DRUG DEVELOPMENT EXECUTIVE - Poseida Therapeutics: Creating the Next Wave of Cell & Gene Therapies With the Capacity to Cure

Poseida Therapeutics is a clinical-stage biopharmaceutical company bringing together scientists, entrepreneurs, and inventors united behind one goal – using advanced genetic engineering to change how diseases are treated. With its core proprietary technology platforms spanning gene insertion, gene editing, and delivery tools, Poseida aims to make the promise of single-treatment cures, greater accessibility, and off-the-shelf therapies a reality for patients in need. Drug Development & Delivery recently interviewed Eric M. Ostertag, MD, PhD, Chief Executive Officer of Poseida Therapeutics, to discuss the company’s innovative approach to develop safer, more effective, accessible and affordable cell and gene therapies for patients.

Q: Your CAR-T product candidates are developed using your proprietary piggyBac® DNA Delivery System. How does this work and what are its benefits?

A: Our uniquely designed, non-viral piggyBac DNA Delivery System is a transposon technology that efficiently delivers extensive genetic cargo into cells.

The piggyBac platform offers many advantages over the retroviral systems. First, piggyBac can accommodate a much larger therapeutic transgene than the viral systems, allowing us to insert greater cargo, including useful tools, such as a safety switch that could be activated to eliminate cells in a person at any point after administration, if desired. It is also more efficient at gene insertion, offers a safer insertion profile, and is less costly to manufacture. However, the most significant advantage of using piggyBac for the creation of chimeric antigen receptor T (CAR-T) cell therapies is that it preferentially inserts into a highly desirable T cell subtype called the stem cell memory T cell, or Tscm, while the retroviral technologies are almost completely excluded from infecting and transducing the Tscm cell type. Not surprisingly, the type and quality of the cells that comprise a cell therapy will determine how well the cell therapy functions in a person. As it turns out, the Tscm phenotype is directly correlated with the best responses in the clinic and, in some patients, remarkable duration of response. It also results in significant safety advantages, thereby enabling fully outpatient dosing and increasing patient access.

In fact, we recently highlighted initial results in the current trial for our CAR-T in prostate cancer where we’ve seen early signs of meaningful clinical response – one in a patient with a >50% decline in prostate-specific antigen (PSA) just two weeks after treatment; and now a second patient with >96% decline in PSA and a 70% reduction as shown in PET imaging of target lesions at four weeks after CAR-T treatment. Though early, this undoubtedly is an encouraging response.

Q: In addition to your autologous CAR-T candidates, the company is also working to develop allogeneic CAR-T product candidates. Why is this an exciting next step?

At Poseida, we have combined the power of the non-viral piggyBac DNA Delivery System with the safe and efficient Cas-CLOVERTM Site-Specific Gene Editing System to create fully allogeneic versions of our high-percentage Tscm CAR-T product candidates. The cells in these investigational products are derived from younger, healthier donors than the autologous counterparts and have even higher percentages of the desirable Tscm cells. Therefore, the allogeneic versions demonstrate even higher efficacy than the best autologous versions of our product candidates in our most predictive animal models.

In addition, Dr. Devon Shedlock, Senior Vice President, Research & Development at Poseida, has invented a technology that we call the booster molecule, which uniquely allows Poseida to maintain the Tscm cells in our fully allogeneic products, while expanding the cells to create hundreds of doses from a single manufacturing run from a single healthy donor. This invention will lower the cost of CAR-T to the same range as that of a monoclonal antibody or a bi-specific T cell engager (BiTE). We expect the first version of our fully allogeneic CAR-T, P-BCMA-ALLO1, to enter the clinic in the third quarter of this year. We have also developed a “pan solid tumor” version of a fully allogeneic CAR-T, P-MUC1C-ALLO1, that is expected to enter the clinic by the end of this year. We are optimistic that high Tscm, fully allogeneic CAR-T will enable accessible and safe treatments with low manufacturing costs for various cancer types, including both blood and solid tumors.

Q: We are seeing increased interest in gene therapies. What is unique about your gene therapy development and delivery compared to others in this space?

 A: Poseida’s powerful and versatile set of industry-leading genetic engineering tools lays the foundation for developing a safer, more durable, and more efficient suite of treatments, with the goal of single treatment cures for patients with high unmet medical needs.

