This is the second post in an interview series with CEOs of small- to mid-cap companies, in which we ask them about products in development. Here we talk with Randy Milby, Chief Executive Officer at Hillstream BioPharma, Inc, Chester, New Jersey (https://www.hillstreambio.com).

 RANDY MILBY: I’ll start with how I founded the company, Hillstream Biopharma. Until recently, the end of last September, I was the CEO of CorMedix, which is a publicly traded company on the New York Stock Exchange. While I was at CorMedix, there was a paper that came out of Germany that said that taurolidine combined with vincristine, an anticancer drug, had a synergistic effect on tumors. Taurolidine is a cornerstone antimicrobial compound for CorMedix. It’s not an antibiotic but it has antibacterial effects, and some antifungal effects, and it’s one of the active components of Neutrolin®, which is in a phase 3 study. Neutrolin® is an anti-microbial drug developed as a preventative solution to decrease the threat of infection and blood clots (thrombosis), thereby keeping central venous catheters (CVCs) operating safely and efficiently.

So, I thought that the paper out of Germany was interesting because it broadened the pipeline as far as the applicability of taurolidine, and since CorMedix is making its own taurolidine, the product lifecycle could be extended by using it in an anticancer agent. Through my network, I found a company called NanoProteagen based in Boston (a Dana-Farber/Harvard Medical School spinout), who had a nanoparticle-platform technology for drug delivery. I licensed their nanoparticle technology, NanoPro™ for an application of taurolidine and vincristine in a small cancer indication and the data looked very promising.

When I left CorMedix, I went back to NanoProteagen and I said, “hey, this stuff looks so good. Can I license this technology through my new company, Hillstream Biopharma, for two different applications and a possible third?”  And they said “yes”.

What we’re looking for at Hillstream Biopharma are active anticancer molecules that have very narrow therapeutic indices to encase in the nanoparticle. The beauty of the nanoparticle is its size, about 100 nm, which allows it to be taken up by the leaky vasculature of a tumor cell. The nanoparticle is then taken up by the tumor and a change in pH within the tumor causes the payload to be released. NanoProteagen had showed me some cool data with nanoparticle-encased paclitaxel before I orchestrated the license.

I then started looking through compounds with narrow therapeutic indices, and one that I found, which went off patent this month, bortezomib (Velcade®). It’s commonly used in combination with other anticancer agents in multiple myeloma. Multiple myeloma is the second most common hematological malignancy. There were 30,000 cases in the U.S. in 2016. But the problem with many of these drugs, or many of these cancer types is that the patients become resistant to the therapy. As reflected by early NanoProteagen data with paclitaxel, we are proposing based on our preclinical data that nanoparticles of bortezomib would enable bortezomib to be effective even in bortezomib-resistant patients.

The enhanced permeability and retention (EPR) effect is the property by which molecules of certain sizes (typically liposomes, nanoparticles, and macromolecular drugs which are smaller than 150nm) tend to accumulate in tumor tissue much more than they do in normal tissues. In addition to increased uptake due to the leaky vasculature of the tumor, the structure of the nanoparticles prevents or at least slows down the efflux of bortezomib out of the tumor cell, which causes resistance to bortezomib.

So, my “secret sauce” here is really the nanoparticle. And our solution is to not only capitalize upon the efficacy of bortezomib but also minimize the side effects, because it’s the side effects that prevent increased utilization of bortezomib. A lot of patients get peripheral neuropathy or other side effects due to the way that bortezomib is just rapidly absorbed in the bloodstream.

The nanoparticles enable bortezomib to be taken up by the tumor, but if the nanoparticles are kicked out, they’ll circulate in the blood and come back to the tumor. So, we hope to show with our PK data in mice that you have a longer duration of action of bortezomib with fewer side effects.

So that’s what we’re trying to do. We’re currently looking at the effect of encapsulated bortezomib on bortezomib -resistant cell lines, and I should get that data shortly, and then we’re going to do a couple of mice tests just to see effects from a toxicological as well as a PK point of view.  And we’ll take that data for a pre-IND meeting with the FDA by the end of the year.

