Crossing The Blood-Brain Barrier To Target Tumors With CNS Pharmaceuticals

Targeting glioblastoma (GBM) and other malignant brain tumors brings with it the long-standing challenge of crossing the blood-brain barrier, or BBB. In this episode of Sit and Deliver, host Tom von Gunden talks with CEO John Climaco and Chief Medical Officer Dr. Sandra Silberman from CNS Pharmaceuticals about intravenously crossing the BBB to deliver classes of drugs, such as taxanes, proven in treating solid tumors in other locations.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver, where we hear about trends and innovations in the field of drug formulation, development, and the related delivery routes of administration for those. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series. And today, I'm here with two executive officers from CNS Pharmaceuticals, and they'll be talking with us about targeting central nervous system [CNS] diseases, and, particularly, [about] the longstanding challenge of overcoming the restrictions caused by the blood-brain barrier [BBB].

For that conversation, from CNS Pharmaceuticals, I am joined by Chief Executive Officer John Climaco. Welcome, John.

John Climaco, Chief Executive Officer, CNS Pharmaceuticals:

Thanks, Tom. Great to be here.

I'm also joined by Dr. Sandra Silberman, who is Chief Medical Officer there. Welcome, Sandra.

Dr. Sandra Silberman, Chief Medical Officer, CNS Pharmaceuticals:

Thank you for the invitation.  

So, we'll hear from both of you here early in the episode. But, John, probably starting with you: I'd be interested to hear from both of you, given your experience and roles throughout your careers, what brought you to CNS and to the particular challenge of addressing crossing the blood-brain barrier to deliver treatments for central nervous system suffering patients?

John, as founder, you've probably got some interesting perspectives on the startup of this company and you're joining it.

Climaco: Yes, so I've been in biotech for almost 25 years, and I love a tough problem. And glioblastoma [GBM] is certainly one of the toughest in medicine, definitely in oncology. I often say, if there are two cancers you don't want, it's pancreatic cancer and GBM, because these are uniformly fatal. Both have resisted treatment effectively for decades. GBM is an awful, awful disease. I've had the privilege of talking to many patients and families over the years we've been doing this, and it's just a heartbreaking situation.  I continually say, we have to do better. We have to do better in overall survival. That's still measured in months for these patients.

So, when I was introduced several years ago to Dr. Waldemar Priebe at the MD Anderson Cancer Center, who developed our initial lead compound, Berubicin, which is a novel anthracycline that was specifically designed to cross the blood-brain barrier, I saw something that really hooked me. And that was, I guess, a slightly contrarian approach to the problem of GBM.

You see, for many, many years, as one might expect with one of the most difficult challenges in oncology, the absolute cutting edge science — the sexiest stuff, the targeted therapies, the immuno-oncology work — was all aimed at this disease as though these tumors themselves were incredibly unique, that they behaved differently than other tumors, that they were resistant to traditional cytotoxic chemotherapy or other therapeutics. And that was going to be the only way to approach these tumors.

What I saw with Dr. Priebe’s approach was something a little bit different. And that was based on the notion that, in fact, when you attempt to treat these tumors in the lab, at the bench, they respond to traditional therapeutics almost exactly like other solid tumors do. They have sensitivities. You can exploit those sensitivities with drugs that are well-known. But the problem is you can't replicate that performance in human beings. And the clear reason for that is the blood-brain barrier, which is this specialized network of cells that's both an active and passive barrier to protect the brain.

And so, while you can elicit response from these tumor cells at the bench using the same drug, you can't in a human being. And what Dr. Priebe had developed was a drug that was specifically designed to bypass the blood-brain barrier. And more importantly, in some ways, to me, it was based on a class of drugs that had been around for in clinical use for over 50 years. That was the anthracycline class. And essentially everything I'm saying about anthracyclines, we could duplicate with taxanes, which is the class from which our current lead compound, TPI 287, comes from. Again, another class of drugs that's excellent in solid tumors around the body but doesn't cross the blood-brain barrier.

When you modify these molecules — it’s very difficult chemistry to do this. But if you can create a highly lipophilic version of an anthracycline, for example, you can abrogate the transport mechanisms of the blood-brain barrier and get these molecules that are known to be safe, known to be effective, inside the blood-brain barrier.

And what you see is responses to the tumor. You start to see a change in the tumor, you see tumor shrinkage, you see extension of overall survival. You see exactly the kinds of things that these patients need to improve their chances of beating this disease or, at a minimum, living a materially longer life.

And focusing on the transport and delivery immediately struck me as the way to unlock a key component of this disease.

