Newsfilter article unlocker

Good morning, everyone. I'm Samanth Kulkarni, a Senior Biotechnology Analyst at Canaccord Genuity, and I'd like to thank all our institutional clients for your ongoing support of our equity research franchise and efforts here at the firm. In the spirit of getting differentiated companies out to you at our conference, we have Clean Nanomedicine. There's an extremely different approach that it is taking to tackle the extremely challenging indication that it's going after. and they're at a really interesting point in their evolution as a company and we have for clean we have ceo rob etherington and cfo morgan brown they know everything about the company so we're going to try to get all that done in 25 minutes so we'll keep this interactive we do have a mic going around so if anyone in the audience has a question or two please feel free to raise your hands don't be shy and i'll get the mic across to you we'll keeps interactive as i said so i'll kick it off so rob could you set the stage for exactly what's going on given the extremely interesting times that CLEAN is living in right now. Interesting, because we've just had five meetings with the agency, the most recent of which was in March, and we announced on May 3rd the outcome of that meeting. So to be entirely candid, we walked into the meeting not exactly sure where the agency was. We heard from them previously that our survival data, which they have understood clearly, cannot work by and of itself for the possibility of accelerated approval. They've said pretty clearly that survival alone is not a surrogate biomarker. Survival is not the answer. It's not a biomarkers, and that there needs to be a biomARKER. So in the spirit of that, they asked us to go see if we could see concordant biomARKer data elsewhere. And Clean announced that we did so with the $45 million funded expanded access protocol that NIH gave us from the Act for ALS. And so we have this concordant data set between the Healy data set during the placebo double blind and the EAP, where we both dropped neurofilament light in both cases about 10%. And so after the presentation at the most recent meeting in March, I was accompanied by Jinzi Andrews, who runs the NIH-sponsored EAP. By Dr. Merit Sudovich, who was the primary clinical investigator here in Boston of the Healy Program, and by Dr. Bob Bowser, who is one of the world's experts in neurofilament light and its biomarker impact, and has testified on behalf of other companies at the agency around the same thing. And after the presentation of the three of them, I basically asked the FDA, what would you best like us to do? Because we had received just a few days previous to the meeting, post-meeting or rather pre-meetings notes that I have here in my hand, and I'll read it directly. The proposed data may be capable of supporting the submission and review of an application under the accelerated approval for the treatment of ALS, but, and that's an important but, you need to demonstrate not only the substantial evidence of effectiveness of an effect, that's exactly how they phrased it, the effectiveness of effect on CNMAO8 on neurofilament light, but also that the modest magnitude, this 10 percent, of the change, modest magnitude of change in neurofilament is reasonably likely to predict clinical benefit. And then, for the next three pages, they gave us a number of, shall I call them breadcrumb trails, things they wanted to see. And so, for the last three months, we've been working extensively on that, and we announced that data yesterday morning. So, just to give a little bit more context from the meeting, this is a long answer to your first question, Samant. But the agency basically told us at that meeting in March, is 10% clinically meaningful? That is the key question. We're not exactly sure. That's the reason we want this opportunity to accept an NDA, review it, dig into the data, but to really see how neurofilament light is tied to clinical benefit. And so those comments, plus the comments in the uh divisions uh minutes gave us the data we announced yesterday got it that's a great background so just to step back a bit you have a really different product candidate it's gold nanocrystals it's not really a classical pharmaceutical it's a biocatalyst far from classical um so could you give us a brief i guess history on how you came about this candidate and what that might mean for its place as a potential treatment for these challenging indications that you're going after? So first of all, for those of you that aren't familiar, this is the acid. This is an oral suspension of nanoparticles suspended in water. If I was to be blindfolded and drink a glass of water versus this acid, I could not tell the difference. It would taste like water because it's primarily composed of water. In this are trillions of nanocrystals at 13 nanometers in size on average. That is small enough to come into my gut, cross into my bloodstream, and cross up across the blood-brain barrier. We see evidence of these nanoparticles in the tissues of the body, including the eye, the spine, and the brain in animal work. And what is going on is we're driving a bioenergetic metabolite change in failing mito. And in the case of ALS, for example, in neurodegenerative diseases generally, but ALS in particular is where we've really staked our primary claim, the neuron is under such stress and such de-stress that it is completely compromised, and by consequence, it dies. And when it dies, it leaves a cytoskeletal protein remainder in the bloodstream, which we can measure. So that leads us to the neurofilament biomarker thesis. But back to the primary point, this is an intersection of physics and material science into biology. It's not classically chemistry in any way. The nanoparticle is serving as a catalyst to drive a decrease in reactive oxygen species, an increase in dicatinamide adenine dinucleotide, as well as ATP, adenosine triphosphate, two of the essential building