RARE Daily

A New Therapy Offers A Different Approach to Inhibiting the Complement System

May 27, 2021

Earlier the month the U.S. Food and Drug Administration approved Apellis Pharmaceuticals Empaveli to treat paroxysmal nocturnal hemoglobinuria (PNH), a rare and life-threatening condition in which the body’s immune system destroys the oxygen carrying red blood cells. Like existing treatments Soliris and Ultomiris, Empaveli works to inhibit the complement system, but it is the first therapy to target the portion of this immune cascade known as C3. We spoke to Cedric Francois, co-founder and CEO of Apellis, about Empaveli, what advantages it may provide over existing therapies for PNH, and other indications the company will pursue for this medicine.

Daniel Levine: Cedric. Thanks for joining us.

Cedric Francois: Thank you so much for inviting me, Danny.

Daniel Levine: We’re going to talk about Apellis, the rare condition PNH, and your recently approved therapy to treat the condition. Perhaps we can begin with PNH. For listeners not familiar with it, what is it?

Cedric Francois: PNH is a rare disease of the bone marrow. It is caused by a mutation in the bone marrow that is what we call, somatic, meaning that it’s a mutation that we acquire typically during our adult life or during childhood, you are typically not born with it. Because of this mutation, patients with PNH create red blood cells that are overly susceptible to destruction by this old part of our immune system called complements. There are two mechanisms by which these red blood cells in patients with PNH gets destroyed. One is called intravascular hemolysis. The best way to think of that is that red blood cells, not too long after they enter the bloodstream, quite literally explode inside the bloodstream. The second mechanism by which these cells get destroyed is called extravascular hemolysis. This Is when these red blood cells get tagged by this complement product and that leads them to be removed from the liver and the spleen in a very short period compared to how long red blood cells are supposed to live, which is typically 90 to 120 days. Three to four months is what a normal red blood cell is supposed to live and in patients with PNH it is much shorter, probably only days or weeks.

Daniel Levine: How does the condition manifest itself and progress?

Cedric Francois: The name of the disease is paroxysmal nocturnal hemoglobinuria and that’s a little bit of a misnomer because in most patients it’s neither paroxysmal nor nocturnal, and many patients do not have hemoglobinuria where you actually pee blood. The first manifestation that many patients with PNH will have is often fatigue, looking tired and not feeling good. At some point they may actually notice blood in the urine. Sometimes that happens at night, but not necessarily. As is the case with many rare diseases, it can often take a long time before PNH is actually diagnosed in patients. First of all, you typically need a general practitioner who has an eye for things like that and will look at the blood exam and may notice that a value that we call lactate dehydrogenase, which is a marker of these red blood cells exploding in the bloodstream, is elevated. A good general practitioner will see that as a warning sign and may start thinking in the direction of PNH, but ultimately a well-trained hematologist will make the determination based on some very specialized tests.

Daniel Levine: How have patients with the condition been treated and what’s the prognosis for them today?

Cedric Francois: If we go back to before 2005, this was a terrible disease that was lethal in about a third of patients over the course of five years. The main mechanism by which patients passed away was through thrombosis, the formation of blood clots. Essentially patients with PNH, before there were any treatments available, were susceptible to the formation of blood clots and once these blood clots start forming, it would be out of control. These were terrible manifestations that would typically lead to death. I believe it was in 2005 or 2007, that the first product got approved in PNH and that product was called Soliris. Soliris is an antibody that blocks complement, which is the system that attacks the red blood cell, and does that in a way where it is very good at controlling the intravascular hemolysis. It does not do anything about extravascular hemolysis, but it does control intravascular hemolysis. Soliris is a life-saving drug for patients with PNH. I cannot overstate the benefit that Soliris, and a similar mechanistic drug, Ultomiris, have been for patients in terms of saving lives. However, drugs that control this complement system in the way Soliris and Ultomiris do, do not control extravascular hemolysis. By not doing that, these patients often continue to suffer from anemia and from transfusion dependency, and that is a mechanism that we can control with Empaveli, the newly approved drug.

