Targeting ALS with Synergistic Combinations of Therapies

After Alon Ben-Noon had a chance meeting with patient advocate Shay Rishoni, who suffered from the neurodegenerative condition ALS, he was so inspired by the experience that it led to his founding of NeuroSense Therapeutics to find a treatment for the condition. The company is pursuing synergistic combinations of existing therapies to go after biologic targets underlying the core pathologies of the disease. We spoke to Ben-Noon, CEO of NeuroSense, about the company’s approach to developing therapies, its current lead therapeutic candidate, and its efforts to target other neurodegenerative conditions beyond ALS.

Daniel Levine: Alon, thanks for joining us.

Alon Ben-Noon: Thank you, Danny.

Daniel Levine: We’re going to talk about NeuroSense, ALS and the company’s efforts to repurpose existing therapies to treat this rare neurodegenerative condition. Before we get into all of that, I I’d like to start with Shay Rishoni. Who was Shay, and how did your meeting him lead to the work of NeuroSense?

Alon Ben-Noon: First of all, thanks for mentioning Shay. Shay was a super active person, an ALS patient who took a role to also become the CEO of Prize4Life, a nonprofit organization that advanced assistive technologies for people that suffer from ALS. When I met Shay, I was overwhelmed to see how much he was able to do in this field of ALS while he was completely paralyzed. When I thought about it, I’m fully functioning. I have functioning arms and legs and wasn’t doing a tenth of what he was from his bed. It didn’t make sense to me that in 2016, there was no solution, no cure, but also no good treatment for this disease. At the time I was very much involved in the biotech industry, knew great scientists. So, I went on to found NeuroSense Therapeutics with one major goal: to find and to develop an effective treatment for ALS patients. I don’t know the genetic diseases, and of course, ALS is the one that is most important for us and for me personally. And I did it with several scientists that I knew, and we started doing the research. I’ll tell you all about that.

Daniel Levine: People meet patients with rare conditions all the time. What was it about that meeting that so moved you to establish a company focused on finding treatments for that condition.

Alon Ben-Noon: You know, Shay had a great personality. He didn’t try to convince me to get into the field, but in a way, he did so in his own special way. You’re right. People meet people, other people with certain diseases, it doesn’t make them go and found a company to treat these indications. But I was fortunate enough to know bright scientists in the field. And honestly, I was shocked by the way that Shay was—his condition—the fact that he was completely paralyzed, communicating only via eyes through computer software. When he was looking at me, he just moved his eyes, not a single muscle in his body moved at that time. I have to add that Shay passed away in May 2018, but before he did, I was fortunate enough to share with him our outstanding preclinical results. He was overjoyed to hear our about our progress and I told Shay that now, since we have a therapy to develop and advance here, we will name it PrimeC as a tribute to him, to his legacy, since his last name, Rishoni, translates to prime in English. He was very moved, very excited about this.

Daniel Levine: For listeners not familiar with ALS, what is it, and how does it manifest itself and progress?

Alon Ben-Noon: ALS is a fatal disease that leads to paralysis, and death within two to five years on average from diagnosis. In this disease, the motor neurons that are responsible for activating muscles—these cells are degenerating and dying. Usually, the patient dies once the muscles that activate the lungs stop functioning. Today it takes several months from onset of early symptoms until a patient is being diagnosed and patients are losing time, although there isn’t yet an effective treatment that they can take.

Daniel Levine: What therapies exist and what’s the prognosis for a patient with the condition today?

Alon Ben-Noon: To date, as mentioned, there is no effective treatment. There are only two FDA approved drugs out there and both of them with mild effects on increasing lifespan to some extent. Therefore, of course, there is a huge unmet need.

Daniel Levine: You began by looking at existing therapies that might be used to treat ALS. What was the case for this strategy to treat ALS and why were you focused on looking for potential combinations of therapies?

Alon Ben-Noon: Our innovative approach uses a combination therapy that aims to tackle several protein and targets in these diseases in ALS and degenerative diseases in order to create a clinical benefit for the patients. It is important to note that it’s not a classic repurposing. It is actually a combination therapy and a sophisticated formulation that utilizes two existing molecules in unique doses and maximizes the effect we found to have between these two compounds on several pertinent biological targets.

Daniel Levine: You began by screening approved FDA drugs, targeting the main pathologic pathways of ALS. What are the pathways you’re targeting and what’s understood about the role they play in the disease?

Alon Ben-Noon: Good question. What we are targeting is RNA synthesis and iron accumulation and neuroinflammation that our hallmarks in ALS pathology. And therefore we knew that we wanted to find drugs that could modulate these pathways. PrimeC is composed of two compounds that affect these pathological pathways.

Daniel Levine: You used the zebrafish model of the disease to screen drugs. How broadly did you look at potential therapies and what was the process for testing combinations of therapies?

Alon Ben-Noon: Okay, zebrafish offer unique advantages for for modeling aspects of some model known diseases, including ALS. They have a similar, yet simplified nervous system compared to humans. SOD1 is the gene, the mutant of ALS, also the TDP-43 is another mutant of ALS. The SOD1 and TDP zebrafish models of ALS have demonstrated, in zebrafish-like mice that show hallmark features of ALS. And we tested components of primeC separately, and the final formulation of primeC in the zebrafish. The final formulation contained the optimal doses of each of the compounds. We tested them in the zebrafish model in conjunction with the McGill University and our findings provided the effective doses in Russia, between the compounds, as well as demonstrated the clear synergies between the compounds that assist us moving forward to the clinic with the right ratio and the right doses for PrimeC.

Daniel Levine: But did you just screen a library of all approved drugs? Was there some kind of reason why you excluded some drugs or included others?

