Lentiviral vectors (LVVs) offer numerous advantages for production of adoptive cell therapies. Integration of LVV genetic material into host-cell DNA enables stable and long-term expression of the therapeutic gene in the target cells, leading to longer therapeutic effects once the cells are infused into the patient. LVVs are also highly efficient at transducing a wide range of cell types and can have a large carrying capacity relative to adeno-associated virus (AAV), allowing the delivery of larger or multiple therapeutic genes. Furthermore, LVVs can be engineered to include safety features, such as self-inactivation mechanisms or inducible gene expression systems, which can aid in regulation of transgene expression or provide the ability to eliminate modified cells if necessary.

The most commonly used platform for generating LVVs in the R&D and clinical space relies on transfection of four individual plasmids. The disruption of LVV genes required for competent viral replication have been eliminated, while the structural components required to assemble virus particles have been retained. This advancement maximally reduces the potential recombination events that could lead to undesirable replication of competent lentivirus (RCL) formation in patients. While safety has been addressed, transient transfection of four plasmids to generate LVVs in this manner is challenging. Sourcing the plasmids can be difficult, and the efficiency of the reaction is influenced by numerous process parameters.

There is significant interest, therefore, in developing stable producer cell lines that simplify LVV production, afford high yields of high-purity LVVs, and measurably lower costs for manufacturing.

Producer cells are generated by introducing the gene of interest (GOI) into an LVV packaging cell line that already has stably integrated the vector-coding LVV structural proteins and a viral envelope to impart cellular tropism. This stable producer cell line then undergoes multiple rounds of clonal selection, and if a suspension system for better scalability is desirable, then subsequent serum-free suspension adaptation is required. The result is a monoclonal, highly characterized, GOI-specific stable producer cell line.

To overcome the cytotoxicity to producer cells associated with constitutive over-expression of the LVV envelope and the regulatory protein Rev required to generate viral products, two approaches have been developed. With inducible systems, the expression of viral cytotoxic proteins is regulated by the addition of an inducer or the removal of a suppressor to control initiation of LVV production at a defined timepoint and thus limit expression of the cytotoxic viral products to the time of production only, explains Luca Peterfay, process development scientist II at Charles River. Common systems turn transcription on or off using tetracycline or doxycycline (an analog of tetracycline) antibiotics (Tet-on and Tet-off systems, respectively) via the tetracycline response element (TRE).

In constitutive systems, continuous expression of all vector components occurs, with nontoxic envelope alternatives to vesicular stomatitis virus G (VSV-G) engineered into the producer cells. “This approach limits titers and transduction efficiency compared to VSV-G enveloped systems, but allows multiple vector harvests, extends production campaigns, and reduces overall LVV manufacturing costs,” Peterfay observes.

There are many reasons to use producer cells for viral-vector manufacturing, says Brian Tomkowicz, senior director of R&D for Center for Breakthrough Medicines. In addition to being designed to prevent the replication of viral vectors and eliminate the risk of generating replication-competent viruses (RCVs), producer cells are engineered to lack essential viral genes or have other safety features to minimize the chance of vector release or dissemination during production, he notes.

Simplified process flows can also be achieved with producer cells due to elimination of the multi-plasmid transient co-transfection step, observes Peterfay. As importantly, producer cells enable efficient vector production of high-quality viral vectors through incorporation of all the necessary components for viral protein expression, assembly, and packaging of the therapeutic gene, according to Tomkowicz. Furthermore, producer cells can also be grown in large-scale bioreactors, allowing the production of large quantities of viral vectors. Tomkowicz also adds that the implementation of limited perfusion-based systems for continuous production at scale will enable the scalability crucial for meeting rapidly growing demand while simultaneously lowering manufacturing costs.

Production of viral vectors with consistent quality and characteristics, meanwhile, ensures reproducibility and consistency throughout the manufacturing process, contends Tomkowicz. The use of monoclonal, highly characterized producer cells in chemically defined media (CDM) without animal-derived products increases reproducibility and reduces batch-to-batch variation, Peterfay agrees.