blocks that are driving what energy is required regardless to drive function. And so what we're really working to do is to see if we can keep that neuron, despite the assault of the disease, effective and able to not just fight back against the disease but to keep function. By function, I mean in the case of ALS, that would be a survivor driver, cardiac and pulmonary function. But that leads us to a key question. We're often asked, well, why is there not other function besides just survival? And that's really what happened yesterday, which is, I think, quite notably the case, is we found yesterday in this work we've been undergoing for 90 days to look at neurofilament and its trajectory, that if, in fact, we look at functional benefit, we found that we were quite concentrated in neurofilament stabilization or declining subjects, that is to say, where the drug helped the neurofilment. And in that case, we do see an ALS-FRS statistically significant benefit and also breathing capacity through slow vital capacity. Now, both of these were post-hoc because both of These were addressing exactly the question the agency asked us to pursue, is we need to understand against concurrent control sets, not natural history, if you've got an effect. So I guess conceptually you're trying to prove what a clinically meaningful reduction in NFL levels is. What's your best answer to that? So we just did that assessment using actually natural history where it applies, looking at people who never got any of our drug for certain, and we have a decade about of data in more than 2,000 subjects across the ANSWER-ALS and the APST data sets where ALS researchers have tracked survival and function as a natural history set. And we found, looking AT that data set, that 10% reduction, though seemingly modest, does have a survival link. And it was P0001 and P001 with respect to the two different studies. And so there's an asset that the agency approved on neurofibrillator alone from a company here in Boston only a couple of years back in SOD1 ALS, which constitutes one to two percent of ALS subjects. Clean is not applicable for that indication. We're not going after SOD1. We're going after the rest of the disease. But what we see is that in that case, there was a 55% reduction, but no clinical benefit from the clinical studies. And so the question the agency is asking is, in your case, your effect is more modest. So we want to be assured that is the better word, that your neurofilament drop, modest as it is, is it in fact modest? Is 10% relevant? And can you tie directly to ClinBenefit? And that's where the critical piece of what happened yesterday resulted is we can. So conceptually, if one were an ALS patient without any, I guess, on standard of care now, what would happen to NFL levels over time? Well, the standard of care is radicava and more importantly, riluzole. So that's actually a pretty interesting, that's why ALS remains so crazy as a disease. We have about 100 new diagnoses every week. We have 100 deaths every week on average, data reported by both CDC and by the ALS associations. And so that's why ALS seems on one hand small, but on the other hand it's not, because who's coming in with new diagnosis is unfortunately going out with this two to four year survival rate. So the key thing, I think, is neither riluzole nor radicava have shown neurofilament changes in their indications. Lou Gehrig was diagnosed in the 1930s with ALS, famously lending his name to the disease. It took 60 years before Riluzol was approved. That was approved in the mid-90s. That drug still remains today's standard of care. It was approved on a modest survival benefit, and everybody's effectively on Rilzol as standard of care, and our asset was placed on top of Rilazol standard of and in some cases, Radacava too. Today, Mitsubishi's, Radicava, originally Mitsubishis, is not used as much, but pretty much everyone's on Realizol. Neither has a neurofilament benefit. And so the only drug presently with a biomarker indication and ongoing confirmatory phase three is the SOD1 asset from a company here in Boston. So what's unique about the clean situation is we are the first heterogeneous, that is to say 98, 99% of all other ALS patients that have ever shown in a phase two clinical study during the double-blind placebo-controlled period a neurofilament reduction. We're the only company to have shown that same in the EAP, which was an assessment and an investigation proposed by the division in November of last year. And now we're also the only country to have showed and to published, against concurrent controls that you have statistically significant data sets in both survival and in function, function defined as ALS-FRS or function defined as SBC breathing capacity. And what we're talking about actually is a 38% lower risk of death on survival, and that's a PO37. And that's over actually a four-year assessment period with concurrent controls that were randomized, and that's maybe worth some explanation in a second. but also on the functional benefit for those patients who had neurofilament decline or stabilization, they're also the ones that are seeing an ALS-FRS improvement at a P03 and SVC breathing capacity improvement at P003. And so just one comment about what we mean by concurrent control. When the three regimens for Healy were randomized at the same exact time, same protocol, same clinical sites, same inclusion criteria, similar exclusion criteria. I say similar because patients that came into our arm could not have a gold allergy. Sumat mentioned the assets based on gold. There was some specific drug-related exclusion allergy issues for the other two arms. But then you've got 480 individuals that were all randomized to three arms and concurrently followed for more than three years and so the agency said can you get that data and what I mean by that is both the other assets had were negative both other assets the company's closed down their programs no neurofilament benefit no