Category Archives: Genetic Therapy

A team of genome engineers at a startup biotech has been working for years to create a cell therapy with the hope that it will cure an aggressive form of cancer. After much grueling trial and error at the editing bench, they are ready to evaluate their drug candidate in clinical trials. Things are going well, and theyre ecstatic to see that tumors are shrinking, T cell counts are rising, and the disease is retreating. But theres a cloud on this bright horizon. A side effect is showing up with some of the patients in the trial, one which might have long-term consequences for their well-being. The scientists have an idea: What if they can flip what they call an off-switch on one pair of genes theyve identified that could turn off this side effect of the drug while retaining the new drugs curative powers? It sounds like an easy fix but its implementation is going to take a long time.

In the current regulatory environment, after an important discovery is made, a trial alteration is required, which is a costly and lengthy process that limits the ability to bring novel unique therapies quickly to patients with high unmet needs. If those genome engineers at the startup want to make even the slightest improvement to their drug candidate, which may attenuate the previously mentioned serious side effect, theyll be required to start all over again with a 2.0 version. This kind of versioning is customary in the biotech industry and can often be a race against time.

In our current climate of drug innovation, pharmaceuticals are being developed through hyper-precise genetic editing. No longer relegated to a siloed discipline, blockbuster drugs are being developed by the team efforts of gene therapy, cell therapy, gene editing, protein engineering, synthetic biology and artificial intelligence. These combined disciplines provide limitless capabilities to develop new therapies. This agile capacity could make in-trial drugs incrementally safer and more effective.

An example of what can emerge from this multidisciplinary world, that is making it relevant, is the invention of allogeneic CAR-T cell therapies. An artificial gene coding for a designed Chimeric Antigen Receptor (the CAR part of the word) is delivered by a synthetic vessel called lentivirus into T cells, white cells which are our bodies immune response fighters. Then, through synthetic biology, T cells are edited out (or in) to gain or lose specific functions. This process is made possible by using a gene editing tool called TALEN, which are enzymes that can be engineered to cut specific sequences of DNA. The engineering of TALEN is powered by deep learning algorithms. We may refer to the treatments that arise from this work as cell therapy or gene therapy, but its high concentration of sophisticated technologies working together.

In 2015, during the annual meeting of the American Society of Hematology (ASH), the complete remission of the first patient treated with off-the-shelf CAR-T cells was announced. It took nearly 20 years of trial and error at the editing bench to go from concept to the first patient treatment. Now, five years later, the number of ongoing trials in the sector of cell and gene therapy is rapidly increasing. A report released in March 2020 by the Pharmaceutical Research and Manufacturers of America (PhRMA) identified 362 investigational cell and gene therapies currently in clinical development, a 20% increase since 2018.

Though the increase in trial numbers and the multitude of advances in the way we utilize gene and cell therapies seem positive, there is not a direct correlation between the advance in research we see in the lab and the way patients are treated in the clinic. Furthermore, the drugs that these patients receive were invented many years ago. To prove this point: Approved cellular therapies providing revolutionizing cures, like the first two autologous CAR-T products Yescarta and Kymriah, were invented over 15 years ago, and have side effects, due to the CAR-T persistence resulting in B cell aplasia (disappearance of B cells). Improvements have yet to be implemented in the compound and will need to be evaluated in a clinical setting.

The current paradigm in pharmaceutical development is that patients will get the Older Gen drugs with the afferent side effects rather than the Next Gen therapies that could solve the issue, because of the length, cost and complexity of the current regulatory framework not allowing for the implementation of improvements in the drug development phase.

While rapid, responsive versioning is the norm in other industries, like software, computer or rocket science development, the obvious difference in the pharmaceutical sector is that there are distinct ethical and safety concerns in conducting responsive versioning in trials on human beings; the safety of patients in clinical trials is paramount. That being said, what if we could expedite the process and bring innovation to patients faster within a fitted regulatory framework?