Not least of the benefits Tomkowicz highlights is reduced costs due to elimination of the need for large quantities of good manufacturing practice (GMP)-grade plasmids and avoidance of negative impacts of bringing foreign DNA into production cells. Eliminating the need to source large quantities of high-purity plasmids also reduces timelines, adds Peterfay. Both agree that if a constitutive system is employed, longer processing periods and multiple harvests can cut viral-vector production costs even further.

The many advantages of using producer cell lines must be balanced with the limitations of deploying this approach. The generation of the stable producer cells is an additional step prior to the initiation of production, and this step can potentially increase preclinical timelines by several months, according to Peterfay. “The generation of stable producer cells is a complex and time-consuming procedure, which entails tedious cell-line development due to the numerous clonal isolation steps followed by extensive screening procedures,” she explains.

For the constitutive approach, Peterfay also notes that due to replacement of the VSV-G with a low-cytotoxicity alternative envelope, titers may not be as high as those achieved via transient transfection, and transduction efficiency can also be lower. “The limitation in titers can be compensated by longer processing times and multiple harvests; however, due to the reduced transduction efficiency higher doses might be required to achieve the required therapeutic effect in patients,” she says.

Finally, Peterfay points out that due to the large size of the viral insert introduced into the host cell, the long-term stability of producer cells is a concern, as compromised stability will likely result in reduced productivity.

Realizing target quality attributes is essential

When developing producer cells for LVV production, the goal is to engineer cells with several important target quality attributes. A short population doubling time of less than 24 hours is ideal to reduce GMP occupancy time and operating costs, according to Peterfay. High productivity and the ability to produce high titers of LVVs is essential to ensure efficient and effective delivery of therapeutic genes to target cells, Tomkowicz adds. High cell densities should be achievable in chemically defined media and prolonged harvest times should be tolerated, notes Peterfay.

Producer cells should maintain the integrity and stability of the LVV genome during production, according to Tomkowicz. “This attribute is crucial to prevent genetic alterations or rearrangements that could impact vector functionality or safety,” he says. Peterfay also stresses the importance of genetic stability without selective pressure, as the addition of antibiotics during GMP manufacturing significantly increases costs and may pose regulatory concerns.

“It is also essential,” states Tomkowicz, “that producer cells do not generate RCLs during vector production, as they could lead to uncontrolled viral replication and potential adverse effects in patients receiving gene therapy.” In addition, he observes that producer cells should have minimal levels of impurities such as host-cell proteins and DNA contaminants and demonstrate consistent performance over multiple production runs, maintaining consistent vector yield and quality attributes.

“These properties and characteristics are important to ensure the safety, efficacy, and consistency of the LVV production process,” Tomkowicz emphasizes. “High vector yield enables cost-effective production and efficient delivery to target cells. Genetic stability and absence of RCLs reduce the risk of adverse effects. Low impurities ensure the purity and safety of the final vector product. Consistent performance enables reliable and reproducible manufacturing processes, which are critical for clinical applications,” he concludes.

Producer-cell generation for LVV production can be proprietary and company-specific, but typically involves a similar series of steps, according to both Peterfay and Tomkowicz. The process starts with vector design, which is then followed by transfection or transduction to stably integrate the vector coding elements into the packaging cell genome. Next is selection and clonal expansion of host cells that have successfully integrated the vector. Single-cell cloning is performed in adherent, stable producer cells to generate a monoclonal population. Finally, through improvements in next-generation sequencing, rapid and cost-effective mapping of producer cell lines ensures that integration events during clonal selection did not activate proto-oncogenes, thus providing added safety for patients.

Characterization and screening assays, such as vector yield determination, genomic analysis, and testing for RCL generation are then performed on the resulting cell lines to evaluate their vector production capabilities, genetic stability, absence of RCLs, and other desired properties and identify clones with highest yields, fastest growth, and high stability. If the stable producer cells are intended for use in suspension processes, suspension adaptation is then performed. The selected cell lines are then scaled up in culture and process optimization pursued to maximize vector yield.

The resulting production process is validated to ensure consistency, quality, and safety, and appropriate quality-control measures are implemented to monitor critical parameters and assess the final vector product for impurities and potency.

