David D. Miller, principal, Alpine BioVentures

Mitchell H. Gold, MD, says his passion for drug discovery and development arose from a tragedy: His mother died of metastatic breast cancer when she was 26 years old, and he was 4.

In the years that followed, he has pursued that passion to cure cancer and other diseases, both as an entrepreneur and as an investor. As CEO of Dendreon, he led its development of Provenge® (sipuleucel-T), an autologous cellular immunotherapy for prostate cancer that won the FDA’s first approval for a cancer immunotherapy in 2010.

Dendreon struggled with underperforming sales and increased competition from other developers of cancer treatments, filing for Chapter 11 bankruptcy protection in 2014. Dendreon’s assets were sold to Valeant Pharmaceuticals, which in 2017 sold Dendreon to Chinese-owned Sanpower Group for $820 million. Sanpower sold Dendreon a year later to Chinese department store chain Nanjing Cenbest for CNY 5.97 billion ($844 million).

Gold was replaced as Dendreon’s CEO in 2012, and soon after established Alpine Biosciences, selling that company in 2014 to Oncothyreon (which changed its name to Cascadian Therapeutics before being acquired in 2018 by Seattle Genetics).

Together with David D. Miller, Gold also co-founded Alpine BioVentures, a life sciences investment firm that does not disclose the size of its assets under management. Alpine BioVentures’ portfolio has included Gold’s current drug development company, Alpine Immune Sciences, founded in 2015; Angion Biomedica, a developer of therapeutics for injuries to the kidneys and other organs; and Mavupharma, a cancer and infectious diseases drug developer acquired last year by AbbVie.

On June 18, AbbVie and Alpine Immune Sciences reached a deal of their own: Alpine Immune Sciences granted AbbVie an option to exclusively license worldwide rights to Alpine’s lead candidate ALPN-101, a Phase II-ready, first-in-class dual CD28/ICOS costimulation antagonist being developed for systemic lupus erythematosus (SLE). During the option period, Alpine will conduct a Phase II trial of ALPN-101 in SLE.

AbbVie agreed to pay Alpine $60 million upfront, and up-to-$805 million tied to AbbVie exercising the option as well as to achieving development, regulatory, and commercial milestones. Should it exercise the option, AbbVie will conduct all future clinical development, manufacturing, and commercialization of ALPN-101. Alpine will be eligible to receive tiered royalties on net sales of ALPN-101.

Investors in publicly-traded Alpine Immune Sciences greeted the news with a stock surge that sent shares more than doubling on June 18, to $10.95 a share from $4.66 the previous day.

Gold, Founder and Managing Partner Alpine BioVentures, and Executive Chairman and CEO of Alpine Immune Sciences, recently discussed ALPN-101, the accomplishments and challenges of both companies—joined briefly by Miller—and the rise and fall of Dendreon with GEN Edge in an interview lightly edited for length and clarity.

How and why was Alpine BioVentures started?

GOLD: Alpine BioVentures was started in 2013, with a goal of creating new companies that were tapping bold scientific ideas. It was really around company formation, and the model was, and really it still is, that we seed fund companies, and then we typically either go out and syndicate a round around them, or we transact with another company that takes the science forward.

The first company was built shortly after I came out of Dendreon, where I helped developed the world’s first cancer immunotherapy, Provenge. And when I left there, I wanted to find a way to deliver antigens in vivo. So we licensed a piece of technology from the Department of Defense at Sandia National Labs. That asset was a nanoparticle drug delivery technology that we ended up selling about 9 months after we seed funded it to a company called Cascadian Therapeutics in Seattle, and Cascadian eventually got purchased by Seattle Genetics.

The second company we built out of the fund was a company called Alpine Immune Sciences, which is a company we started in 2015. And the goal was to create engineered multi-specific molecules that could modulate the immune system. This is 2015, so bispecifics and multi-specifics weren’t a big deal yet. But probably the biggest forward-looking thought that we had, which really was transformative idea to target the B7 family of proteins and in particular the costimulatory axis on immune system cells called CD28.

Why did Alpine focus on targeting CD28?

GOLD: CD28 had been targeted before, by a company called TeGenero, and when they did so, they had agonized the pathway too much, and they created a cytokine storm, and seven patients got dosed in the U.K., and all of them ended up going to the ICU. So that scared most people, and drug developers stayed away from that axis until just recently.

