As you’ve probably gathered from the post title, I’ve made a pivot with my company, Highway Pharmaceuticals.
For those of you who aren’t aware, I initially started Highway based around my excitement for cyclosporine’s possible utility in neurodegenerative diseases. Cyclosporine, an immunosuppressant, showed intriguing possibilities in neurodegeneration in trials in the 80s and 90s, back when we thought all neurodegeneration might be autoimmune diseases in disguise.
Cyclosporine was abandoned as a neurodegenerative treatment (although not as an immunosuppressant) because of variable efficacy, severe and unpredictable side effects, and an unclear mechanism. Years later, we found the mechanism relating cyclosporine to neurodegeneration, but by then Biogen had solved neurodegeneration using their drug Adulhem (just kidding). Meanwhile, I believed that I found a way to make cyclosporine more consistently efficacious while lowering the incidence of side effects.
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I wanted to bring cyclosporine back into the mainstream and test it for neurodegeneration. Not only did I think neurodegeneration was important in a general sense, but also in a very personal sense. Neurodegeneration runs in my family. I’ve had multiple close family members end up with dementia in their old age, and it’s a terrible thing. In fact, I’d say it’s the single most important unsolved medical problem facing us today.
I knew I couldn’t just jump straight from zero to neurodegeneration, though, especially given my previous background as, um, “science blogger”. I’d be asking investors to trust these assumptions
a) Cyclosporine is the right drug for neurodegeneration
b) My version of cyclosporine is better than the old version
c) I/my company can take my version of cyclosporine through the complicated, expensive trials necessary to prove that my version is better than the old version
These are big asks! Even worse, there’d actually be another hidden assumption in there that you wouldn’t notice unless you were familiar with the biotech industry:
d) Single asset drug repurposing can get funding and be successful 
So I decided to allay at least one of those assumptions. Instead of trying to prove that cyclosporine was the right drug for neurodegeneration, I decided to start by just getting an approval of cyclosporine for an autoimmune disease, chronic spontaneous urticaria (CSU), that it was already being used off-label for.
That would at least allow me to ignore assumption a) for now, and assumption c) would be a lot easier. CSU is essentially autoimmune hives, so trials in it, although still medical trials, come down just looking at someone’s skin and seeing if it clears up. It’s a lot easier to run than neurodegeneration, where you have to somehow look inside people’s brains. After I prove safety and efficacy in CSU, I planned to go onto neurodegeneration as well as other autoimmune diseases (i.e. a homerun and a few base hits simultaneously).
This is still a tall order for a guy whose background was, again, science blogger. But things went surprisingly ok, all things considered. I linked up with an excellent corporate attorney and patent attorney, both of whom agreed to let me use their services on a pay later basis. I found a COO with significant experience in biotech who was interested in the work. And I started making a great network of people who were, if not fully bought into the work I was doing, at least interested in it.
I felt good! The next step was in sight: a test of the drug in humans, to see if we actually saw the blood levels of cyclosporine that I expected we would. We had contracted with a CRO in the Netherlands and were raising the $1+ million needed to actually carry out the test when – pop! – the biotech markets imploded. Suddenly, investors literally stopped returning my (and everyone else’s) emails.
At this point, I faced an impasse. I could keep with my initial plan, and hope to somehow scrape together enough money to test the drug in humans in a historically challenging funding market. The thing that troubled me about this is that biotech, as a business largely built on perception, is also very dependent on momentum. The farther away you get from your last achievement the more investors worry that you’ll not see the next one. I could spend 2 years raising money and then get stuck in a quagmire of lost hopes, years away from my last achievement and years away from my next one.
I decided to take a different route: raising money to test my drug in animals. Now, this wasn’t a new idea. A bunch of people had suggested I try testing my drug combo in animals before testing it in humans, although I had always resisted because I thought the drug metabolism at play wasn’t an easy translation, and then I’d just have to do a whole different study in humans.
But, now I had different incentives. Given the money I had, an animal trial was all I could afford. However, this got me thinking: what was the next step going to be? Even if I tested my drug in animals, I’d still have to raise money to test my drug in humans again. Granted, I’d have more data (an animal study), but I wasn’t sure that was going to be higher quality data than the preclinical studies I based my development work on already.
So I decided to take the plunge. Not only would I test my drug in animals, I decided to develop my drug for animals as well. The downside of this was something I knew from the beginning: lower revenue potential. Animal drug spending is mostly out-of-pocket and also people generally aren’t willing to spend as much money on their pets’ health issues as their own. The upside however, was considerable, especially for someone in my position:
a) Lower development costs. Getting cats to take a drug just requires bribing them with cat food, not money.
b) Easier regulatory environments. Not only do you not need to talk to the FDA before testing your drug in animals, cats are way less likely to sue you if they get sick from your drug. Of course, we’d still do our best to make sure they didn’t, but it’s less likely to sink the entire company if they do.
c) Friendlier regulators. On the human side, the FDA mostly considers their responsibility to be to stop unsafe or ineffective drugs from entering the marketplace, and believes that allowing safe and effective drugs to enter the marketplace is a secondary goal. On the animal side, the FDA is generally happy that anyone is developing drugs for animals at all (instead of just repurposing them from human drugs), and so is more helpful. The animal FDA is also much less likely to get yelled at if they make the wrong decision, to be fair.
