" Hello everybody, I'm Milind Desai from the Cleveland Clinic where I am the Vice chair for Heart Vascular Thoracic Institute and I direct our Hypertrophic Cardiomyopathy Centre. It is great to be here.

So, as we know, HCM has a prevalence of 1 in 500 and MyBPC3, it is an abbreviation for myosin binding protein C3, is the most common, common within this cluster of genetically inherited HCM. So it is very common. Almost a third, if not more of these patients have this type of mutation that results in hypertrophic cardiomyopathy.

An important finding in these patients, the MyBPC3 patients, is that they are missing about 40% of the protein that is key in maintaining appropriate functioning of the sarcomere of the cardiac sarcomere. So that lack of a complete protein amount is what results in the downstream manifestation of the disease, including very thickening of the heart muscle, stiffness, et cetera.
So that is the concept behind, if we replenish this missing protein, can we reverse or slow the progression of disease? So thus far most of the drugs are not disease modifying. There is new cardiac myosin inhibitors that are thought to be potentially disease modifying. This is taking it to the next level where we are slowing the progression or perhaps even reversing the disease if everything works out the way we think it will.

So basically what it is, is this is a very smart way where we are utilising adenovirus associated, so AAV9 wires, so Adeno wire. So that's a common cold type virus which has been stripped of its own DNA and engineered to have a cassette inserted within this, the virus which basically has the DNA trigger, MyBPC3.

So essentially once you do this one time infusion, the infusion goes straight to the heart. It does not seem to the virus does not have affinity for other organs. From there there's a cascade of events where this, the DNA cassette is excreted, then DNA turns into rna, RNA turns into the protein, the missing protein and whatever that is thought to be excess is dissipated through the hepatic system.

So basically this is, you are delivering a payload of, potentially you are delivering a payload that ultimately results in generation of the missing protein.

So this is clearly an early phase. So phase one study, so this is a primary reason for the phase one study is to understand safety. It is not certainly, you know, efficacy is an endpoint, but not the key endpoint safety and feasibility of doing, doing this. So this is essentially a phase one study.

There's two, three steps before that the step zero, the way I look at it is you have to identify obviously the patients who have this mutation. A truncating mutation, not a... Yeah, you're looking for a truncating mutation which results in loss of protein. You have to make sure there are no antibodies to the virus, so you have to have the right type of population. And obviously symptomatic hypertrophic cardiomyopathy patients.

The first three patients that we are describing were all non obstructive patients who had all undergone surgical myectomy, but they were still symptomatic despite relief of outflow tract obstruction. They all had advanced diastolic dysfunction, thick heart, et cetera.
And essentially what we found was that the process, the logistics process in these first three patients was A feasible, B safe. And obviously it has to be done under the umbrella of immunosuppression, where we use prednisone and sirolimus over an extended period of time of multiple weeks.

And then essentially what we demonstrated, that not only was this feasible, but it was safe. And then we have been able to successfully wean all these patients off of immunosuppression.
And in terms of the efficacy, again, mind you, efficacy was not the focus of this study. Efficacy. All the patients are in NYHA class one. Everybody is alive. Essentially there is stabilisation of function and biomarker markers and some improvement, but this is still very early and small numbers. So all steps in the right direction.

There were non TN201 related adverse events, but everything was addressed. And as I said, patients are all off of immunosuppression and in class one, obviously like any new drug or therapy development, it has to go through the obligatory testing.

So phase one will morph into a phase two and maybe if needed, phase three trials. And then look, if you are an optimistic, glass half full kind of a person that I am, I tend to be. And let's fast forward 10, 15 years down the road, okay? And we have worked through the process, all the kinks, we have done the obligatory testing.

This could theoretically be, be a one time infusion where you come in, get this infusion, get monitored for a little bit beyond immunosuppression for a little bit and then you could have slow progression of disease or in some lucky individuals halt the progression of disease.

So this is truly this, if the process works, this has the potential of changing the game. The way we look at this. Not just this mutation, but it can pave the way for many other mutations and many other therapies so the first data is on the lower dose. So the next part of the phase one study will be on the higher dose.


We need to figure out what is the Goldilocks situation, what works the most efficaciously while maintaining the very optimal safety signals. So that's what's ongoing right now. Phase. And then that will morph into a broader patient population exposure, perhaps expanding to the rest of the world. So the obligatory next steps are already underway.