopharm drug and IL-12 gene therapy

Glioblastoma has been so hard to tackle because its a heterogeneous tumor: Its not one set of malignant cells, but really a population of cells that all have different attributes relating to the genetics of the disease, Cooper said. A treatment may take out some of those tumor cells but leave the rest alone.

One of the things thats appealing about IL-12 is that its a weapon that activates T cells, Cooper said.

Controlled IL-12 combines an IL-12 gene therapy with Ziopharms pill, veledimex, which can switch the gene therapy on and off as well as tune it up and down. Patients received one dose of veledimex before undergoing surgery to remove their brain tumor. During the surgery, adenovirus vectors that carry the IL-12 gene were injected directly into the tumors. The patients then took veledimex, which turns on IL-12 production in the tumors, waving down T cells to attack and destroy the cancerous tissue.

Its an ideal approach, Cooper said, because the T cells act like little cellular scalpels, eating away at the tumoreven tendrils of it that have penetrated normal brain tissue, beyond the borders where a surgeon can safely operate.

Veledimex is a crucial piece of the puzzle because of how powerful IL-12 is.

Protein IL-12 has been delivered systemically through intravenous injections back in the day, but the side effects were intolerable because IL-12 activated the immune system globally, Cooper said. The trick to harnessing IL-12 is to be able to regulate it rather than giving it to the whole body and hope the patient survives that encounter.

Even though Ziopharms gene therapy is delivered directly to brain tumors, it is inevitable that IL-12 will seep out into circulation, Cooper said. And thats where the switch comes in.

If we get a call, say, from Chicago saying a patient has a fever and impending cytokine storm, we can guide the treating physician from Boston to hold off on the next mornings dose. And that typically takes care of the problem. The fever goes away and we can restart the veledimex, he said.

Next up, Ziopharm is looking forward to the Opdivo data maturing. It will also finish enrolling a phase 2 study combining its treatment with Sanofi and Regenerons PD-1 blocker Libtayo in the first half of this year, despite the COVID-19 pandemic, Cooper said.

Looking ahead, we will have a continuum of data readouts this year and into next year, showing survival and MRI imaging of the monotherapy and in combination, he added. [They will] allow the company to make a decision about the phase 3 trial. With a sizable cohort of patients about the study, well be able to sit back and say, look: Where do we think we can develop and prove this is a drug?

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ASCO: Ziopharm's IL-12 gene therapy boosts survival in hard-to-treat brain cancer - FierceBiotech

Forbion has led a $62.5 million round for Prilenia Therapeutics to fund two late-stage trials in Huntingtons disease and amyotrophic lateral sclerosis. Michael Hayden, the former Teva R&D chief whos been serving as chairman, will now take over as CEO to oversee the program for pridopidine, which agonizes the sigma-1 receptor (S1R). Morningside and Sectoral Asset Management also joined, as did Talisman Capital Partners and Genworks 2.

Australias CSL Behring is teaming up with Seattle Childrens Research Institute to develop stem cell gene therapies for rare primary immunodeficiency diseases, starting with Wiskott-Aldrich Syndrome and X-linked Agammaglobulinemia. They are among 400 primary immunodeficiency diseases, in which the human immune system is dysfunctional. Expanding our gene therapy portfolio into an area of immunology well known to CSL exemplifies how we are strategically growing our capabilities in this strategic scientific platform and are collaborating with world class institutions to access innovation with the potential to vastly improve patients lives, noted CSL R&D chief Bill Mezzanotte.

Hyloris Pharmaceuticals, a Belgian company dedicated to reformulating well-known drugs, is looking to tap the public market by listing on Euronext Brussels. The IPO is expected to provide us with the resources needed to finance the development of our existing portfolio of product candidates, as well as establish a commercial infrastructure in the United States for our IV Cardiovascular portfolio (excl. Sotalol IV, which is commercialized through a partner), where we will focus on addressing prescribers in a cost-efficient manner by concentrating on specialized care facilities such as hospitals, CEO Stijn Van Rompay said in a statement.

GHO Capital has put the $1 billion-plus fund it closed at the end of last year to use, buying X-Chem froman affiliate of The Carlyle Group and Hellman & Friedman. The company specializes in DNA-Encoded Library (DEL)-based discovery services and has licensed over 70 research programs to biopharma partners over the years.Matt Clark, a co-founder and the current SVP of chemistry, will replace Rick Wagner as CEO.

Dublin-based Avectas has enlisted Scott Simons lab at UC Davis to characterize cells engineered on its platform, with the goal of informing the development of next-gen cell therapies. A major focus of our group is to understand how chemical and mechanical forces acting on immune cells enable them to localize at sites of inflammation, Simon said in a statement. The partnership with Avectas will help us evaluate how these same forces play a role to delivering mRNA and proteins to immune cells and thereby extend their therapeutic applications.

Irelands Shorla Pharma has closed its Series A at $8.3 million to advance a slate of drugs for rare, orphan and pediatric cancers. Seroba Life Sciences led the round, which featured other local investors as well as family offices in Canada.

Christian Angermayer, founder of the mental health and psychedelics biotech ATAI, is trying to bring the Australian biotech Bionomics and its PTSD drug back from the near-dead. Bionomics stock flatlined to $0.04 after the drugs failure in a Phase II trial, but the company, which has also partnered with Merck on Alzheimers, has since reformulated the drug, and Angermayer is betting it might now work. His firm Apeiron put down $5 million and underwrote $15 million in funding to put the compound back into trials.

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Forbion leads $62.5M round for neuro startup as ex-Teva R&D chief takes control; CSL Behring inks gene therapy pact in immunology - Endpoints News

Before it even started, ASCO 2020 was one for the books. Held virtually for the first time in its history instead of at Chicagos massive McCormick Place conference center, the American Society of Clinical Oncologys big meeting also shrank from five days to three last weekend.

After following ASCO news from afar, STATs Adam Feuerstein on Wednesday continued in that vein, hosting a virtual chat with three noted oncologists to get their take on the future of cancer therapy. After big news from AstraZeneca in lung cancer, Johnson & Johnson in multiple myeloma, and Allogene in off-the-shelf gene therapy, they paused to reflect on their field and ASCO 2021. Here are some of their observations:

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Recapping ASCO, talking cancer therapy combinations, and looking ahead - STAT