Yes. Dr. Silberman, would you like to join and tell us a little bit about how your experience and perspective is brought to bear on the work being done there at CNS and your interest and involvement in it?

Silberman: Absolutely. I'm an oncologist — hematologist/oncologist — by training. I was a fellow at Harvard, and we had many patients with glioblastoma and we had nothing to treat them with. We had surgery, we had radiation therapy, but none of the drugs that we had —and I used anthracyclines many, many times in my work; I used taxanes many, many times — and they're still being used. And, as John said, we know the limitations of their toxicities, but we can manage those, but we also know the ability of them to target tumor cells.

So, when I got into the pharmaceutical industry, first I was working on some targeted drugs, which were very, very effective. And that became the focus of many of the industry to only look at those types of drugs. And then it was immunotherapy. But we knew that many of these drugs don't cross the blood-brain barrier.

And so, what they were doing in glioblastoma was, actually, when they did surgery, they would add the drug right into the surgical site. So that was a way to cross the blood-brain barrier and see if they could deliver effective therapy. Unfortunately, this was not very effective either. And, as John said, taking a molecule and remanufacturing it so that it does cross the blood-brain barrier. And, you know, as he also said that, when you look at these glioma cells in the lab, you can kill them with your drug. And the only problem is getting them into the brain. This seemed the best way to start looking at molecules, looking at potential better treatments for this disease.

We've had so few treatments for this disease. I can count on one hand the number of drugs that we use. Again, we still, after 50 years, still use radiation therapy. We still use surgical therapy. And we still use the two drugs, the only two drugs, that we can get into the brain. So having a drug that could get into the brain that we knew was effective was a remarkable step for me.

And I know anthras [anthracyclines] quite well. The problem with anthracyclines has been, you can't give too much of the drug without causing cardiac disease, cardiomyopathy, cardiac failure. So, we looked at the Phase 1 studies with Barubicin, the anthracycline that crosses the blood-brain barrier, and there was no cardiotoxicity. And there were active changes in these tumors. They shrunk. And in one case, we had a complete response, and that fellow is now, I have to say, alive 18 years later, which is sort of unheard of.

So, as John said, we developed a very focused Phase 2 program, which compared it to the only other drug that was used in this situation. And we showed that our activity was as good as this other drug. And so, we have a lot of evidence that this should be brought further. We are doing a lot of studies to look at, maybe, combinations using it earlier on.

But now we have another drug called TPI 287, and that's a taxane. And taxanes are very manageable. We use them in breast cancer, we use them in lung cancer, and they're very effective. And so, they're very effective in glioblastoma. But this one crosses the blood-brain barrier.

And I have to say that a Phase 1 study we looked at showed that, in heavily pretreated patients with glioblastoma — meaning, they had gotten everything off the shelf:  they had gotten targeted therapy, they had gotten immunotherapy, and they all progressed after that or were refractory. And when they received this drug, some of them had complete responses. We had three complete responses in the Phase 1 program.

So, we licensed this drug, and we are about to start a unique program with this drug in that we are looking at a very quick understanding of, can we reproduce the effect that we see in the Phase 1 study, which was giving us the dose that we're going to use in the Phase 2 study?

And we have some sites around the United States that can enroll very quickly. And then, after that, immediately going into a Phase 3. We've already talked to the FDA about this, and they're very enthusiastic about us getting into a program where we can look at the drug and compare it to the standard of care

For our audience and folks listening, how might we envision what the patient experience of receiving these treatments will be as these advancements take hold and are successful? What will the dosing look like? What's the route of administration, frequency, and that sort of thing?

Silberman: Yes, well, with all our patients — we had 168 patients in our Phase 2 program, and there was no problem. We administered it in days one, two, and three. We saw very few side effects. But I will tell you that every single investigator told me, we [i.e, they]  had nothing for these patients. So, what are they experiencing? They're experiencing hope. They're experiencing enthusiasm that somebody is doing something that's going to make a difference in their lives.

With TPI 287, same thing. That's delivered once every three weeks as an IV infusion. So, they're given intravenously. The delivery intravenously gets circulating much, much faster. There are problems with oral delivery with a lot of different drugs because of absorption and different issues with concomitant medications. So, with IV delivery, I think that what we have is a way to get the drug to where it needs to be.

Climaco: I think the patients and the clinicians, the investigators, have a sense of confidence that clinical trials often don't have. And the reason is the same one that, at the core, attracted me to the business to begin with, which is, we're starting with something that we know works. We know anthracyclines and taxanes are safe and effective against solid tumors. We know this from decades of clinical work and thousands of papers in the literature and studies and all the like. So, we know that. The issue is, of course, as I said earlier and Sandra said, getting these effective drugs to the site of the tumor when you're talking about a CNS tumor.

