A Longstanding Academic-Nonprofit Collaboration Gives Rise to an ALS Drug Company

In February, ProJenX launched to develop novel, brain-penetrant therapies that target defined pathways for the treatment of the rare neurodegenerative condition amyotrophic lateral sclerosis and other brain diseases. ProJenX lead candidate is prosetin, an experimental therapy developed through a collaboration between Project ALS and researchers at Columbia University. We spoke to Stan Abel, CEO of ProJenX, about ALS, the company’s lead therapeutic candidate prosetin, and the company’s ongoing relationship with Project ALS and Columbia University.

Daniel Levine: Stan, thanks for joining us.

Stan Abel: Danny, thank you very much for inviting me. It’s my pleasure.

Daniel Levine: We’re going to talk about the rare neurodegenerative condition ALS, ProJenX, and its collaboration with Project ALS and Columbia University to develop a potential therapy to treat the condition. Let’s start with ALS, though. For people not familiar with it, what is it, and how does it manifest itself and progress?

Stan Abel: Sure. ALS, which is the abbreviation for amyotrophic lateral sclerosis, [is] more commonly known as Lou Gehrig disease after the famous baseball player who was diagnosed with it in 1939. ALS is a devastating progressive neurogenerative disease that affects nerve cells known as motor neurons in the brain and in the spinal cord, and that causes a loss of muscle control. Ultimately as the disease progresses, you lose more and more motor neurons. Eventually the ability of the brain to communicate with the rest of the body and dictate movement becomes lost. This initially shows up in symptoms such as weakness in the limbs and it starts to affect the way that you walk and you move. Then it kind of advances into affecting your speech and your ability to swallow and eat, and also your breathing. Sadly, the progression leads to respiratory compromise and eventually respiratory failure, which is the leading cause of death in people with ALS. ALS is considered to be universally fatal within two to five years. So, you know, a very aggressive and devastating disease. It’s considered a rare disease. And the definition in the United States is when you have a patient population of fewer than 200,000. We estimate that there’s approximately 30,000 people living with ALS in the United States, with some estimates worldwide at above 400,000, and in the United States there are about 6,000 new cases annually. The reason why the prevalence is not higher is that ALS is such a devastating disease that people don’t live long with it. That’s why the total number of cases at any given time stays around this 30,000 range, but it is growing and the incidence is increasing.

Daniel Levine: Is there any reason to explain why the incidence is increasing?

Stan Abel: Well, that’s a good question. These motor neuron diseases, or neurodegenerative diseases, do have a have a correlation with age, and as our population ages, that could be a contributing factor. But we don’t really have a very good understanding of the etiology or the causes of the disease, but the numbers do seem to be increasing.

Daniel Levine: It would be helpful if one reason was that there were disease modifying therapies for the treatment, but I take it that’s not the case. What’s the treatment for someone with ALS today?

Stan Abel: Well, unfortunately there’s no cure for ALS. There’s really no effective treatment that will halt or reverse the progression or the damage that’s been done, or the loss of motor neurons. There are only two drugs approved by the FDA for the treatment of ALS. One is known as riluzole, which was approved back in 1995, and there’s data that supports that it may extend life by two, three months—overall a fairly modest effect. And then in 2017, the FDA approved a drug called edaravone, which was indicated as a neuroprotective agent that could potentially slow the advance of ALS. But subsequent to the drug’s approval, additional studies have shown the effect of the drug to be quite modest. So sadly, there’s still very limited options for a diagnosis of ALS.

Daniel Levine: How well understood is the biology underlying ALS, and why has it been so difficult to develop effective therapies for the condition?