We said, Look, if it’s that powerful, then we want to try and find a way to engineer a protein on our platform to target it. So, we seed funded a great group of entrepreneurs, and they developed two sets of molecules. One was a molecule that could block the CD28 axis for autoimmune diseases, in addition to the ICOS pathway which is another key T cell Co-stimulatory signal. And that molecule is called ALPN-101, and it’s just finished Phase I trials in healthy volunteers, and it passed that with flying colors, and now it’s going into the Phase II studies in Graft versus Host disease as well as other inflammatory indications.

Now the flipside of ALPN-101 is we engineered a molecule that would not block CD28 but actually would turn it on, would agonize it, and that molecule is called ALPN-202, and that’s now getting ready to dose its first patient. Now why is that important? CD28 turns out to be the key costimulatory molecule that is necessary to activate naïve T cells in the tumor. When we went down that path, most people were targeting other costimulatory pathways like 41BB or OX40. We went after CD28 because it is the principal T cell co-stimulatory receptor present in naïve T cells.

Regeneron [Pharmaceuticals] put out a paper that they’re also focusing on CD28, and releasing this suite of molecules on that axis. So, I think CD28 is going to become the new IL-2. Everyone’s going to want to get a CD28 costimulator. We have one. Regeneron is developing one. Sanofi has a program there. But we ended up being pretty lucky that we picked it early. Now it’s going into humans, and we’ll see results probably in the early part of next year

How does Alpine BioVentures approach company formation?

GOLD: It’s really centers on bold scientific ideas around platforms. So all three companies I told you about were platform companies, as opposed to a single molecule—Mavu was a single molecule for cancer. But the other two companies were really platform-based companies.

The way we look at company formation is, we really want to be able to white-board out an area that we think there’s a huge unmet scientific need, where we have a particular area of expertise. That could be in immuno-oncology, where we develop and commercialize drugs. Or it could be in the world of inflammation. Which is really just the flip side of the same coin for immuno-oncology.

In terms of Alpine’s portfolio, you’re not as big as many other firms. Do you like that, or are you looking for more?

GOLD: Our model is a little different. We take on an operational role, which I don’t know if we’ll continue to do, because it’s difficult to scale that way. But to date, when we’ve seed funded companies, we typically take on an operating role. And so, because of that, we can’t really bring on as many portfolio companies as a result of that. But I think in the future, now that we’ve had consistent returns, we may get away from that model and provide less operational expertise, more coaching through board activities as opposed to active operating roles.

In terms of funding, at what phases do you like to go in?

GOLD: We like seed funding. That’s our passion. And the reason that we like seed funding is, one, we can take a substantial ownership position in the company, but more importantly, we can kind of guide the company from its embryonic stage, bring on the right management team, and really have a hand in the science, as opposed to coming in much later stage, where a lot of that has already been engineered into the molecule and it’s very hard to go back and change that.

In addition we have a group of investors that we tend to do a lot of investing with, so that as we form these companies and they get through the key hurdles that we have as gating elements and then we’ll bring it out to a broader group of investors, and we’ll typically syndicate around it.

What types of companies are you interested in? Any particular diseases? Or what types of platforms?

GOLD: We tend to get a lot of oncology deal flow, mostly because I think that’s where our domain expertise is. Seattle tends to have a good focus there. But it’s shifting a little bit to the inflammation side.

Meaning more companies are in Seattle?

GOLD: No, no, no. The companies are not all in Seattle. In fact, one of our companies, Angion Biomedica, which my partner Jay Venkatesan, MD, is running (as President, CEO, and Director) is based in San Francisco.

How do you come across the companies and the entrepreneurs?

GOLD: Typically, it’s science that we want to generate internally. For example, we have been wanting to target the prostate cancer space for a while, because we had a lot of development expertise there. So we have been pursuing science, developing a molecule on our own with academic investigators, and some industrial collaborators as well, to really flesh out an idea that we haven’t taken public yet, to see if we can kind-of transform the way that enzalutamide-resistant prostate cancer is treated.