The great majority of genetic diseases manifest in the pediatric population. These patients are often typically the most severely affected. Unfortunately, almost all gene therapy strategies, such as adeno associated virus (AAV) and nanoparticles delivering therapeutic mRNA, are non-integrating, and are therefore transient. Non-integrating technologies are especially ineffective in the pediatric patient population because these patients have a rapidly dividing liver that will quickly eliminate expression from mRNA or non-integrating transgenes. Some AAV companies have increased the viral doses in order to compensate for this low-level and transient expression, but high viral doses can have lethal side effects.

At Poseida, we have been developing a substitute for viral delivery that is still able to stably integrate a therapeutic transgene, enabling a potential single treatment cure. There are two crucial components to this viral substitute.

The first component is a safe and efficient system for insertion of therapeutic transgenes into the genome, and the solution is to use the piggyBac DNA Delivery System. The second component, the ability to deliver therapeutic transgenes into a specific cell or tissue without triggering the immune system, is provided by Poseida’s proprietary biodegradable DNA and RNA nanoparticle technology. These two technologies combine to uniquely enable potential single treatment cures for children affected with otherwise untreatable metabolic and other genetic diseases.

Q: What initial indications for gene therapy are you targeting, and why were they chosen?

A: We have several gene therapies in development addressing life-threatening metabolic diseases, including Ornithine Transcarbamylase (OTC) deficiency, a rare metabolic disorder in which the liver cannot efficiently remove ammonia from the body, which then causes potentially fatal toxicity. OTC deficiency is caused by mutations in the OTC gene responsible for the final metabolic step in the urea cycle. We are also studying the use of our nanoparticle-based gene therapy system as a potential single treatment cure for hemophilia A.

When determining the disease indications we wanted to target, we focused on the unmet medical need and in particular are targeting the pediatric patients that cannot be treated successfully with standard gene therapies. In the case of OTC deficiency, there are few approved treatments, and they are expensive and not completely effective. Liver transplant can be curative, but it is not always available to children who need one and is fraught with high cost and high morbidity and mortality. However, the fact that liver transplants can be curative tells us that sufficient expression of the therapeutic transgene in the liver should result in a complete cure. We know that we have a huge competitive advantage in the pediatric population because typically transient gene therapies will not work. In the case of hemophilia A, there is a large number of pediatric patients who would benefit from our potential single treatment cure approach. Here again, standard non-integrating gene therapy approaches will not work. Furthermore, the therapeutic transgene for this disease, Factor VIII, is too large for AAV-based delivery.

Q: The company is working on gene therapy delivery mechanisms with the goal of replacing AAV with nanoparticle technology. Could you share more about your nanoparticle technology and its benefits versus AAV?

A: Poseida’s nanoparticles are made from biodegradable materials. Like a virus, they are able to carry DNA or RNA into a specific cell. Unlike a virus, they do not trigger the full wrath of the immune system and are therefore a much safer alternative. As additional advantages, patients do not have pre-existing immunity, and they don’t develop immunity so they can be re-dosed if necessary. In addition, nanoparticles have a much larger cargo capacity than AAV so can be used to treat a larger range of diseases, and they are easier and less costly to manufacture.

At Poseida, we have designed fully biodegradable nanoparticles that can encapsulate nucleic acids, such as those required by the piggyBac DNA Delivery System or the Cas-CLOVER Site-Specific Gene Editing System. We have already demonstrated that we are able to encapsulate the piggyBac system and achieve long-term stable transgene expression in animal models with a single injection of these safe and effective viral substitutes. While the road to safe and effective gene therapy vectors has been a long one, we are now on the verge of achieving single treatment cures for numerous genetic diseases.

Q: Where do you see your gene therapy program going and what are the next steps?

A: Our goal is to develop gene therapies that will cure a disease rather than just treat it. It may sound ambitious, but our technology platforms have the potential to correct the underlying genetic problem that causes these diseases and permanently correct or replace the gene, thereby providing a potential lifelong cure.

The next important steps will be continuing our preclinical work with researchers and clinicians who are the world experts in particular diseases and then extending our work into the clinic. It will also be important to address any skepticism around gene therapy. With the FDA approval of mRNA vaccines for COVID-19 and the 2020 Nobel Prize awarded for CRISPR gene editing technology, more people outside of the life science industry are learning about how these types of therapies work and the promise they hold.