So, I think that the patient experience in a trial, when you're talking about one of these drugs, is a little bit different than usual in the sense that they [patients] can be educated to understand that, while this is a clinical trial and this is an experiment, the drug at the heart of the trial comes from a class that has been around for 70 years.  We know exactly what this drug is going to do to your body. We know how it's going to affect you. We know how it's going to affect the tumor. We know what the side effect profile is. We know what the toxicity profile is, although, as Sandra said, we learned a lot about Berubicin’s toxicity profile, particularly the fact that we saw no evidence of cardiotoxicity in hundreds of patients, which would make it unique among anthracycline, historically.

So, I think the patient experience, as Sandra said, is almost uniformly positive. You're talking about, first of all, people that don't have any other options. And so, there's hope. But that hope [has been] grounded in grasping at straws that someone has put together some trial of some therapeutic that is unknown. This [our approach] is, in fact, a little bit different: These are trials with drugs that are very well understood, that are very efficacious, that are very safe, but that traditionally don't go to the site of the tumors that these patients are unfortunately suffering from.

I want to give you both an opportunity to talk about any opportunities or challenges in terms of the formulation science, the delivery mechanisms, positioning the business itself, which you're excited to continue to work on. Anything come to mind that's the next thing to target?

Silberman: Okay, well, I can definitely talk to that because it's exciting right now because we're working with preclinical models to look at additional CNS tumors that may be responsive to these drugs that have no other options. I’m specifically talking about pediatric tumors.

The other exciting thing is that there are combination therapies that we haven't even begun to look at. And I think that — if you go back to what [Dr.] Roger Stupp did at the turn of the century, which was defining temozolomide, the standard of care, as being better in combination with radiotherapy rather than temozolomide after radiotherapy. I mean, that simple little thing made such a difference in overall survival in that patient population. So, we're not only looking at pediatrics, but looking at combination therapies.

And last but not least, there are some other primary and metastatic diseases to the brain that have no treatment options. One is a primary CNS lymphoma. Lymphomas are usually treated with anthracyclines, but you can't get an anthracycline to the brain. So that would be very promising.

And in metastatic disease, where we know that these diseases are responsive to these drugs systemically. The brain is a sanctuary, so the tumors get there and are, essentially, hiding from the drugs that you're trying to give, but they're still sensitive. So, these drugs are really promising in terms of getting to these metastatic disease cells that are growing in the brain.

And there's a number of them: There's breast cancer. There's lung cancer. I am seeing prostate cancer. The better our systemic therapies are, the more these cells go into the sanctuary of the brain. And I think that the outlook for drugs like this is just very promising. I'll leave it up to John to summarize.

Yeah. John, any final thoughts from you about taking the company and its work forward?

Climaco: Yes, I mean, a couple of things. First, I'm incredibly excited about our TPI 287 program. While we were working on Berubicin, we were looking for another molecule that would fit the bill of what we specialize in. And we did diligence on almost 300 different programs. And we settled on TPI 287 as something that really was squarely what we were looking for: a traditional chemotherapy molecule [with] lots of history behind it, engineered across the blood-brain barrier. Proud of the team about that.

And I would say the other thing that I'm excited about is that we have begun some work to look at the patients that are standout responders to our programs. Again, this is traditional chemotherapy. This is — I might say sometimes — this is the carpet-bombing approach to hit these tumors. This is not the laser strike; this is the sledgehammer. And yet, among the patients, there are patients that clearly stand out as performing much better than other patients, whether it's overall survival, whether it's response to the treatment and tumor shrinkage.

And I am absolutely passionate about trying, to the best of our ability, to understand what makes those patients different. What can we learn about those patients to improve the way that these drugs function, to improve future drugs, to improve targeting, to improve transport, all of those things? There's information there.

It has been very difficult in the past because GBM is an incredibly complicated problem, [a] multifactorial issue — lots of things going on with these tumors. The tumors themselves: the literature has recently begun to indicate very strongly that they're extremely heterogeneous. So, they're going to be very difficult to hit effectively with targeted therapies. Again, another reason we think our approach is the approach here. But even so, we still want to understand what is it about certain patients that makes them particularly receptive to this therapy.

Well, I want to thank you both for joining me to share your perspectives on the work there. The passion from both of you is clear, and the likely impact on the patient community is very promising. So, thanks again for joining. I also want to thank our audience for joining for another episode of Sit and Deliver. And we'll see you next time.