Daniel Levine: Talk to me a little about the complement system itself. How does it work and what role does it play in PNH?

Cedric Francois: Complement is a subjectively fascinating system that is hundreds of millions of years old. You should think of it as the first way for us to have immunity, to be able to protect our organisms against outside forces. The way in which complement does that is this the central component of the complement system, which we call C3. This protein floats around in the body and, like paint, paints all of the cells in our bodies continuously. At that point in time, every cell in the body has a task to remove that C3 product from the cell surface. Cells that are not doing that properly are cells that are removed by another part of our immune system called the reticuloendothelial system. That system normally functions very well and our own normally functioning cells have a way of controlling the accumulation of that product in a way that’s highly effective. In patients with PNH, that control of the cleanup of that product from the cell surface is not working well. Because it does not work well, the immune system is tricked into thinking that the cells are sick or in trouble, and they are to be honest, but they’re still functioning well in terms of oxygen carrying capacity, et cetera, but they get removed prematurely from the circulation or they can also explode in the bloodstream.

Daniel Levine: You mentioned Soliris. The approach that’s been taken to date has been to target C5, which is part of the cascade of activity. What’s the advantage to targeting C3 rather than C5?

Cedric Francois: So, that goes back to what I mentioned earlier about intravascular versus extravascular hemolysis. If you target PNH with something that controls C5, you can prevent the red blood cells from exploding, but you cannot prevent the paint from accumulating on these red blood cells, because that is what drives extravascular hemolysis. By targeting C3, instead of C5, you can control both extra-, but also intravascular hemolysis.

Daniel Levine: One of the issues with the existing C5 complement inhibitors is that they only work on a portion of the population. Is there any reason to expect that this would allow you to address the non-responders or would this address a different population?

Cedric Francois: That is a bit of a misconception as well. In patients with PNH, when they are on treatment with C5 inhibitors, with the exception of a handful of patients that have a genetic mutation that prevents the antibody Soliris from binding to its proper target, almost every patient will respond to a C5 inhibitor like Soliris and Ultomiris. The problem is, however, that if you only control intravascular hemolysis and not extravascular hemolysis, your body still needs to compensate for that by producing as many red blood cells as possible in the bone marrow. Some people do that better than others. That is why a third of patients with PNH on treatment with a C5 inhibitor will still require transfusions. They just cannot compensate for the continued loss due to extravascular hemolysis. A third of patients will continue to suffer from anemia. The other third of patients may have more normal hemoglobin levels and not necessarily be anemic, but can only get there again by maximum output from the bone marrow. The bottom line is that to properly control PNH it is important to target intra- as well as extravascular hemolysis.

Daniel Levine: You recently won approval for Empaveli. What do we know about Empaveli from studies to date in terms of its safety and efficacy?

Cedric Francois: Empaveli, in total, and when I say in total that means not just in PNH but also in the other indications that we are studying, has right now a safety database that covers what we call approximately 300 patient years. So, imagine 300 patients being dosed for a year or 150 patients being dosed for two years, that’s how we think about that in the context of safety. We’ve done a lot of work already with Empaveli. The work that we did in PNH was initially focused on: is this a treatment that can control both intra- and extravascular hemolysis? Once we felt very good about Empaveli doing that, we said, how can we make it as easy as possible for patients and physicians to consider a treatment that can cover intra- and extravascular hemolysis in PNH, and do it in a way that is as comfortable as possible? The way in which we did that is with the phase 3 clinical trial, which we called Pegasus, which was the rock of the submission that led to approval. We said, we’re going to do three things in one clinical trial. Number one, we are going to try to show that Empaveli is a drug that can treat PNH, and of course we did that. Number two, we’re going to show that this drug Empaveli is not just equivalent, but actually superior to Soliris in terms of the hemoglobin levels that are generated in patients with PNH, and we did show that superiority on hemoglobin levels. The third piece, which is maybe the one I’m most proud of, is we said, if I’m a patient with PNH and I’m on treatment with Soliris or Ultomiris, and I’m for example, transfusion dependent or I’m anemic and I want to do something about it, what are going to be the fears that inspire me? The fear that stood out when we thought about this is: what happens if this doesn’t work for me? Can I at least go back to where I was before? So what we did in the Pegasus study is we said, we are going to take all 80 patients who are on treatment with Soliris, and we are going to switch all patients over to combination therapy with Soliris and Empaveli at the same time for one month. The reason why we did that is, during that one month we believe that we would already see the benefit from Empaveli, but then after one month of combined treatment, we took away the drug Empaveli from 39 of the 80 subjects in this study. Unfortunately, that was the very sad part of this study that these 39 patients lost the benefit that they had experienced during that one month. It did establish the safety database that you can safely switch between these two products. These 39 patients for a period of four months had to then continue or be back on treatment with Soliris alone. After which, the subjects had the opportunity to forever go back on treatment with Empaveli. We’re incredibly grateful for these 39 subjects that essentially allowed us to create the data and the science needed to be able to offer this to patients as an approved product today.