MILLER: Zytiga® (abiraterone) and Xtandi® (enzalutamide) are moving farther forward in the treatment paradigm, now into patients who are hormone sensitive, and even don’t have metastatic disease yet. Nearly all of these patients—90% of them fail precisely the same way. And what we’re hoping is, working with our collaborators, that we can come up with a drug to treat that failure, and extend these men’s lives.

GOLD: That’s a company that is still at the proof of concept phase. So, we have not been able yet to get that research plan past the stage of overcoming key hurdles so that we could then provide additional funding.

One thing I do want to tell you: I’ve been in the industry for a long time. This is probably the most productive time from a research perspective, and an industrial perspective, that we’ve ever had. We’re already on our third or fourth generation engineered cell therapies. We’ve moved away from kind-of very specific monoclonal antibodies into bispecifics and multispecifics. The gene therapy revolution is here to stay. People are investing in it. And we’re not just seeing engineered cell therapies for cancer. We’re starting to see them now for autoimmune disease.

That trend is going to continue, and the best way to kind of see that: My mom died of breast cancer when she was 26. I was like 4 years old, about to turn 5. I had set out, I want to cure cancer. I tell you, I’ve been working on cancer for 20+ years. You feel like you make progress, but you never really see it in the numbers.

What gave me chills down my spine this year was when I saw the American Cancer Society come out with the fact that for the first time, we’ve really significantly lowered the rate of cancer, and I think that’s a result of what the industry has been doing, But also, the American public is eating better. They’re smoking less. They’re taking better care of themselves. But it’s also because we’ve developed better therapies, particularly immunotherapies.

I think if you can think 10 years ahead, or two years ahead from now, what’s the industry going to look like? And it’s going to be, we’re going to be able to have a significant impact on how people live on this planet. That’s why we invest in companies, and that’s why we create them. And that’s really where the most fun is: Seeing people getting on that playing field and being successful there is worthwhile.

Given your own history personally and professionally, is cancer sort-of a sweet spot for your firm?

GOLD: That’s probably where I like to play the most. So yeah, I think that is a sweet spot for our firm. But Alpine Immune Sciences, for example, has two programs: One in cancer, and the other one is in autoimmune diseases and inflammatory conditions. We started that company with a cancer—the idea was around cancer, and providing a costimulatory signal while blocking checkpoints. But it turned out that the same science could also be applied toward autoimmune diseases, so of course, we had to go there.

Will the company stay on those two fronts?

GOLD: Yeah, I think so. For a small company like us, that’s a lot for us to chew on. I can tell you that we’re pretty excited about—it’s the best immunology team I’ve ever assembled at a company. And I’ve been at a lot of them.

They’ve been working on this one program to really find a way to modulate B cells, which can be very difficult. And they’ve been working on it, I’d say, for four years. I meet with them every two weeks at a staff meeting, and every week I’ve tried to kill that program for four years. And they would go back and just not listen to me. And finally, four years later, they came to me with data that was so convincing that I’m glad I didn’t kill it. And so now we have another unique drug, we call it Alpine 30x. We haven’t discussed it publicly yet. But it is a very unique molecule. It’s going to be able to impact both T and B cells in a very meaningful way.

For what types of cancer?

GOLD: It won’t be for cancer. It will be for B cell mediated diseases. Typical ones would be, like, Lupus, Sjogren’s disease, other diseases like that.

Where is that now, clinically?

GOLD: It’s preclinical, so we’re just now kind-of getting ready. We’re doing our IND paperwork right now we will take that program out of Stealth mode in 2020.

And then there’s collaborators, so we’ll probably form more collaborations using our programs and our immunology team and the platform to develop immunomodulatory domains others can use on their molecules to make them more potent, very similar to the way that Seattle Genetics did early on, and others with their ADC technology.

Is it fair to say the firm is more of a leader in funding rounds, as opposed to a participant?

GOLD: We like this concept of–everyone has been working on antibodies. These are not antibodies. These are actually the functional domains themselves. That was kind-of the incendiary moment when we realized, Hey, we can just use what the immune system has already developed. Then we can use our expertise and genetically engineer—these would normally mutate over hundreds of thousands of years, and humans would develop new kinds of immunosuppression.

All we did was, we took that 100,000- to 200,000-year evolution process for your immune system, and we shrunk it down into 90 days, which we call directed evolution. And the resulting products were billions of new domains that we could then study and figure out if we can use them from a therapeutic perspective.