Our first approach for the FDA is to encapsulate the same dose of Velcade that’s currently on the market and demonstrate that it has less side effects, and a longer duration. Hopefully, it may most likely have the same efficacy; it could even have better efficacy at the same dose.

But then, from a pipeline point of view, we will encapsulate a higher dose of bortezomib because you’re getting the drug inside the tumor while not getting all those peripheral side effects. These nanoparticles encapsulate the bortezomib, but it’s only released once it’s in the tumor, so therefore, you’re not getting the side effects that you would have just by giving bortezomib alone.

That’s it in a nutshell what we’re trying to do. As I mentioned, my first approach from a regulatory point of view is using the FDA-approved dose of bortezomib. It will be a 505(b)(2) regulatory approach, and because that, a lot of the safety data is already available. I would just be “piggybacking” on what’s already been done.

STEPHEN STRUDWICK: So, getting more specific, why was bortezomib specifically chosen for this approach?  You looked up various combinations of drugs that are off label and decided to go with that one?

RANDY MILBY:  Yes, the main things I was looking for were: one is the narrow therapeutic index. We were looking for products that had issues and we felt, could these issues be alleviated by the nanoparticles? The reason that bortezomib isn’t used in many tumor types, other than multiple myeloma, is because of its side effect profile. The peripheral neuropathy was number one. Could be as high as 50%, and people discontinued therapy. The other thing was that I needed a drug that had a long history of safety and extensive use by physicians who felt comfortable with it.

It’s interesting to note that bortezomib is commonly used as triple or doublet therapy for multiple myeloma. Another interesting facet of the NanoProteagen technology is that you can add more than one agent within the same nanoparticle (eg, doublets or triplets). In the future, I’m going to encourage NanoProteagen to do triplets. So, then you could have everything, I call it “one-stop shopping within one narrow particle.”  But that’s a little “further down the road” right now.

STEPHEN STRUDWICK: So, you’re saying that you could combine more than just Velcade within these nanoparticles.

RANDY MILBY: Yes. So, it depends upon the chemistry of just how the compounds interact together. NanoProteagen has done two agents (ie, doublets), but they haven’t done doublets with Velcade yet.

Partly because I’m self-funding at this point, I feel I will have more of a “reason to believe” in pursuing Velcade doublet/triplet nanoparticles once we get the Velcade resistant cell line data. Then I’ll go back to the financial community. In this space, even if it sounds interesting, even if it sounds exciting, I need the data. Once I have the cell line data it takes me to that one step, and I call it an “inflection point”, you must meet certain inflection points. Then I’ll go back to the financial world and say, “listen, this is the cell line data that I promised you, this is the timing, and then I’m going to have the mice data, and then we’ll do the pre-IND meeting.”

So those are stepping stones along the way.  Hopefully, if they’re all positive, the valuation of the company increases.

KLARA CZOBOR: Sure, absolutely.  And when do you think you’ll have the cell line data?

RANDY MILBY: I should have my Velcade-resistant cell line data very shortly. Regarding the mice data, we just started dosing in the mice recently, so that’s going to be a little longer. But I’m doing only six mice with the dose escalation at this point. We’re going to do a larger mice study after that.

KLARA CZOBOR: Sure.

STEPHEN STRUDWICK: Hillstream is developing a novel proprietary nanoparticle formulation of bortezomib (HSB-407) at the currently FDA-approved dose. What would you expect to see when you add HSB-407 to a Velcade-resistant cell line? How would that overcome the resistance of this cell line?

RANDY MILBY: That’s a very good question. So, what we would see though, you’d still get tumor shrinkage. You’d certainly still get a kill based upon the way that the tumor takes up the nanoparticle. So, there is some work that suggests that these nanoparticles prevent resistance from forming. But the “proof is in the pudding” because these tumors are very smart, and even within one human tumor, you can have different types of resistance that develop. We’re “keeping our fingers crossed” on this point. I know the technology works in the regular cell line, but working in resistant cells would be a way that we could go after an orphan drug designation.