Alon Ben-Noon: Yes, absolutely. So we definitely screened several potential drugs and this lab had already screened dozens of other drugs for CNS indications, none of which gained any effect that was similar to PrimeC. So, we were certain that PrimeC, also when we compared it to riluzole—the standard of care—PrimeC achieved much better results than riluzole. So, like no other drug. We were convinced that this drug can actually create the clinical benefit that we need in ALS.

Daniel Levine: You found a synergistic better fit between the two components, one, a well-known antibiotic, the other, a well-known anti-inflammatory; but was that just fortuitous that there was this synergistic approach or was there some reason to expect that?

Alon Ben-Noon: We actually hypothesized that there is a synergism between these two compounds. Since there is lots of data from the literature about other indications using several drugs and combinations, we knew that celecoxib and ciprofloxacin has a potential to stimulate the CNS system. So, it was another reason for us to choose these two compounds among others that we tested. And of course, we also understood that both compounds have their own attributes to target certain pathological pathways that we need to create a biological change in these targets.

Daniel Levine: And to get to those two, did you have to see significant activity independently for each before selecting them in combination?

Alon Ben-Noon: We saw that celecoxib had little to no effect at all alone, but we also knew that 20 years ago, celecoxib was tested in a phase 3 study in ALS and didn’t achieve its primary endpoint. We didn’t expect much from celecoxib, but we hypothesized that ciprofloxacin is actually enabling the celecoxib to have an effect on the downstream, of the COX-2 enzyme and vice versa. Celecoxib also assists more ciprofloxacin to get into the cells and to get more cipro to the targets themselves.

Daniel Levine: So, the combination that you’re calling PrimeC—you know, I’ve seen other companies try this type of approach and oftentimes they’re using drugs that require different dosing regimens, maybe different dosing than you would give a patient individually. How did you arrive at optimal dosing and how tricky was it to combine these two separate molecules in a single therapy where they could be correctly dosed?

Alon Ben-Noon: So, part of our extensive preclinical work was both to determine the unique doses, which then when combined work synergistically to have an optimal effect, but also to formulate the drugs together in a way that would take advantage of their different pharmacokinetic profiles. You are right. It’s not trivial at all, but first we learned what are the doses that we want to use and the ratios. And then we created a formulation that consists of these two compounds, taking into account the different pharmacokinetic profiles and the way that we can actually create a release profile that can maximize the activity between these compounds. So, it wasn’t trivial at all. It was a challenge for us, but now we have a formulation ready, and novel formulation, and we are moving forward to the next clinical stage.

Daniel Levine: And in terms of the biological mechanism of action for this combination therapy, how well understood is it?

Alon Ben-Noon: According to our biomarker analysis, which was carried out in collaboration with Massachusetts General Hospital, we uncovered a large set of biomarkers that are relevant to ALS. We identified and characterized these biomarkers and then evaluated the effect of PrimeC on these biomarkers. We found PrimeC to have a statistically significant effect on biomarkers such as TDP-43 and prostaglandins that are involved in neuroinflammation, as well as many others. What was totally fascinating, though, was the fact that we see that there was a clinical relation between the biological activity of PrimeC and the clinical outcome in phase 2a clinical study that we carried out. So, you see clearly that when we reduce DDP-43, which is a toxic protein in the motor neuron cells, we could also slow down the disease progression.

Daniel Levine: And what’s noted about PrimeC from the studies you’ve done to date?

Alon Ben-Noon: According to the preclinical studies, PrimeC improved locomotor and cellular deficiency in the ALS zebrafish model, two different models, which indicated a neuroprotective effect. I won’t get into the details of this preclinical program because we carried out a clinical study and completed the phase 2a study with 15 patients with ALS who were to treated with PrimeC for a period of 12 months. Not only did we meet the primary endpoint, which was safety in this initial study, but we also observed an effect on both ALSFRS and forced vital capacity. We were able to attenuate the deterioration of the disease by 30 percent with regards to forced vital capacity and 18 percent on ALSFRS. Currently, we are moving forward into a phase 2b multinational, placebo-controlled study in ALS, which we intend to initiate in several weeks.

Daniel Levine: You’re also pursuing treatments for Parkinson’s disease and Alzheimer’s disease based on the work you’ve done with PrimeC. How much commonality exists between these conditions and what’s the approach you’re taking there?

Alon Ben-Noon: Our pipeline includes, as you mentioned, therapies for Alzheimer’s and Parkinson’s disease, which we intend to be IND ready by the end of 2022. We are currently investigating the extent to which there are similarities between the pathology of these diseases, and whether PrimeC or a variant of PrimeC—celecoxib and ciprofloxacin—will be utilized as a disease modifying platform. The combination can be a disease modifying platform technology for these indications, as well, since we know that Parkinson’s and Alzheimer’s share same mechanism with ALS and now we are exploring it further.

Daniel Levine: How is NeuroSense funded and how far will existing funding take you?

Alon Ben-Noon: Initially NeuroSense was funded by me and an angel investor. Then when the preliminary results were received, family and friends joined for another round. Then we raised money from a European VC, after which we also went for crowdfunding in Israel, and we raised additional an additional $1.5 million approximately. And then we went to an IPO on the NASDAQ in December 2021. We raised $12 million in the IPO and recently additional $4 million through warrants that were exercised, due to a pop in the stock. So, now we are fully funded to complete the phase 2b clinical study that we are now initiating in ALS. And even beyond that, through Q3 2023, this will allow us hopefully, to reach this significant inflection point that we’re expecting in Q2 2023 upon revealing the results from the phase to B clinical study.

Daniel Levine: Alan Ben noon, CEO of NeuroSense Therapeutics. Alon, thanks for your time today.

Alon Ben-Noon: Thank you very much, Danny.

This transcript has been edited for clarity and readability.