We hypothesized that we could increase overall exposure and improve free drug that could penetrate the
tissue if we engineered our compound to lower its isolelectric point. Our clinical compound TX45 can be seen in green, and as you can see, with a reduced pI we have a ten-fold increase
in exposure.
How does this translate into potency in animals? Renal blood flow in rats is an excellent pharmacodynamic marker
for relaxin because it captures its rapid systemic vasodilation effects. That makes it an ideal setting to benchmark our compound against a high pI comparator. Start on the left of this slide. As I mentioned, when you give
equal amounts of these drugs, you get a ten-fold increase in exposure with TX45. However, engineering to reduce the pI, also decreased potency in vitro by a factor of ten. If this
was just about optimizing blood PK, one would expect that equal amounts of the drugs, would show equal in vivo potency, because you would need ten times more TX45 to activate RXFP1.
However, despite the decreased in vitro potency, in vivo, as you can see, our drug is ten times more potent than the comparator compound. 0.3 mpk of
the high pI comparator compound has similar effects on renal blood flow as 0.03 mpk of TX45. In contrast, 0.3 MPK of TX45 shows much greater effect than the comparator. And we attribute this to less drug trapping in the
glycocalyx, resulting in more free drug becoming available to activate the receptor in tissues.
We have data suggesting we have a potential best in
class relaxin fusion protein, and weve chosen Group 2 Pulmonary hypertension in patients with Preserved ejection fraction heart failure (HFpEF) as our first indication for several reasons:
First, Group 2 PH with HFpEF is a substantial unmet need population with no approved therapies: it is a large population in the US and the five-year
mortality in this disease is high.
Second, the mechanism of action of relaxin matches the pathophysiology of the disease.
We also believe there is a clear, reasonably quick path to approval because an outcome study is not needed to get approval or reimbursement in Group 2 PH,
which should enable an earlier entry to market compared with CHF. Also, there may be a pricing and reimbursement advantage if the first indication is in a subset of CHF, with highest unmet need.
Beyond Group 2 PH there is the potential to expand to other types of pulmonary hypertension, to larger heart failure indications, and also renal disease.
When people talk about pulmonary hypertension, theyre usually referring to Group 1 PH, also known as PAH, because that is where most drug discovery and
development efforts have focused to date. Group two, PH is pulmonary hypertension associated with left heart failure. And over the last few years, two subtypes have been identified which I will describe on the next slide. Preserved
ejection fraction heart failure (HFpEF), affects several million patients in the US, and more than 600,000 of those have elevations in the pulmonary artery pressure and therefore have Group 2 pulmonary hypertension. More than 500,000 of these
have Ipc-PH, isolated post, capillary pulmonary hypertension.
With these patients, elevated pressures in the left side of the heart, backflow into
the pulmonary circulation, leading to elevated pulmonary pressures. Their pulmonary vasculature is normal. And if you can treat their heart failure adequately, which has been difficult with current therapy, their pulmonary artery pressures
should come down.
In contrast, combined pre and post capillary pulmonary hypertension (Cpc-PH) represent more than 100,000 patients in the US. These
patients have both increased pulmonary pressure due to backflow, but in addition, their pulmonary vasculature starts to look like Group 1 PH. They get muscularization of the arteries and a narrowing of the lumen. And as blood is pushed
through a smaller lumen you get an increase in pulmonary vascular resistance, which is how you differentiate them from patients with Ipc-PH.