While the steps involved in producer cell development can be readily outlined, effective implementation is not an easy task. Maintaining long-term stability of the integrated vector can be challenging, says Tomkowicz, as it may be prone to rearrangements, deletions, or silencing over time, affecting vector production and consistency. Ensuring stable integration of the lentiviral vector into the producer cells’ genome is, therefore, crucial, but defining the number of generations where the selected clone is stable without selective pressure and maintains high productivity can be difficult, Peterfay observes.

Preventing the generation of RCLs during vector production is equally critical for safety reasons, but controlling and eliminating any potential RCL contaminants is a challenge that requires rigorous testing and screening protocols, according to Tomkowicz. Similarly, optimizing productivity and achieving consistent high-level expression of viral proteins can be challenging, as it depends on the host cell line, transfection/transduction efficiency, and the vector design itself. “Developing clonal producer cell lines with consistent vector production can be challenging due to genetic heterogeneity within the initial population of transfected/transduced cells. It may require multiple rounds of cloning and screening to identify and select stable and high-yielding clones,” he comments.

Tomkowicz adds that screening of stably integrated clones for LV packaging can be exhaustive. It is necessary to ensure the appropriate stoichiometry and high copy number of integration events to achieve optimal viral titers of intact virus particles. In addition, induction systems must be compatible with GMP manufacturing, be completely off when not desired, and have a large dynamic range upon induction.

Potential negative impacts of the transgene on the host are a secondary concern when trying to generate producer lines, according to Tomkowicz. For instance, if expression of the GOI during clonal selection impacts overall cell health another level of GOI silencing may be required.

Peterfay, meanwhile, points to the need for the constitutive LVV producer cells to overcome the limitations of using VSV-G to improve transduction efficacy in order to lower the doses required.

These challenges are magnified by the difficulties associated with implementing robust assays and screening methods to assess vector quality, absence of contaminants, and genetic stability, according to Tomkowicz. “Developing effective assays is essential to achieve thorough characterization and quality control of producer cells to ensure the safety, purity, and potency of final LVV products,” he says.

Scaling up producer cell lines from small-scale research settings to large-scale manufacturing can also pose challenges. “Adapting the production process to bioreactors, maintaining optimal culture conditions, and ensuring consistency and reproducibility at a larger scale require careful process development and optimization,” Tomkowicz states.

Ongoing efforts to address key challenges

Several technologies and approaches have been developed to help address the key challenges associated with produce cell development for LVV manufacturing. Vector engineering is a focus, according to Tomkowicz, with the goal of optimizing vector design and incorporating genetic elements that enhance stability, expression, and packaging efficiency, thereby improving vector integration and stability in producer cells. “To that end, gene editing tools such as CRISPR/Cas9 are being used to precisely engineer producer cells, facilitating targeted integration of the vector and reducing genetic heterogeneity,” he says.

The cytotoxic and cytostatic effects of some viral products in inducible systems, such as tetracycline-inducible expression systems, are limited by better controlling of gene expression through the use of inducible promoters, according to Peterfay. In constitutive or continuous packaging systems such as STAR cells, meanwhile, the cytotoxic limitations of VSV-G are reduced by nontoxic or low-toxicity envelope glycoproteins suitable for LVV pseudotyping, she says.

There is also some interest, Peterfay notes, in exploring the engineering of cell lines other than HEK293 derivatives, such as primary human amniocytes, to increase robustness and tolerance. Tomkowicz agrees: “There are efforts directed at developing novel cell lines or modifying existing ones with improved characteristics such as higher vector production capacity, enhanced stability, and reduced immunogenicity.”

Some companies are implementing more stringent screening and selection processes to identify and isolate high-yielding, genetically stable producer cell clones through methods such as fluorescence-activated cell sorting (FACS) or limiting dilution, Tomkowicz adds. To overcome labor-intensive cell engineering and cloning steps, meanwhile, Peterfay observes that high-throughput automated equipment solutions are being developed. Similarly, Tomkowicz observes that advanced analytical techniques and quality-control measures to detect and eliminate RCLs are also being developed.