So, the nanoparticle is being taken up by the tumor but, and this is what’s interesting, is that the technology can prevent a reflux or prevent the way that the tumors can reject it. There is some type of component in the backbone of the nanoparticles, the size of them, and the consistency, which prevents the cell line from, I call it, “spitting it out.” The data for paclitaxel demonstrated that to some degree, but I just need a little more data for bortezomib.

STEPHEN STRUDWICK: So, you’re looking at a twofold mechanism in that you’re looking at enhanced efficacy based on enhanced uptake, and “less spitting out” as you would say. And when it comes to the clinical trials, you’re looking at reduced side effects because the nanoparticle specifically goes to the tumor.

RANDY MILBY: Right. So, our phase 1 study, for example, will be looking at the side effects but also just what the PK data looks like. If you look at the PK data for bortezomib, you have a huge spike right away, which causes those side effects. But what we anticipate is that it’s not going to spike as quickly when encapsulated in the nanoparticle because it’s not all in the bloodstream and it’s not hitting the tissues.

And to your point, it’s getting taken up by the tumor cell, so it either stays in the tumor or leaves. If it is rejected by tumor efflux, the bortezomib has not been released yet from the nanoparticle because it must stay in the tumor long enough for the change in pH. There’s a pH in the tumor that is more acidic than the bloodstream that causes the release of the payload.

STEPHEN STRUDWICK: In addition to HSB-407, Hillstream is also developing a novel proprietary nanoparticle formulation of bortezomib with up to a 50% increase from the currently approved dose of 1.3 mg/m² (HSB-408). So, for HSB-407 and HSB-408, especially, would you have to go through all phases of FDA testing with them?

RANDY MILBY: For HSB-408, yes, my hypothesis there, and according to the scientists, is that with HSB-408, you could go with a higher dose. Not for HSB-407, as I’m using the same FDA-approved formulation of bortezomib, the 1.3 mg/m2, same formula or same dosing.

Due to funding, I’m focused on HSB-407 right now, and it’s estimated that 12-20 patients are needed for the phase 1 trial, and then the phase 2 trial will probably have about 50 patients per arm, so maybe 100 patients overall. You don’t need the wealth of safety data with HSB-407.

I’m going to have to do a lot more work for HSB-408, but it will be pretty exciting, obviously, because what the scientists and the physicians at Dana-Farber believe, and I meet with them every month, is that these nanoparticles will open up new tumor types and new cancer types to bortezomib because a lot of the original studies were done by Millennium, which is now Takeda, but it was the side effects that kept bortezomib from being utilized in other cancer types.

STEPHEN STRUDWICK: Oh, absolutely, and that brings me to the side effects. I mean, there are peripheral neuropathy which, as you say, can be up to 37% of patients, but there are other side effects associated with Velcade.

RANDY MILBY: Yes, exactly.

STEPHEN STRUDWICK: Do you anticipate that those side effects will be at least relieved with this new formulation?

RANDY MILBY: Yes, that’s what the hypothesis is, and I believe it will be. I have emphasized peripheral neuropathy because it’s the one that many patients deal with. I know physicians say we know how to deal with it, but it would be beneficial if you didn’t have these type of side effects, or if you didn’t have to be concerned about these side effects, and still use a drug that you’re familiar with; still use a drug that you know is efficacious but you don’t have the same side effects. It should give the physician a lot more comfort with the product, and its use in combination.

So, it’s initially all about the side effect profile and possibly the efficacy, but mainly, what we’d like to alleviate first are the side effects.

STEPHEN STRUDWICK: Yes, I mean, the efficacy should be there based on the dose that you are giving. So, do you anticipate that treatment adherence will be increased with your type of therapy?