Stan Abel: YeahThe data or the evidence suggests that there’s potentially both a genetic component as well as an environmental aspect to it. There are two categories of a ALS diagnoses, the familial, which is about 10 percent of the diagnoses. And that is the result of a specific genetic mutation that has been passed down from a parent. To date there have been well over 50 genetic mutations, specific genetic mutations, that have been identified in familial ALS. Then the remaining 90 percent is referred to as sporadic ALS, where there’s really no specific known cause. Ultimately, in these patients, their cells stop functioning properly and they produce dysfunctional proteins that cause stress throughout the motor neurons and then ultimately the motor neurons start to die. And these could have environmental influences that cause the genetic mutation, but there’s really no known specific cause.

Daniel Levine: ProJenX was created out of a long term research collaboration between Project ALS and Columbia University. How did the company come about?

Stan Abel: Yes, well, I have the pleasure and the responsibility of telling you this story as someone who’s been involved with ProJenX for two months. I’ve been the CEO of the company for two months. It’s an amazing story about a visionary collaboration that began over 20 years ago. Project ALS, which is a leading not-for-profit organization committed to ALS research, was founded by three sisters, Jennifer, Meredith, and Valerie Estes in the late nineties. Jennifer was diagnosed with ALS. and once she got the diagnosis confirmed, the physician told her, “Go do whatever you want, eat as many big macs as you want. There’s nothing I can do for you. Your prognosis is that you’ll probably be gone in two to five years.” Jennifer found that answer unacceptable. Through her sisters and other family, they created Project ALS to try to work with the research community to do better coordination of what is happening with these patients, what’s happening with the underlying biology, coordinating research, and then also supporting the development of treatments for ALS. So they partnered with researchers at Columbia University, initially Dr. Hynek Wichterle at Columbia, and then Brent Stockwell at Columbia University. It’s a fascinating story of the evolution of drug development in that Hynek was the first researcher to actually get stem cells to differentiate into fully functioning motor neurons. At the time that was a major breakthrough, but it was still challenging because of the limited availability of stem cells and the limits of having enough motor neurons to work with for research purposes, and then additional discoveries over the coming years—one by Dr. Yamanaka from Japan, who basically figured out how to make stem cells from other cells in the body. So now we can actually take blood cells or skin punch cells from ALS patients and create stem cells, really an endless supply of stem cells, to support research. How that research unfolds is once you start expressing these ALS disease cells or cells from ALS patients, then Hynek developed a way to actually create and stress those cells to accelerate the disease process so that clues on the source of the disease will be revealed. ALS is a disease of aging so you’re creating brand new stem cells. They’re not 30, 40, 50 year old living cells. So there had to be a way to really accelerate that process so that clues could be revealed and that did occur. Through that work, what’s referred to as ER stress, or endoplasmic reticular stress, was identified as a common feature across both sporadic and familiar forms of ALS. So, now you have a model where you actually can create disease cells. Now you can start screening to look for interventions that interfere with that process. And in the case of ProJenX and Columbia and Project ALS, Hynek worked with Brent Stockwell at Columbia, and synthesized libraries of small molecules, to look for activity that would reduce ER stress. And then also look for the evidence that would be preserved motor neurons, or increasing survival of motor neurons in these in vitro models. So, they developed a screening platform from working with cells from ALS patients where they could actually take those cells and screen compounds against them to see which compounds were active in preserving motor neuron or increasing motor neuron survival. Now, I just skipped over 20 years of effort, but it’s really an amazing story. And from that effort arose a series of small molecule compounds that became very high interest. They showed activity in preserving the survival motor neurons. And that’s how prosetin was discovered, from optimizing that group of compounds from those models.

Daniel Levine: And what was the decision in taking that compound and building a company around it?