Given that the use of producer cell lines for LVV production is a relatively new technology, developers of these solutions must be aware of various regulatory considerations when pursuing this route for GMP LVV manufacturing.

The main regulatory concern, according to Peterfay, is the potential for genetic drift in LVV producer cells due to the presence of the large LV insert. “Developers need to define the lifespan and the number of generations over which producer cells are stable to ensure that the product generated is consistent and has the same quality attributes from younger and older generations,” she explains. Stable producer cells also must remain stable without selection pressure, as the use of pharmaceutical-grade antibiotics is very expensive and can raise regulatory concerns, she adds.

Overall, notes Tomkowicz, the regulatory landscape regarding the use of stable producer cells for production of LVVs used in adoptive cell therapy manufacture is complex and varies across different regions. FDA (1) and the European Medicines Agency (EMA) (2), for instance, have specific guidelines and requirements for the development and manufacture of gene therapies using LVVs. Topics addressed include genetic stability, safety, quality control, process validation, GMP compliance, and specific requirements for regulatory filing, among others.

Even with the challenges facing the development of stable, effective producer cell lines for LVV manufacturing, both Peterfay and Tomkowicz believe eventual widespread adoption of this strategy to be likely, but there is uncertainty as to the timeline.

“If a stable cell line with the packaging plasmids was created that meets all the quality attributes discussed earlier, it could be patented and offered to clients to simplify their production flows and reduce timelines and costs,” Peterfay comments. Only the transgene would then require subsequent stable transfection using the stable producer cells already containing the packaging plasmids, which would substantially reduce the timelines for operation. She estimates that it will take approximately 10 years before producer cell lines for LVV manufacturing gain full trust and routine use in the biopharmaceutical industry, with the exact timing a function of both continued stable producer cell development work and regulatory/clinical expectations.

Tomkowicz does not specify any timeline, but agrees that given the rapid advances in gene therapy and the increasing recognition of LVVs as powerful tools, it is plausible to expect wider adoption of stable producer cells. He also agrees that the timeline will depend on research progress and regulatory considerations in addition to technological advances, such as advances in cell-line engineering technology, improvements in the quality of integration events such as can be achieved using transposase technology, increases in scalability and manufacturing efficiency, the development of more robust quality-control and characterization solutions, and the advent of standardized processes and guidelines. “Collaboration between academia, industry, and regulatory agencies will play a crucial role in driving the necessary developments and establishing the foundations for widespread use of stable producer cells in LVV production,” Tomkowicz concludes.

 Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), Guidance for Industry

Guideline on Quality, Non-Clinical and Clinical Aspects of Medicinal Products Containing Genetically Modified Cells 

Cynthia A. Challener, PhD, is a contributing editor to 

Articles

Features

Stable producer cell lines show real promise despite continued development challenges.

Exploring Producer Cell Development for Lentiviral Vector Manufacturing

Waters Corporation announced the launch of the XBridge Premier GTx BEH size exclusion chromatography (SEC) columns on August 1, 2023. The new SEC columns are designed to improve analysis while lowering the cost of gene therapies, specifically for adeno-associated viral (AAV) vectors.

According to a company press release, the columns aim to reduce the cost of gene therapies by using 3 to 10x less sample, generating faster results, and offering more drug substance information. Additionally, a new multi-attribute quantification method is intended to double analytical speed, quadruple sensitivity, and increase resolution of target analytes by up to 50%.

According to the release, SEC is a technique used for aggregate and fragment analysis in the research, development, and manufacturing of biotherapeutic proteins, such as insulin and monoclonal antibodies. The Xbridge columns are designed to take robust physicochemical characterization and quantitative measurements. Aiming to double the speed of measuring the potency and safety of AAVs, the SEC columns are intended for process development, formulation studies, regulatory filing support, ongoing process monitoring, and quality control.