In recent years, several new clinical processes were created, intended to streamline and expedite drug development and clinical trial evaluation. To name a few: the creation of Phase 0, basket, and umbrella clinical trials. Though Phase 0 trials seem to address the expedition of the trials themselves, if any changes are made within this phase, a full IND application with the usual three pre-approval phases is still required to re-version your Phase 0 trial. Essentially, with simple proposed modifications, you are being asked to start from scratch, from a regulatory standpoint.

When the chance for failure in clinical trials (specifically in anti-cancer drug clinical trials) is so high (failure rate is more than 90%) and when more than half of these new drug candidates in oncology fail during later stages of clinical development, the path to expediting the implementation of versioning and revision during early-stage trials is fundamental to address patients needs, in a timely manner.

If a mechanism existed, by which series of versions of a product line could be tested, then adapt it or tune it up, according to the response observed in clinical trials, patients would have access to innovation faster and the modern medicine will progress further at a quick pace. Of course, preclinical proof of concept requirements and CMC must be part of the regulatory equation, but the ability to streamline testing of various versions of a therapeutic concept in the clinic could trigger a huge developmental acceleration to the benefit of patients.

The proposal would be to open a new era in drug development and adapt the regulatory environment to the speed of innovation and its opportunities in the interest of patients. The current regulatory framework and IND process (Investigational New Drug) seems set in stone for a single product development.

What if different versions of a product candidate could enter in clinical development phase under the same Investigational New Therapy (INT) number? In this INT, and under an initial umbrella Core Protocol (without making any shortcuts on product candidates manufacturing, quality and control or preclinical assessment of any of the versions of the therapy), incremental versions of the product candidate could enter in small clinical cohorts. Once there is a sign of meaningful efficacy and good safety profile on one of the versions, then this version of product candidate would be pushed into expansion and pivotal trial targeting a registration. In jurisdiction without the IND concept, the proposed Core Protocol will be associated with a Core Product Dossier holding the required information for each of the product candidate versions.

The goal of this process would be to get away from the track to get onto a larger road, with boundaries, where nimbleness is allowed to adapt the right version before moving to commercialization. This would be in the best interest of patients to get the latest therapy faster in a safe setting.

Andr Choulika is a virologist and a biotechnologist. He is the founder & CEO of Cellectis, a biotechnology company. He is also one of the inventors of nuclease-based genome editing in the 90s.

Biotech Voices is a contributed column from select Endpoints News readers. Read previous pieces here.

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Biotech Voices: Next-gen therapies are evolving fast. The drug development model needs to keep up - Endpoints News

Dublin, Jan. 11, 2021 (GLOBE NEWSWIRE) -- The "Bacterial and Plasmid Vectors Global Market Report 2020-30: COVID-19 Growth and Change" report has been added to ResearchAndMarkets.com's offering.

Major players in the bacterial and plasmid vectors market are Sigma-Aldrich Inc., ATUM, QIAGEN, Promega Corporation, Thermo Fisher Scientific, Inc., GenScript Biotech Corporation, Takara Bio Inc., IBA GmbH, Bio-Rad Laboratories and New England Biolabs.

The global bacterial and plasmid vectors market is expected to decline from $0.36 billion in 2019 to $0.34 billion in 2020 at a compound annual growth rate (CAGR) of -7.62%. The decline is mainly due to the COVID-19 outbreak that has led to restrictive containment measures involving social distancing, remote working, and the closure of industries and other commercial activities resulting in operational challenges. The entire supply chain has been disrupted, impacting the market negatively. The market is then expected to recover and reach $0.52 billion in 2023 at a CAGR of 15.48%.

The bacterial and plasmid vectors market consists of sales of bacterial and plasmid vectors and related services by entities (organizations, sole traders and partnerships) that develop bacterial and plasmid vectors for biotechnological applications. Bacterial vectors are DNA molecules that are the basic tool of genetic engineering and are used to introduce foreign genetic material into a host to replicate and amplify the foreign DNA sequences as a recombinant molecule. The vectors are used for introducing a definite gene into the target cell and command the cell's mechanism for protein synthesis to produce the protein encoded by the gene. These are used for the production of protein in biotechnology applications.