Stan Abel: That’s a great question. What’s amazing about this effort is that until ProJenX was founded late last year and then provided seed funding–this was all funded out of Project ALS and Columbia University–Erin Fleming, who is our VP of operations at ProJenX, actually spent the better part of a decade with Project ALS overseeing and running this process. And then, when ProJenX was formed, became the first employee of ProJenX. Their drug development, as you probably know, is very expensive. There are only certain things that you can do with a budget of $2 to $3 million, and what I described through research funding and grants, you can get small molecules and you can start to characterize those small molecules and even do some of the early IND enabling work. But at some point, when you start thinking about clinical trials, the capital requirements go up dramatically. So, our founding investor and actually interim CEO, who I just recently replaced when I joined a couple months ago, Eric Kyle, from Medical Eexcellence Capital had met Hynek and sat in a presentation where Hynek described all of the research that I just highlighted. And that started a conversation which led to the creation of ProJenX, the licensing of the technology from Columbia into ProJenX, and then the initial financing receipt funding of $5 million from Medical Excellence Capital, and that all unfolded this year. So, this is a very recent, very relatively, very new company.

Daniel Levine: And you had mentioned Jennifer. I take it, the company’s name is derived from her name in some way?

Stan Abel: It is. ProJenX—Jen is after Jennifer Estes and actually her sister, Valerie is on our board of directors.

Daniel Levine: And what attracted you to take the job as CEO?

Stan Abel: Well, I’ve been blessed to have a really a great career in biotech. I left Eli Lilly back in the early 2000s and—I’ll skip over the details—was fortunate enough to build and sell three biotech companies. And [I] had been, sort of, last couple of years serving as a board member and an advisor to small companies. Eric and I started talking about what he was doing at Medical Excellence Capital, and he introduced me to ProJenX and just described the company to me and said that they were starting a CEO search. And the fact that ProJenX was focusing on ALS, which is such a horrible disease with so limited few options and such an extreme unmet need, immediately caught my attention. I found it very interesting. And then when I learned about the story from Project ALS to Columbia University, to how ProJenX was created, I was very moved by it, quite frankly. That energy, that passion that created the science behind prosetin and it’s now resulted ProJenX is still very much a part of the culture of the company. I met Erin. She was the first employee of the company, and you could immediately sense that passion. And I was quite excited about the prospect of joining the company.

Daniel Levine: What’s MAP4 kinase and what role does it play in ALS?

Stan Abel: Sure. So, protein kinases are a very broad, sort of universe of what’s referred to as intracellular or cell surface proteins that dictate certain signaling pathways and biological processes in terms of metabolism and responses to injuries and adaptation, growth, all those things. And there are many, many, many, many protein kinases. Prosetin is an inhibitor of MAP4k, meaning it blocks the activity of a specific kinase family called MAP4k, which is mitogen-activated protein four kinases. So when Hynek was screening for activity in this ER stress-mediated for motor neuron loss, a MAP4k inhibitor revealed itself was being strongly neuroprotective. That led to the effort to optimize a small molecule compound that would block the activity of MAP4k.

Daniel Levine: And how well understood is the role it plays within ALS?

Stan Abel: Well, honestly, the biology behind ALS is very complicated. As I mentioned, so far in familiar ALS, they’ve found potentially over 50 genes that are implicated in the disease. And in terms of the disease process, those genes somehow their signaling became faulty. The proteins that they’re creating or synthesizing are miscoded or misfolded, and they don’t function properly. That then leads to the cascade of pathology with ER stress and then, motor neuron death. The field has been struggling, trying to find targets that are really effective against interrupting that pathology, because there’s so many potential genes out there that people are interested in looking at. You might even look at specific proteins that have been misfolded, or that could be implicated in causing the progression of motor neuron loss. What’s interesting about this approach for prosetin is that this drug was developed from the start by following ALS biology, by taking ALS cells, by identifying, or creating a model that would actually show how those cells were stressed and ultimately how those motor neurons died. And then specifically looking for activity that would preserve those motor neurons. So MAP4k really revealed itself as a target that would be effective across both familial and sporadic ALS, and it should be. Our hope is that blocking MAP4k will have a robust response and improve symptoms and hopefully extend lives in people living with ALS.

Daniel Levine: As you mentioned, your lead experimental therapy is prosetin. What is it and how does it work?