"We are witnessing a revolution in medicine thanks to gene therapies like AAVs," said Erin Chambers, vice-president, Consumables and Lab Automation, Waters Corporation, in the release. "A small quantity of a gene therapy, such as one of the best-selling eye treatments, can retail for more than $400,000 per eye. This makes it imperative that process and formulation development tests measure multiple attributes of the drug at once while consuming as little of it as possible. It's why Waters' low adsorption … SEC columns are such a good choice for process development, formulation studies, regulatory filing support, along with ongoing process monitoring as well as quality control."

New Technology

Waters XBridge Premier GTx BEH size exclusion chromatography (SEC) columns are designed to improve analysis while lowering the cost of gene therapies.

Waters Launches SEC Columns for Gene Therapy Applications

On July 24, 2023, Teva Pharmaceuticals, Inc., a US-based affiliate of Teva Pharmaceutical Industries, and Alvotech, an Iceland-based biotech company specializing in biosimilars, announced that they are expanding an existing strategic partnership for the development and commercialization of several biosimilar candidates. Under the expanded agreement, Teva will also acquire subordinated convertible bonds—to be issued by Alvotech—for $40 million.

With the expanded agreement, Teva will have exclusive commercialization rights in the United States for two new biosimilar candidates and line extensions of two current biosimilar candidates. Alvotech will be responsible for the development and manufacturing of these four candidates. The agreement includes milestone payments, the majority of which will be paid upon approval of the products and upon achieving significant sales milestones. Teva and Alvotech will share the profit from the commercialization of the biosimilars.

In addition, Teva will be involved in overseeing manufacturing activities and quality control at Alvotech’s manufacturing facility in Iceland. Teva is on site in Iceland to actively support Alvotech and to help ensure that the facility is fully ready for an FDA inspection, according to a company press release.

Meanwhile, the partners will continue to work closely on the pending US approval of AVT02, an interchangeable high-concentration biosimilar candidate for Humira (adalimumab). Under the existing partnership, the companies are also collaborating on four other biosimilar candidates, including AVT04, a proposed biosimilar for Stelara (ustekinumab), which is currently pending FDA approval. Furthermore, Teva’s investment under the expanded agreement (i.e., the acquisition of subordinated convertible bonds) will be used by Alvotech to fund the continued development of its biosimilars pipeline in the near-term.

“We welcome Teva’s continued partnership, and this expansion of our partnership agreement,” said Robert Wessman, chairman and CEO of Alvotech, in the press release. “We remain focused on preparing for a successful pre-approval inspection and resolving any outstanding issues identified by [FDA] to be able to bring our biosimilar candidates to patients in the US with Teva as soon as possible.”

News

Teva Pharmaceuticals and Alvotech will expand their partnership for the development and commercialization of biosimilar candidates.

Teva Pharmaceuticals and Alvotech Expand Existing Biosimilars Partnership

AbbVie and Calibr announced an expanded strategic collaboration to continue to advance several innovative preclinical and early-stage clinical assets on July 26, 2023. The partnership is an extension of the collaboration from AbbVie and Scripps Research that was formed in 2019, according to the press release.

"We've made significant progress to advance rapidly many preclinical and clinical development programs across small molecule, biologics and CAR-T modalities," said Thomas Hudson, MD, senior vice president, research and development, chief scientific officer, AbbVie, in a press release. "Working together with Calibr, AbbVie is excited to explore and further develop the potential of novel technologies and new clinical indications to bring breakthrough medicines to patients."

Further, Calibr will present AbbVie with a certain number of new discovery targets and preclinical assets of mutual interest for option considerations, according to the press release.

"AbbVie has been a trusted partner to Scripps Research for many years, as proven by our successful ongoing R&D collaborations spanning numerous disease areas that have yielded four clinical stage programs," said Peter Schultz, PhD, president and chief executive officer of Scripps Research and Calibr, in a press release. "This expansion represents an important step forward in our mission of translating scientific insights and discoveries into innovative, clinically validated drugs, and we believe it is a model for biomedical industry-nonprofit R&D partnerships."

AbbVie plans to provide Calibr with research option payments over the course of five years to obtain a first-exclusive option to develop and commercialize candidates from independent preclinical research conducted by Calibr. In addition, Calibr is able to receive additional payments from AbbVie, such as option exercise fees, success-based development and commercial milestone payments.