North America was the largest region in the bacterial and plasmid vectors market in 2019. Asia-Pacific is expected to be the fastest-growing region in the forecast period.

In May 2018, Vectalys, a France-based company engaged in manufacturing and commercializing lentiviral vectors for gene delivery, and FlashCell, a company engineering non-integrating lentiviral delivered RNA therapeutics, announced their merger to create a new gene therapy company - Flash Therapeutics.

Flash Therapeutics is expected to collaborate on the two complementary businesses of Vectalys and FlashCell and combine the emergence of cell and gene therapies as major new therapeutic modalities for the treatment of incurable diseases. Flash Therapeutics is a new gene and cell therapy company based in Occitanie, France engaged in developing gene and cell-based therapies by leveraging its bioproduction technologies and lentiviral platform.

The high cost of gene therapy is expected to limit the growth of the bacterial and plasmid vectors market during the forecast period. The cost of gene therapy treatments approved by the Food and Drug Administration is between $0.3 million and $2.1 million. Moreover, the cost of Luxturna gene therapy for certain inherited retinal diseases (IRDs) is $0.4 million per eye and LentiGlobin, a gene therapy by Bluebird Bio designed to increase the levels of hemoglobin, costs around $2.1 million. Stringent government regulations, long approval processes, and high production costs are the major factors leading to the high cost of gene therapy. Thus, the high cost of gene therapy is expected to hinder the growth of the bacterial and plasmid vectors market in the near future.

The focus areas for many companies in the bacterial and plasmid vectors market has shifted to mergers and acquisitions to enhance production capabilities. Large prime manufactures are forming joint ventures or buying small or midsized companies to acquire new capabilities or to gain access to new markets.

The increasing prevalence of cancer and infectious diseases is anticipated to boost the demand for the bacterial and plasmid vectors market over the coming years. Bacterial vectors are used for the delivery of recombinant proteins into target cells for the treatment of cancer and various infectious diseases. According to the World Health Organization (WHO), cancer is the second leading cause of death worldwide, responsible for an estimated 9.6 million deaths in 2018.

The growing prevalence of cancer and various infectious diseases and the increasing demand for bacterial and plasmid vectors for gene therapy are projected to propel the market revenues for the bacterial and plasmid vectors market.

Key Topics Covered:

1. Executive Summary

2. Bacterial and Plasmid Vectors Market Characteristics

3. Bacterial and Plasmid Vectors Market Size and Growth 3.1. Global Bacterial and Plasmid Vectors Historic Market, 2015 - 2019, $ Billion 3.1.1. Drivers of the Market 3.1.2. Restraints on the Market 3.2. Global Bacterial and Plasmid Vectors Forecast Market, 2019 - 2023F, 2025F, 2030F, $ Billion 3.2.1. Drivers of the Market 3.2.2. Restraints on the Market

4. Bacterial and Plasmid Vectors Market Segmentation 4.1. Global Bacterial and Plasmid Vectors Market, Segmentation by Host Type, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion

4.2. Global Bacterial and Plasmid Vectors Market, Segmentation by Application, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion

5. Bacterial and Plasmid Vectors Market Regional and Country Analysis 5.1. Global Bacterial and Plasmid Vectors Market, Split by Region, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion 5.2. Global Bacterial and Plasmid Vectors Market, Split by Country, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion

Companies Mentioned

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Global Bacterial and Plasmid Vectors Market Report 2020: Market is Expected to Recover and Reach $0520 Million in 2023 at a CAGR of 15.48% - Forecast...

DUBLIN--(BUSINESS WIRE)--The "Cell and Gene Therapy Global Market Report 2020-30: COVID-19 Growth and Change" report has been added to ResearchAndMarkets.com's offering.

Cell and Gene Therapy Global Market Report 2020-30: COVID-19 Growth and Change provides the strategists, marketers and senior management with the critical information they need to assess the global cell & gene therapy market.

Major players in the cell and gene therapy market are Gilead Sciences, Bristol-Myers Squibb, Novartis AG, Amgen, Merck, Organogenesis Holdings, Dendreon, Vericel, Bluebird Bio and Fibrocell Science.