The only real question was what I would use my cyclosporine combo for. This was a tricky issue, because the serious side effects that are present in cyclosporine for humans don’t really affect cats or dogs. They get minor side effects (vomiting and diarrhea in about 30% of pets), but not major ones, which is one of the reasons why I didn’t think they had similar enough metabolism in the first place. Given that one of my big selling points for my combo was avoiding major side effects, I needed to focus on a different angle.
What I decided to look for instead was any animal disease in which cyclosporine was both annoying to administer frequently and where its unpredictable bioavailability had affected its efficacy. I found it in feline stomatitis, an inflammatory disease that affects about 1% of cats and gives them terrible sores on their lips and mouth. The normal treatment for this disease is full or partial dental extraction (teeth pulling), which is both expensive (about $1k), a sad thing to do to a cat, and doesn’t even work in all cases. Following dental extraction, cyclosporine is often used as a supplementary treatment to reduce inflammation, and there had also been a few promising studies showing cyclosporine could sometimes be used as a replacement for dental extraction as well.
That’s where I knew my opening could be. Although cyclosporine was often effective in feline stomatitis, it wasn’t always. Given that cyclosporine had the same variability in bioavailability in cats as it does in humans, I suspected this was due to variations in blood concentration, which was further supported by a small vet study. Furthermore, it’s difficult enough to give drugs to a healthy cat, never mind one that has sores in its mouth. This is when giving drugs less frequently to a cat could be a big advantage for patient compliance.
So, a drug like mine, which results in consistent blood concentrations, requires less frequent dosing, and coincidentally also needs smaller pill sizes, could be a big hit in feline stomatitis. Excited, I reached out to some people I knew in animal health, who introduced me to vets. I confirmed my ideas with these vets, and armed with knowledge, went back to convince the people who worked with me. They were on board, too, so I forged ahead and made the switch.
I had my indication, I had my plans, and the rest was, well, not history exactly, because I’m still doing it. The rest will be history eventually. For right now, we’ve got our first pilot trial in cats planned for this fall.
That’s our story so far. Now, to fulfill the imperative of the second half of this essay: why others (maybe you!) should do the same.
Transitioning from humans to animals isn’t easy. There are different challenges and different rewards. However, if you’re like me, and think that developing drugs is a morally good thing to do, I think developing drugs for animals is at least something to consider. It’s easier overall, it’s cheaper, and you still have the chance to help both animals and the people that love them. Plus, there’s no rule that says you can’t simultaneously develop for humans once you’ve got good results in animals.
As for me, well, if any of you reading this have interest in animal health, please reach out. Now that I’ve found some sort of new home for my company, I’m eager to get to know my neighbors and well-wishers.
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 If this is unfamiliar to you, let me break it down. Single asset is what it sounds like: instead of having multiple drugs being developed at once, you only have one drug being developed. This is as opposed to drug platforms, which are like drug “engines” that you put money into and they spit out drugs, usually involving some idea of an AI secret sauce that gets better the more data you put into it.
Drug repurposing, on the other hand, means that you’re taking a drug that’s been developed for one purpose, and using it for another. This is as opposed to new chemical entities, which are drugs developed from scratch.
Almost every biotech investor will agree that, theoretically, single asset drug repurposing should work. In fact, almost all of them will agree that, in practical terms, drug startups end up as single asset companies anyways, because it’s so expensive to take a drug through trials. By the time your drug is tested in humans, you’ve already chosen your horse. Even Moderna, who raised tons of money, went public, and harped constantly about how they were developing a million drugs that were going to end every single disease, ended up with just one drug they managed to get approved in the 10 years since they became a company.
They’ll also agree there’s no reason drug repurposing shouldn’t work. They’ll agree it’s de-risked, because your manufacturing is taken care of, and the safety issues (at least in people in general) are already known. Development should be cheaper and there’s less likelihood the FDA will get mad at you for some random reason.
And yet, then they’ll say, “Of course you and I know that. But, your success isn’t dependent on just me. You need to get multiple investors to all agree to fund your development program, and biotech investors in general prefer platform plays and new chemical entities. I just don’t think you’ll be able to get follow-up funding, and then I’ll be stuck.”
Believe me: this is the exact conversation I’ve had like 20 times. Venture capitalists are pattern-matchers, for better or for worse. When it’s worse, sometimes it can really feel like herding lemmings: they won’t go anywhere other VCs haven’t already gone.