Daniel Levine: How is the drug expected to be priced relative to the C5 complement inhibitors?

Cedric Francois: We decided to price the drug at a discount to Soliris and at parity to Ultomiris. As we’ve discussed, it’s a drug that is superior on hemoglobin levels to Soliris and a drug that we believe will improve lives and elevate the standard of care in PNH. It will be priced at parity with Ultomiris. Now to make sure that every patient who needs Empaveli can have access to it, which is really important to us as a company and to myself as a physician, we are going to have a program called Empaveli Assist, which is going to help patients that may not be able to afford the drug to make sure that no patient has to be without a drug.

Daniel Levine: In October you entered into a global agreement with Sobi to commercialize and develop the drug. Sobi has exclusive ex-U.S. rights. You’ve retained ophthalmological indications. What were the financial terms of the deal and how is it helping you expand indications beyond PNH?

Cedric Francois:

We did the deal with Sobi for several reasons, most importantly, the fact that Sobi is a company that culturally was aligned with Apellis. It’s a company where we felt that they are going to have the interests of patients at heart just like we do. The second important reason is that Sobi, especially in hematology, the specialty where a drug like Empaveli will get administered, has a stellar reputation and several products approved within hematology in Europe and in the rest of the world. Here’s a partner that could lift some of the important weight off Apellis, because these are enormous undertakings as you can imagine to make sure that regulatory work goes through as quickly as possible and that the distribution and the access to the medication ex-U.S. is also handled as expeditiously as possible.

Daniel Levine: How broadly applicable do you think Empaveli might be as you consider additional indications?

Cedric Francois: Empaveli is now only approved for adult patients with PNH. It’s currently in what we call the registrational testing, which is the last phase of testing before hopefully gaining approval, in four additional indications. There is currently an ongoing trial in ALS, amyotrophic lateral sclerosis. There is a phase three clinical trial that is about to start in C3 glomerulopathy, which is a disease of the kidney. That’s going to be a trial that also covers another rare disease of the kidney called immune complex membranoproliferative glomerulonephritis. This drug will then also be tested by Sobi in two additional hematological indications. The first one is a disease called cold agglutinin disease, and the second one is a disease called hematopoietic stem cell associated thrombotic microangiopathy, which is a disease that is associated with high mortality and is believed to be linked to complement activation

Daniel Levine: Has the agreement helped you, as you think about your own commercial organization and the launch in the United States?

Cedric Francois: Absolutely. On one hand, it alleviated some of the very high financial burden that developing drugs mean for a company like us, but also the partnership, speaking now for more than half of year of working together, has been about as good as we could have hoped for. This is a very collegial and collaborative way of determining how we design the clinical trials, how we implement them, where we implement them, and there’s no doubt in my mind that will ultimately lead to a broadening of indications in the future hopefully. One or more of the four that we spoke about.

Daniel Levine: Cedric Francois, co-founder, president, and CEO of Apellis. Cedric, thanks so much for your time today.

Cedric Francois: Thank you so much, Danny.

This interview has been edited for clarity and readability.

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