The global cell and gene therapy market is expected to decline from $6.68 billion in 2019 to $6.92 billion in 2020 at a compound annual growth rate (CAGR) of 3.61%. The slow growth is mainly due to the COVID-19 outbreak that has led to restrictive containment measures involving social distancing, remote working, and the closure of industries and other commercial activities resulting in operational challenges. The entire supply chain has been disrupted, impacting the market negatively. The market is then expected to recover and reach $13.23 billion in 2023 at a CAGR of 24.10%.

The cell and gene therapy market consists of sales of cell and gene therapies by entities (organizations, sole traders and partnerships) that develop cell and gene therapies. Cell therapy refers to the transfer of intact, live cells that are originated from autologous or allogenic sources and gene therapy refers to the introduction, removal, or change in the genome for treating diseases. The market consists of revenue generated by the companies developing cell and gene therapy products by the sales of these products.

In December 2019, Roche, a Swiss multinational healthcare company, acquired Spark Therapeutics for $4.3 billion. The acquisition supports the commitment of Roche to bring transformational therapies and innovative approaches to people with serious illnesses. Spark Therapeutics will continue to work within the Roche Group as an independent company. Spark Therapeutics, headquartered in Philadelphia, is a fully integrated commercial company involved in the discovery, production, and distribution of gene therapies for genetic disorders including blindness, hemophilia, lysosomal storage, and neurodegenerative diseases.

The cell and gene therapy market covered in this report is segmented by product into cell therapy; gene therapy and by application into oncology; dermatology; musculoskeletal; others.

Limited reimbursements preventing patients from receiving treatments are expected to limit the growth of cell and gene therapy (CGT market. In 2019, Trinity Life Sciences, a life sciences solution provider, researched national and large regional commercial health insurance plans in the US. It found that the confluence of increasing price, patient volume and number of CGTs on the market is likely to change the reimbursement model for CGTs and impact payer budgets by 5-10%. Payers realize that financing needs to be generated for cost management due to the uncertainty surrounding reimbursement of ancillary costs. Limited reimbursements and uncertain insurance plans are preventing patients from receiving high-cost CGT, which is expected to limit market growth.

Chimeric antigen receptor (CAR) T-cell therapy is shaping the cell and gene therapy (CGT) market. (CAR) T-cell therapy is a combination of cell and gene therapy in which T cells are collected from the patient's blood and are genetically engineered to produce modified receptors at their surface, known as chimeric antigen receptors (CARs). These modified T cells with special structures (receptors) are reinfused into the patient. Then, the modified receptors of T cell help in targeting the surface antigen of the cancer cell that ultimately results in the killing of tumor cells in patients.

In 2020, the US-FDA approved Bristol-Myers Squibb's two CAR-T cell therapies to treat lymphoma and multiple myeloma and is set to be launched. Currently, FDA approved CAR-T cell therapy treatments like Tisagenlecleucel for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) in children and Axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma.

Steady investment and consolidation in cell and gene therapies contributed to the growth of the cell and gene therapy (CGT) market. After recognizing the potential of the CGT market, 16 out of the 20 largest biopharma companies by revenue, added CGT products to their portfolio.

Key Topics Covered:

1. Executive Summary

2. Cell And Gene Therapy Market Characteristics

3. Cell And Gene Therapy Market Size And Growth

3.1. Global Cell And Gene Therapy Historic Market, 2015 - 2019, $ Billion

3.1.1. Drivers Of The Market

3.1.2. Restraints On The Market

3.2. Global Cell And Gene Therapy Forecast Market, 2019 - 2023F, 2025F, 2030F, $ Billion

3.2.1. Drivers Of The Market

3.2.2. Restraints On the Market

4. Cell And Gene Therapy Market Segmentation

4.1. Global Cell And Gene Therapy Market, Segmentation By Product, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion

4.2. Global Cell And Gene Therapy Market, Segmentation By Application, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion

5. Cell And Gene Therapy Market Regional And Country Analysis

Companies Mentioned

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Global Cell and Gene Therapy Market Report 2020: Market to Recover and Grow at a CAGR of 24.1% in 2023 - Forecast to 2030 - ResearchAndMarkets.com -...