Humanity has changed. People have always evolved from external pressures. And now, for the first time, what’s happening is, we can actually direct our own evolution and determine what we look like as a species, whether that’s through what we are doing at Alpine, or through techniques like CRISPR. So we’re not going to only evolve by external pressures, but we’re actually going to direct our own evolution through genetic engineering. And Alpine is creating molecules in that way.

You’ve seen the cell therapy field evolve and grow. What were Provenge’s challenges, and Dendreon’s, that maybe we don’t see as much of now?

GOLD: It’s several. One, early on, when we first started working on Provenge, no one believed—I know this is hard to believe now, but you have to go back—no one believed the immune system could actually be used to fight cancer. That concept of immuno-oncology was just not believed in. And I think because we were first, we had all the headwinds. We had to prove that.

Number two, it was a different time when we came out and we priced Provenge, we priced it at $93,000 for a course of treatment. It was our launch price. And frankly, that shocked a lot of people. I think people would be shocked now if a cell therapy came out at $93,000, but because it would be so low. You’re seeing them launched now at $300,000 or $400,000.

We were in a different pricing environment, then. And I think if Provenge would have priced in the $200,000 to $250,000 range, it would have been a much different story. That being said, I don’t know. Provenge is doing around $400 million in revenue today, and it’s transforming thousands of men’s lives with prostate cancer.

In fact, one of my friends, I’ll tell you this story, he had prostate cancer on biopsy that was localized to the prostate. And he heard about Provenge ‘cause he’s a friend of mine. And he went and got it, paid for it out of his own pocket. He went back and they biopsied his prostate to see if his cancer was still there, and it was gone.

This is a transformative medication that I think really launched the whole field of cell therapy, whether it’s Juno [Therapeutics], or Kite, or Allogene, or all of the others that have followed behind it.

Dendreon paved the way for all that. It never would have happened if it wasn’t for Dendreon.

How much were payers an issue?

GOLD: It was a challenge, because the challenge with Provenge was that we were selling to physicians’ offices, and physicians’ offices had to take ownership of the product. And then they had to get paid by Medicare. But until that process became streamlined and more repeatable, they were carrying the balance –there was a huge pent-up demand for Provenge. So, until they had a reliable reimbursement system, sometimes they would be carrying $300,000 to $400,000 on their books as a private practice. So they had to get confidence that they would get reimbursed.

We launched it in the urology community, which wasn’t really accustomed to dealing with taking on that much debt on their balance sheet. So, that was a new process, because we were going into a new physician population, and they had to get accustomed to it.

Where you see a lot of the drugs today, like Kite’s drug or Gilead’s drug, and what’s going on in the field with Novartis [Zolgensma® (onasemnogene abeparvovec-xioi)], those are all getting purchased by hospital systems. So it’s not by individual physician practices.

Does it help also that there are bigger players than what Dendreon was?

GOLD: I don’t know if that would have mattered. I think the fact that we were first, and the fact that we were going into physicians’ offices as opposed to large hospital systems, and I don’t know if the size would have mattered here.

But it was fun being on the front end of that. I guarantee that if you talk to Arie Belldegrun [co-founder and executive chairman of Allogene, founder and former chair, president and CEO of Kite Pharma] or Bob Nelson (co-founder and a managing director of ARCH Venture Partners), or Hans Bishop who was with me over at Dendreon and went on to Juno (and is now CEO of GRAIL), they’ll tell you that Dendreon kind-of paved the way for them. We got approval in 2009, then all those companies really got their funding. That to me is what’s exciting.

So, that cycle is really what makes biotech so healthy. Here we are, we’re seeing another cycle. We’re seeing more and more of these—the beautiful thing about biotech today is that there’s capital there to fund these companies. But you have this kind-of really serious intellectual bent from the entrepreneurs that want to build new companies, and the executives that want to be there.

In the old days, I would say, when the Immunex executives sold Immunex, they didn’t recycle into new companies, they all kind of hung up their cleats and retired. And now, you see executives like Hans Bishop and Steve Harr (MD, President and CEO of Sana Biotechnology) and others, when they sell these companies, they are immediately on to their next one within weeks to months. And that’s super healthy for our industry.

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