Stan Abel: Yeah, it’s a novel orally available, meaning you can actually either formulate it in a pill or drink it in a fluid, which is important for ALS patients to be able to do that in a fluid—makes it much easier to ingest. But importantly, prosetin has been designed to be highly brain penetrant. Not all small molecule drugs, in fact many or most don’t cross the blood brain barrier to get into the brain to treat ALS. It’s very important to get into the CNS and in the brain where these motor neurons are present and where the pathology is taking place. So prosetin has been optimized to access the brain and specifically target this important pathway in the disease.

Daniel Levine: And what’s known about it from the studies that have been done to date?

Stan Abel: Sure. We are in phase one clinical trials. So, just to recap, initially with optimizing the compound, which means you’re looking to improve its characteristics. You’re trying to improve its brain penetration. You’re trying to improve its stability. You’re looking at how it behaves in vitro to make sure that it has good drug characteristics. Then you take a compound like prosetin that you like as a drug candidate. And then you start going through a battery of tests, looking at in vitro safety and pharmacology. And in addition to efficacy, you have to look at how to manufacture it, how to make it and scale it up. All those things are a part of a very robust package of data that goes into what’s called an IND that you file with the FDA. An IND is an investigational new drug application. So, there’s been a whole body of preclinical work that goes into the IND you submit to the FDA. And then, if everything is in order, then you’re allowed to proceed into humans. So, that step from preclinical into first human exposure is obviously a big, important step. We started enrolling earlier this year, a phase 1 trial. So, the development process is, you know, phase 1 is early safety and PK, and if that goes well, then you can move into a larger phase 2 trial where you’re looking at efficacy, and then traditionally you then would move into a big phase 3 trial, which could end up having hundreds, or maybe even thousands of patients that you would ultimately submit to the FDA to ask for approval. Now that takes years, and hundreds of millions of dollars. But ALS is a bit unique, as an orphan disease or a rare disease, you have the opportunity to truncate that process. So, our hope is as we complete the phase 1 this year in 2022, that sometime in 2023, we will initiate what is referred to as a phase 2/3 registration trial, which if the data are supportive, could support approval with just that one trial.

Daniel Levine: And so, the clinical path forward would be what?

Stan Abel: Yeah, because it’s an orphan designation and an orphan disease, what normally might take, you know, six, seven, eight years could be significantly truncated into three or four years. So, this year is phase 1. We would initiate the phase 2/3 in 2023, that would take a couple of years, and then you would then submit to the FDA and hopefully have an accelerated review process. And if the data are supportive, this could be a drug that could be available within the next five years.

Daniel Levine: And what is the ongoing relationship with Project ALS and Columbia University, if any? Do they have role in the development of the drug? Is there an expectation of building out a pipeline of other therapies from them?

Stan Abel: Yeah, great question. So, there are two employees, full-time employees at the company right now, which is Erin and myself—not necessarily unusual for an early stage biotech, but we have the ongoing support in the help from a team of folks at Columbia University that still include Hynek Wichterle, Brent Stockwell, Emily Lowry, other people that were involved in the development of prosetin before it was transferred and licensed over to ProJenX. I also mentioned Project ALS. We’re still very close. Valerie Estes is on our board of directors. So, that sort of passion and commitment that has been present in this effort for the last 20 years is still very much alive within proJenX. We’re very pleased that they’re going to continue to support our efforts. We do need to raise money and that’s part of our plans for the summer, this fall, and then that we would use that money to expand the team as we prepare for larger scale clinical trials, as well as build out the pipeline. Prosetin has potential because of its activity and we can look at other neurogenerative diseases. We also have still a library of small molecule compounds that could be advanced for other neurogenerative diseases. So, the whole purpose of that financing will be to advance into the phase 2/3 trial, build our team, and expand the pipeline.

Daniel Levine: Stan Abel, CEO of ProJenX. Stan, thanks so much for your time today,

Stan Abel: Danny, thank you very much.

This transcript has been edited for clarity and readability.