JP Morgan isnt typically a data conference. But there are always exceptions for data that could make or break a company, piquing the interest of potential investors and partners alike.

Data, for instance, like what Sekar Kathiresan is bringing to the virtual conference, showing that a one-time treatment with Verve Therapeutics base editor can keep PCSK9 levels low thereby lowering LDL cholesterol, aka the bad kind out to 6 months. In non-human primates.

The two takeaway figures are 61% LDL cholesterol reduction and 89% cut in average blood PCSK9 protein level. Thats the same level of reduction for PCSK9 as the treatment registered at 2 weeks, when the researchers documented a 59% drop in LDL-C.

What you are seeing is durable lowering of cholesterol and consistent lowering of LDL cholesterol 6 months after administration of the gene editing treatment, Kathiresan told Endpoints News in a preview.

While preclinical, the results mark a significant step for the in vivo use of the next-generation gene editing tool known as base editing. Whereas the first generation of CRISPR gene editing molecules would snip the DNA sequence and let it repair on its own, base editing works by converting one letter on the genome to another.

In this case the construct, VERVE-101, made a single change from A to G in the genetic sequence of the PCSK9 gene in the liver, with an aim to inactivate the gene for good.

As liver cells turn over roughly every 200 days, Kathiresan added, 6-month durability data offer reasonable confidence that the changes are there to stay.

The fundamental problem with coronary heart disease is cumulative exposure to LDL over time, OK? And the fundamental treatment is to lower that cumulative exposure as much as possible, said the CEO, who left behind an academic career and a directorship at Mass Generals Center for Genomic Medicine to steer the biotech. The way to think about this is kind of the area under the curve analysis, you know? You want to keep the LDL down and consistently down for as long a period as possible.

VERVE-101 rides on the pharmacologic validation offered by monoclonal antibodies and siRNA therapies that target PCSK9 but does away with the need for chronic treatment. Each of which he sees presenting its own compliance issues that could lead to insufficient protection.

With toxicology studies underway, Verve expects to dose its first patient some time in 2022. By targeting the initial clinical indication of heterozygous familial hypercholesterolemia, the company will be developing a genetic treatment for a genetic disease before turning to garden variety coronary heart disease.

PCSK9 will just be a start. Kathiresan has identified seven other genes that, as hes discovered over years of studies in population genetics, harbor protective mutations one of them being ANGPTL3, for which Verve has also presented 2-week preclinical data. All eight targets fall into one of three pathways: LDL-C, triglycerides or lipoprotein(a).

Each of those pathways are kind of complementary in terms of risk for a patient, he said. So a medicine targeting each of those pathways should be additive in terms of benefit.

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Looking to leapfrog antibodies and RNAi, Sekar Kathiresan says gene editing approach to cut PCSK9 looks durable - Endpoints News

The FDA has issued draft guidance on the development, testing, and trial design for human gene therapies for neurodegenerative diseases. The document, released on Tuesday, also highlights approval pathways for these novel products.

The draft guidance, which applies to products for both adult and pediatric populations, emphasizes the importance of early communication with FDA before the submission of an investigational new drug (IND) application. The agency pointed to INTERACT meetings, which can be used to discuss issues in a products early preclinical program, and pre-IND meetings, which occur later in development but prior to the submission of an application.

Early interaction with FDAs Office of Tissues and Advanced Therapies (OTAT), part of the Center for Biologics Evaluation and Research, may include product-specific considerations related to the evaluation of drug product purity, identify, potency, and strength.

FDA also recommends that sponsors evaluate the effect of manufacturing process changes on the products critical quality attributes (CQAs). In cases where the effect is not immediately identifiable, sponsors should consider conducting a two-part risk analysis prospectively looking at pre- and post-change product, as well as retrospectively analyzing post-change product samples that have been preserved.

