Revolutionizing OA treatment with advanced gene therapy

Osteoarthritis (OA) is among the most prevalent diseases people face as they age. In fact, in the US alone there are well over 14 million patients suffering from OA of the knee, not to mention those also suffering from OA in other joints like hands, hips, ankles, shoulders… the list goes on and on! And recent trends indicate that without new therapies that can impact the onset and progression of OA, more and more people will develop OA at younger and younger ages due to global trends in obesity, physical inactivity, and joint injuries.

OA is so common, and the treatments are so limited, that it’s really viewed as just a part of life that people have to accept and deal with as they age. Many people are surprised to learn that OA is actually considered a serious disease by global health agencies like the World Health Organization and FDA. As OA progresses, sufferers become limited in their ability to perform the activities of daily living. They become more sedentary and socially isolated, all of which impacts their overall physical and mental health and overall quality of life. In fact, studies have shown that OA not only results in declining health and quality of life, it actually decreases lifespan.

Because OA is a serious disease and impacts so many people, it has been extensively researched in the scientific and medical communities. That research has made a clear case that OA is not just a disease of wear and tear of our joints as was commonly believed. There are known biologic processes that drive OA development and progression, and when they are blocked the onset and progression of the disease is significantly slowed or even stopped! One such mechanism, chronic inflammation caused by an inflammation and immune signaling system in our cells called interleukin-1 (IL-1), has been extensively studied over the past 30 years. For example, when our joint is injured or otherwise mechanically stressed, IL-1 inflammation is turned on to help the body’s immune system respond to these stressors – this is actually a good thing, because this response helps the body heal. Under normal circumstances, as the body begins to heal, our cells produce a natural IL-1 blocker protein, called IL-1Ra, to turn off the inflammation. But as we age, or if our injuries are too severe, our bodies might not be able to make enough IL-1Ra, and we end up in a state of chronic inflammation which has been highly associated with joint degradation – Osteoarthritis.

There are drugs on the market that target this mechanism for patients with systemic inflammatory diseases, and they work really well. In these cases, the drugs need to be infused throughout the body by injecting patients with the IL-1 blocking proteins – daily, weekly, or perhaps monthly. But to date no one has been able to adequately make a medicine with this target that impacts OA in the knee. It’s well understood that the biggest limitation holding these IL-1 blocking therapies back for knee OA is that when these drugs are administered throughout the body, they cannot deliver enough drug to the knee and have it last long enough inside the knee capsule. To get enough drug to the knee you would need to inject directly into it. But nobody wants to get a knee injection every month, let alone every week or every day! The lack of an adequate delivery system to ensure adequate and durable levels of IL-1Ra inside the knee has held back our ability to bring this promising approach to OA.

This is where gene therapy comes in. In its simplest form, gene therapies deliver genes to cells so the cells can make the proteins they need themselves. This field of research has been around for well over a quarter of a century, with over 8 products recently approved by the FDA for diseases that affect relatively small populations. We’re taking this concept to the next logical step by applying this technology for the first time to an important common disease like OA that affects millions of people every year.

Using a gene therapy approach so that cells can make more of the anti-inflammatory IL-1Ra protein may solve the problem of ensuring adequate and durable levels of IL-1Ra inside the knee. It allows us to do that from a single injection, and to date our Phase 1 data appears to indicate that the effects could last for years. But one thing we considered in our product concept is that we wanted to make sure we are mimicking the natural processes of the knee to ensure long-term safety. Our cells do not constantly produce high levels of IL-1Ra. In fact, when inflammation is high our cells produce more, and when inflammation is low our cells produce less. So, we are designing our gene therapy to behave the same way. We believe that mimicking and boosting the body’s natural response gives us the best chance to help return a patient’s knee to a more natural and healthy condition and thereby slow the disease down, ease their pain and improve their function.

Traditional gene therapies often cost millions of dollars per dose. We’ve addressed this by utilizing a more efficient modified adenovirus that has no viral protein coding genes to improve safety compared to earlier adenoviral vectors, while maintaining the delivery efficiency of adenoviral vectors. This would allow for lower doses and more efficient manufacturing, significantly reducing costs. We are really excited about PCRX-201, and the potential this gene therapy has to revolutionize OA care. We are leveraging deep understanding of the molecular mechanisms that drive OA progression – mechanisms that have been well understood for decades. We are applying some of the most important advances in drug delivery by using gene therapy to help cells do more of what they already do to fight inflammation, and we are doing it in a way that mirrors our body’s natural process and in a way that can be cost effective for OA patients. We hope to unlock IL-1Ra to achieve its full therapeutic potential, at the same time that we make gene therapy available to much larger patient populations than has been possible previously.