The partnership is an extension of the collaboration from AbbVie and Scripps Research that was formed in 2019, according to the press release.

AbbVie Expands Collaboration with Calibr to Advance Clinical Assets

Bristol Myers Squibb has exercised its option to enter into an exclusive global license agreement with Germany-based Evotec, a drug discovery company, for selected late-stage discovery programs that were developed and progressed from a collaboration between the companies.

According to a July 11, 2023 press release, the companies originally formed a neurodegeneration partnership in 2016, which proved to be highly productive. Under the collaboration, Evotec and Bristol Myers Squibb generated a pipeline of discovery-to-clinical-stage programs. The current licensing agreement expands on that original collaboration, extending the partnership to another eight years.

Under the license agreement, Bristol Myers Squibb has selected a number of programs (not disclosed) that were developed and progressed in a short time frame using Evotec’s precision medicine platforms. Based on this achievement, Evotec get a $40 million payment and is eligible to earn performance-based milestone payments. The company is also eligible to receive tiered royalties up to low double-digit percentages based on product sales, according to the press release.

“This license agreement will further bolster our joint pipeline of programs targeting several neurodegenerative conditions. We are confident that the strong collaboration of the experienced teams at Evotec and Bristol Myers Squibb will make novel innovative treatment options available to patients living with a broad range of neurodegenerative conditions,” said Cord Dohrmann, chief scientific officer, Evotec, in the release.

Under a global license agreement, Bristol Myers Squibb and Evotec will advance the development of neurodegeneration pipeline assets.

Bristol Myers Squibb and Evotec Extend Neuroscience Pact

Pfizer and Flagship Pioneering, a venture capital firm that creates bioplatform companies, announced a partnership on July 18, 2023 that is centered on creating a new pipeline of innovative medicines. The deal mentions that both companies will invest $50 million upfront to explore opportunities to develop 10 single-asset programs.

According to a Flagship press release, Pfizer will fund and have the option to acquire each selected development program, whereas Flagship and its bioplatform companies will be eligible to receive up to $700 million in milestones and royalties for each successfully commercialized program. In addition, Pioneering Medicines, a Flagship initiative, will work with Pfizer to lead the rapid portfolio creation process.

"Flagship and Pfizer enter into this strategic alliance driven by a shared sense of urgency to develop novel medicines that make a difference for patients," said Paul Biondi, president, Pioneering Medicines, and executive partner, Flagship Pioneering, in the release. "This new partnership brings together the best of our organizations to maximize discovery and development potential from inception to impact through a unique innovation supply chain that sets us on a path to potentially realize transformational medicines more quickly and effectively."

"At Pfizer, we are expanding our efforts to pursue potential breakthrough science with unique approaches and funding mechanisms designed to leverage the dynamic scientific ecosystem," said Mikael Dolsten, chief scientific officer and president, Worldwide Research, Development and Medical, Pfizer, in the release. "This collaboration is an exciting opportunity for Pfizer to bring deep scientific expertise and apply our development and regulatory strength to Flagship's diverse portfolio of technology platforms, translating early-stage innovation to potential medicines."

The partnership will see Flagship and Pfizer work to create a new pipeline of innovative medicines.

Pfizer and Flagship Pioneering Enter Innovation Partnership

Scribe Therapeutics, a genetic medicines company, and Sanofi announced an expanded collaboration on July 17, 2023. The agreement will see Sanofi receive an exclusive license to use Scribe’s CRISPR X-Editing (XE) genome editing technologies for the development of in vivo therapies, including sickle cell disease.

According to a company press release, Scribe will receive $40 million in upfront payment and is eligible to potentially receive more than $1.2 billion based on the successful completion of certain development and sales milestones, as well as tiered royalties. This agreement builds on the companies’ existing collaboration, which is focused on ex vivo editing of natural killer (NK) cell therapies for cancer treatment.