When developing preclinical studies for gene therapy products, the agency recommends focusing on five overall objectives:

When considering pediatric, first-in-human clinical trials where there is more than a minor increase over minimal risk, the agency is calling on sponsors to design a preclinical program that includes studies showing the potential for direct benefit of the gene therapy. Preclinical evidence to support a prospect of direct benefit is most important when clinical evidence of effectiveness is not available from adult subjects with the same disease, FDA wrote.

FDA suggested that innovative clinical designs not only randomized, placebo-controlled trials (RCTs) could be used for clinical development for monogenic disorders with a well-characterized pathogenesis and pathophysiology, such as infantile spinal muscular atrophy due to mutations in the survival motor neuron 1 gene. However, traditional RCTs are likely more appropriate for neurodegenerative diseases with a poorly understood etiology and a variable natural history, such as sporadic amyotrophic lateral sclerosis or sporadic Alzheimers disease.

But sponsors are advised to at least consider innovative trial designs adaptive designs, enrichment designs, dose-controlled studies, or historical controls for any neurodegenerative disorder.

When planning pediatric trials, FDA recommends that sponsors first obtain preliminary safety and effectiveness data in adults. If no prior adult data is available, sponsors should provide a rationale as to why adults studies are not ethical or feasible.

In any clinical trials that are intended to support a marketing application, FDA advises that the primary efficacy endpoints should be either clinically meaningful endpoints or surrogate endpoints that are reasonably likely to predict a clinical benefit.

An effect on a clinically meaningful endpoint would generally be used to support a marketing application under the traditional approval pathway, while surrogate endpoints could be used to support accelerated approval. Use of a surrogate endpoint may be appropriate when a [gene therapy] product directly targets an underlying, well-understood and well-documented monogenic change that causes a serious neurodegenerative disorder, the agency wrote. In these cases, the [gene therapy] product could alter the underlying genetic defect and thereby treat or cure the disease.

RAPS: First published in Regulatory Focus by the Regulatory Affairs Professionals Society, the largest global organization of and for those involved with the regulation of healthcare products. Click here for more information.

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FDA offers first thoughts on neurodegenerative disease gene therapies - Endpoints News

At the end of the study, it was found that the rats had regained their ability to use their paws and were able to pick up sugar cubes to feed themselves, according to The Independent. The gene therapy trial was conducted at Kings College London, U.K. The focus of the work was to repair damage to the spinal cords of the rodents. The spinal cords of the rats had been purposefully damaged to mimic the damaged sometimes suffered to humans after car crashes. Quoted by Sky News, Professor Elizabeth Bradbury, one of the principal researchers, stated: "In some of the tests we looked at such as gripping the rungs of a ladder the treatment worked within one to two weeks."Gene therapyGene therapy is an important aspects of medicine. The process is designed to introduce genetic material into cells. This is to compensate for abnormal genes or, alternatively, to produce a beneficial protein. In cases where a mutated gene causes a necessary protein to be faulty or to become missing, then gene therapy could work to introduce a normal copy of the gene and hence to restore the function of the protein.There are different variants of gene therapy, including plasmid DNA, where circular DNA molecules are genetically engineered so they carry therapeutic genes into human cells; viral vectors, where viruses are used to deliver genetic material into cells; bacterial vectors, where bacteria are modified and then deployed as vehicles to carry therapeutic genes into human tissues; and human gene editing technology, where genes are edited to disrupt harmful genes or to repair mutated genes. There is also patient-derived cellular gene therapy products. With this more recent process, cells are taken from the patient, modified and then returned to the patient.For some scientists, the next phase is germinal gene therapy. This has been achieved experimentally in animals but not in humans.Novel researchWith the new study, the process involved injecting a gene that produces an enzyme called chondroitinase, into the spinal cords of the rats. This enzyme functions to breaks down scar tissue, a tissue that is formed following damage to the spinal cord. he tissue prevents new connections from being formed between nerves. The enzyme is also being used in trials for vitreous attachment and for treating cancer.

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article image Advances in gene therapy to help paralysis - Digital Journal