RANDY MILBY: Well, as you well know, that’s a great question. Adherence is a big issue for any type of medication. I believe adherence would be increased. I think the physicians and the nurses are going to be more comfortable with the product, and the patient is going to feel a lot more comfortable. No one likes those type of side effects. They’ve already got the disease and you don’t need medication side effects “piling on” as well.

STEPHEN STRUDWICK: No, that’s true. You mentioned earlier that an analogy could be made to improvement in safety of chemotherapy with nanoparticles. I mean, from what I remember, nanoparticles have been used to try and reduce the amount of peripheral neuropathy associated with chemotherapy. Is this what your approach is?  I mean, what’s different about your approach versus, say, the Abraxanes or the chemotherapy approaches out there?

RANDY MILBY: Great question. So, I think is it’s the same end goal, but the difference is really in the delivery vehicle. Ours is a little bit different from Abraxane in that ours is a polymeric approach, and we’re encapsulating the drug inside our nanoparticle.

So, the other liposomals have worked as far as alleviating some of the side effects. But what we think with our polymeric encapsulation and being taken up by the tumor cells, is that it’s going to alleviate a lot more. Now, proof will be in the data, of course.

STEPHEN STRUDWICK: Cool. Is HSB-407 administered in a similar fashion to Velcade? I mean, is this a subcutaneous or an IV injection?

RANDY MILBY: Yes, it will be IV. It will be administered the same way, exactly right.

STEPHEN STRUDWICK: So, what challenges do you believe your therapy will face in the marketplace? I mean, what kind of barriers to use do you think that you’ll encounter when trying to actually bring this to market?

RANDY MILBY: Well, I think there is always the barrier of “if you’re comfortable using, why do you switch?” For that barrier, we’re trying to say, listen, if you’re comfortable with Velcade, this is the new and improved version. Obviously, we couldn’t use the brand name, but it’s new and improved.

I think on the clinical side, it’s going to be quite straightforward taking it to market. My upcoming challenge will be getting the money for the phase 2 study, obviously, so that’s why we’re building those inflection points as I mentioned earlier, so that people have the reason to believe and to “put money in”.

STEPHEN STRUDWICK: So, has your company presented data at any recent meetings?

RANDY MILBY: No. I am going to be at ASCO in early June, just meeting with some doctors, and I will be presenting at the 2017 Marcum MicroCap Conference that will be held June 15-16 at the Grand Hyatt Hotel in New York City. That will be probably, that’s the first presentation because I will have the cell line data, my Velcade-resistant cell line data, and hopefully, I’ll have at least some of my initial mice data. Marcum in mid-June will be the first time that we’re actually presenting data. And then, I’ll subsequently place it on the website.

STEPHEN STRUDWICK: Great. So, do you anticipate breaking into phase 1 trials after presentation of this data? You have funding to do that, right, to go to phase 1?

RANDY MILBY:  Yes, I can make that work. I do think after we have the phase 1, then “we’re off to the races” because you will see the PK data, you will see how it works, and you will see some of the side effect advantages. Although as a phase 1, as you know, it’s not for efficacy, but you can see some toxicology; you can see the PK.

STEPHEN STRUDWICK: As far as I can tell. what you want to see is, does the PK of your product relate to the decrease in Velcade side effects?

RANDY MILBY: “Bingo”, that’s exactly right. And that’s what we hope to see on that, and that’s why the phase, getting back to your point, the phase 1 study will be a major inflection point for us because with that, then it’s just raising an appropriate amount of money for the phase 2. I couldn’t go alone with phase 2 because it’s going to be a larger study.

STEPHEN STRUDWICK:  Yes.

RANDY MILBY: And the other thing is as you well know, it’s all about positioning, and at that point, you’d want some named investors to come in because that adds the additional credibility, and it also helps if you’re to partner with someone. Having those type of investors, and it could be a pharma company also, but having that group in there just goes a long way as far as increasing the credibility of the company.