“We are continually impressed by the expertise, rigor, and urgency that Sanofi has brought to our existing ex vivo collaboration, as well as their rapid advancements and innovation in non-viral delivery technologies. Now, we are thrilled to expand our work together into new areas of high unmet need,” said Benjamin Oakes, co-founder and CEO, Scribe Therapeutics, in the release. “This in vivo collaboration further demonstrates the versatility of Scribe’s design-based approaches to CRISPR, which enable greater activity, specificity, and deliverability, ultimately accelerating the development of life-changing therapeutics.”

“We are pleased to expand our work with Scribe, an illustration of our shared commitment to advance best-in-class genome editing therapies for patients in need,” said Christian Mueller, global head, Genomic Medicine Unit, Sanofi, in the release. “We’re encouraged by what we’ve accomplished to date with Scribe in creating ex vivo NK cell therapies and now look forward to accelerating our ability to effectively leverage genome editing in vivo through Sanofi’s innovative research work in targeted lipid nanoparticles, for in vivo therapies with the potential to dramatically improve treatment outcomes and ultimately to change patients’ lives.”

“Scribe’s platform holds tremendous potential to address an unprecedented number of therapeutically relevant targets across the human genome for many serious diseases,” said Svetlana Lucas, chief business officer, Scribe Therapeutics, in the release. “We are excited to partner with companies like Sanofi that offer not only disease and drug development expertise but also the resources and technologies enabling the delivery of our molecules in vivo to specific disease tissues, allowing us to develop better therapies. We look forward to our continued collaboration with Sanofi to expand the application of Scribe’s best-in-class genome editing tools and fully realize the promise of CRISPR for patients as broadly and rapidly as possible.”

The expanded deal, now potentially worth more than $1.2 billion, will work to develop in vivo therapies, including sickle cell disease.

Sanofi and Scribe Therapeutics Expands Genomics Collaboration 

Novartis has acquired DTx Pharma, a US-based, preclinical-stage biotechnology company, for an upfront payment of $500 million plus additional payments of up to $500 million, dependent on the completion of pre-specified milestones, the companies announced in their respective July 17, 2023 press releases.

DTx Pharma focuses on RNA-based therapeutics with its proprietary Fatty Acid Ligand Conjugated OligoNucleotide (FALCON) technology platform, which conjugates small interfering RNAs (siRNAs) to naturally occurring fatty acids to enhance biodistribution and cellular uptake throughout the body. Under the acquisition, Novartis will gain access to the FALCON platform as well as DTx Pharma’s lead program, DTx-1252, a product candidate that targets the root cause of a subtype of Charcot-Marie Tooth disease (CMT)—CMT1A.

CMT1A is the overexpression of peripheral myelin protein 22 (PMP22), a protein that causes the myelin sheath insulating the nerves in the peripheral nervous system to function abnormally. DTx-1252 has been shown to decrease the expression of PMP22 in Schwann cells (target cell type), allowing for the development, maintenance, and function of peripheral nerves, according to DTx Pharma’s company press release.

Also under the acquisition, Novartis will gain two additional preclinical programs for other neuroscience indications. Together with DTx-1252 and the FALCON platform, these assets will expand Novartis’ siRNA toolkit and allow the company to build on its xRNA (i.e., ribonucleosides) capabilities, according to Novartis’ press release.

“I am thrilled that Novartis will be moving forward with our CMT1A therapeutic program and the FALCON platform. With its resources and capabilities in neuromuscular diseases, Novartis is well positioned to accelerate the development of DTx-1252 and provide hope to patients, who are desperately in need of therapy,” said Artie Suckow, co-founder and CEO of DTx Pharma, in that company’s press release.

“We look forward to continuing the development of DTx’s therapeutic programs and bringing new hope to patients with neuromuscular and other neurological disorders for which there have historically been few treatment options,” said Fiona Marshall, president of the Novartis Institutes for BioMedical Research, in the Novartis press release. “We are also excited to bring DTx’s FALCON technology to Novartis and explore its potential to deliver drugs to extrahepatic tissues.”

Novartis’ acquisition of biotech company DTx Pharma boosts its neuroscience pipeline and expands its capabilities in RNA-based therapeutics.

BioPharm International's BP Elements, August 2023