What If We’re Right?

Rhetorical Question or Exciting Opportunity?

At Poseida Therapeutics we take a different approach to – well, almost everything really.

We have always pursued our own path and not followed the crowd in both cell therapy and gene therapy. We are passionate about finding and developing better tools for genetic engineering and, rather than compromising, we look to innovate to solve challenges we encounter along the way.

I speak with investors, analysts, and strategic partners every day and constantly hear comparisons to others in cell and gene therapy and questions and skepticism about our differentiated approach. It’s the cost of pursuing a novel path – but the challenges are relentless. Why are you not doing what Company X does?? Why should we believe that your approach works when everyone else uses other technologies or other approaches?? Why is your data different than Company Y’s data?

Rather than get into a debate over what others are doing, the question that I occasionally ask them is: “What If We’re Right?”

Platform Technologies

At our core, we are a genetic engineering platform technology company with a passion for helping patients. Focusing on developing better tools for genetic engineering is part of our DNA. Our founder, Dr. Eric Ostertag, found a passion and vision for developing better tools for genetic engineering when he was pursuing his MD and PhD at the University of Pennsylvania over two decades ago. That vision remains alive and well today.

We are committed to developing technologies that are designed with genetic engineering in mind from the outset.? Our custom and proprietary tools offer the capacity, specificity, and flexibility needed to support the kind of sophisticated engineering that advanced cell and gene therapies require to potentially deliver products with high levels of clinical benefit while maintaining favorable safety profiles. That has resulted in a large and growing intellectual property estate and no need to rely on others for key technology.

Too many in the industry attempt to use old technologies that were never designed, developed or intended to be used in the ways we now envision. Viral technologies – including lentivirus, gamma retrovirus, herpes virus and adeno associated virus (AAV) – first emerged 30 to 60 years ago and are, in our view, simply not good tools for today’s challenges and opportunities.

We look at the many companies that have struggled and failed in both cell and gene therapy and ask ourselves – “what did they have in common?” ?Probably the most striking commonality today is the use of antiquated viral technology. In cell therapy, most use lentivirus or gamma retrovirus technology for gene insertion. In gene therapy, virtually everyone uses AAV for gene delivery. It might be fair to suggest or conclude that the common problem is that viral technologies simply don’t work well for these applications, can be difficult and costly to manufacture, and, in the case of AAV in particular, have safety concerns as well.? All this is not intended to suggest that there have not been some successes using these technologies – but they are few and the exception rather than the rule.

Cell Therapy for Oncology

In cell therapy, since Poseida’s founding we have always been focused on the goal of allogeneic cell therapy. Like many, we started in autologous cell therapy as a proving and learning ground, but with progress and advancements have shifted to a fully allogeneic focus. In addition, we have been a pioneer and leader in focusing on stem cell memory T cells, or Tscm, as the ideal cell type for cellular therapies. For years, we were the only company talking about Tscm – but in recent times more and more of our peers and counterparts are now on board and discussions at ASCO and in other forums are recognizing the benefits of Tscm.?

Because of our early focus on Tscm, we have had the time to develop a significant amount of technology and tools to enrich and preserve Tscm throughout manufacturing to the final product. We have also filed and obtained significant intellectual property to protect these technologies and findings. While others are starting to focus more on Tscm – we also know that in this quest technology matters. In our view, if you try to use viral technologies and older gene editing technologies, you will never be able to generate high Tscm cell therapy products. Our technology, our learnings and our dedicated focus to this task over several years is what put us in the position we are in today and make our unique products possible.

We also think about allogeneic differently than many others. We don’t believe that allogeneic is just an off-the-shelf extension of autologous cell therapy – we believe that allogeneic done properly is a whole different class of product than autologous. That long-term focus has also driven us to develop technology that has other benefits as we think about future programs – larger cargo capacity allows for multiple targeting – dual CARs or even CAR and TCR combinations in a single construct. Such constructs may help us address known medical problems such as antigen escape, or targeting tumors that have antigens expressed on other tissues where logic gating approaches may be required.? We also include a proprietary, rapid-acting safety switch in our products and have included technology to allow manufacturing benefits like positive selection and our Booster Molecule to increase yield dramatically without sacrificing Tscm – which also reduces costs dramatically. Our large cargo capacity could further support incorporation of various armoring strategies without sacrificing other elements of the genetic engineering strategy. In summary, it’s a complex undertaking – but we think it well worth the effort.

So, what if we’re right?? If we are right that Tscm is the ideal cell type, if we are right that our technology is uniquely suited to creating these high-Tscm products, if we are right that additional technology advancements set us apart from others – then we will emerge as the leader in allogeneic cell therapy.? Most importantly, if we are right then more and more patients will benefit from our technology and products.

Gene Therapy

In gene therapy, we also have taken a different path than most in the industry. We are focused on trying to develop products with what we call “the capacity to cure.” In genetic diseases that means targeting genetic correction of the underlying genetic abnormality. That correction could take many forms and we believe that we have the tools and the technology to go after many approaches – whether gene editing, gene insertion, or both together. Said another way, in these genetic diseases, you can’t hope to develop a product with the capacity to cure if you are not permanently correcting the defect.

We also have a high focus on being able to deliver these gene therapies safely.? We believe that treatments should be possible without the dangerous, or even deadly, side effects seen with many gene therapy approaches and AAV approaches in particular. So part of our focus is also on developing technology and treatment approaches that can reduce the safety challenges of AAV through a hybrid approach – or avoid them altogether through nanoparticle delivery.

Other than a few examples, the gene therapy area has struggled with toxicity, durability, and manufacturing and has done little for the most severely impacted patients. In part, that is an inherent problem of approach and technology. AAV technology, which is over 50 years old and widely used in the space, is not an integrating technology, so it severely limits what is possible medically and clinically.

There is much discussion in gene therapy circles about the concerns around integration or risk of oncogenesis – and those are concerns to be seriously weighed. If you are using AAV, those fears are legitimate as?integration (when it happens) is random and not predictable – and that is scary. However, in our view the right answer is not simply to accept the high safety risks of AAV and also give up on genetic engineering’s curative potential.?

The right answer, and Poseida’s approach, is to use technologies that are designed and intended to permanently correct or integrate in a more controlled way and focus on doing that as safely as possible. We believe that is the path we are on both with our current technologies as well as our next generation technologies and our different delivery approaches. Only by moving in this direction will we unlock the true potential of gene therapy for genetic diseases for the patients who need it most.

So, what if we’re right?? If the real key to safe and effective therapies revolves around permanent correction of the genetic abnormality, if we can deliver these approaches much more safely through hybrid or fully non-viral technologies, if we can deliver clinical benefit to the most severe of these rare disease patients – then we will emerge as the leader in gene therapy.? Most importantly, we will bring hope and treatment options to many patients with rare genetic diseases – often including newborns and infants whose prognosis without treatment is grim.

So – Are We Right?

Only time and data will tell the story of whether we are truly “right” in cell therapy and/or gene therapy. We believe that the signs are emerging that we could be right – although undoubtedly the skeptics will take time to come around.? One thing seems clear – if we are right on either front then we will emerge as a leader in these exciting fields and many patients with cancer and rare diseases will benefit. If patients benefit – so will our other stakeholders as well. That is what drives us forward.

We’ve come a long way from that spark of inspiration that Eric experienced when he was at Penn as a student. The road thus far has been long and not always easy or smooth – technology and drug development seldom is a straight and even path. However, we are making great strides toward our goal and vision of redefining cell and gene therapy.

Join us – because if we are right – it should be an amazing journey.