primary secondary exploratory benefits both companies have moved on and taken their assets kind of out of the ALS development cycle but gratefully at the agency's request and then we notified both companies, they shared with us the entire data set, both their placebo and their active. So when we're talking about concurrently randomized controls, the agency said, we're not so fond of natural history data sets, and we've seen that in a lot of other examples. But in this case, you have this very unique situation where three drugs were all from the same randomized base, treated with the exact same protocol during the exact time period. All three had the exact same OLE, open label extension proposals, and those two other drugs, none of them ever got CNMAU8, yet we have, again, three to four years of follow-up. So that data set, when it comes to clean, becomes this very interesting concurrent control from an original randomized set. And that is the assessment period that the agency suggested we go look at. And again, the thesis is to do exactly what was suggested by, I'll read one of the comments from the agency. We like the data on survival. That's very helpful, but we need to really understand what is your neurofilament change? Is it real and meaningful? And considering HEALY, the OLE, and the EAP is what we see, not just a random event of neurofilment change, But can we use your data to look at where this 10% change is actually connected to clinical benefit, clinical benefit defined as either survival or function or both? So now you're at a point in time where yesterday you said that you are in position to potentially file a new drug application in early 4Q. What needs to happen between now and that filing to get all your boxes checked, I guess, before the filing goes in? So the two clinical study reports that incorporate all of that I've just spoken to are already completed. The agencies also ask us to include our visionary program in SED filing. That's the MS program. We've not spoken about MS at all, but we took the same asset, same dose, and pursued an MS phase two. And there is a whole separate stream of MS discussion that's ongoing with the agency, same division, Division of Neurology under CEDAR. But that, most investors care most about where we are with ALS because of this NDA. And all that's left actually effectively that we're just wrapping up is the Healy CSR. This was, since that's our core data set, that's been the most complicated. It also has a series of partners as part of this, including with Harvard. So we're about halfway finished with that CSR, and in the coming weeks will be done completely with that. And then that whole NDA package will be submitted to the regulatory publisher and onward to the agency. And then what will happen next, as we think from a catalyst perspective, the agency will review the totality of all these tables from a number of phase two programs, five in total, plus all the preclinical and all these CMC discussion. We do all of our own manufacturing. drugs unique and proprietary enough that we have all the CMC in-house entirely. There's not a contract manufacturer that we use. And then the agency will review this application, consider a PDUFA date hopefully by the end of the year if the agency is on time, and then sometime six months after that, around summer, this time next year, we'll have a decision by the agency whether or not they will let us commercialize with the presumption of a confirmatory phase three. And we've not spoken about that at all, but just a quick aside, the confirmatory face three that we proposed to the agency, which has been approved by them as well, is a confirmory phase three with survival as the endpoint, which is not been attempted in ALS for decades. Right. So now that you spoke about catalysts investors we like to think in terms of decision trees and all that kind of stuff so now you're at a point where you could file an NDA in early 4Q most times when an NDIA is filed there's one of two things that can happen either there's an acceptance of the NDA with the issuance of an action date or a refusal to file right what gives you confidence that you are in a position to file an NDA that is acceptable? Mainly the agency's own words in these multiple dialogues. Unlike some of the complicated interfaces with the agency, with other companies, we've had this tremendously useful dialogue. They understand our safety. They understand that to date with patients on drug consistently now, as we announced yesterday, 6.8 years. I have ALS individuals on drug for 6. 8 years in a row to date. That is remarkably, I think, notable in a disease that kills people two to four years. I have over 1,200 collective patient years, so safety is not an issue. Still, with all that data, there's not a single serious adverse event related to drug in our program at all. an MS, not in Parkinson's, and not an ALS either. So that is a remarkable statement. So we have a benefit-risk argument with the agency with respect to safety. We have our commitment to and alignment with the confirmatory phase three with survival as an endpoint. And now we have an accelerated approval argument with biomarkers. So I think the question in front of the agency is is not so much are they going to give us a PDUFA date. I'm not actually at all angsty about a refusal to file. That's really the burdens on the company to prepare the proper NDA with all the respective check marks of its elements, which is what we're now in the last stages of progress on. I think the broader question is not so much if there's going to be a review period that is a PDF date to the company. The broader question is, next year, is this data sufficient that the agency can get their comfort level around on a biomarker neurofilament that has the impact ours does, whether or not that is sufficient data to lead to an approval? Right. So let's say your NDA is filed. It's accepted. You have an action date. You know, in the recent past, this FDA especially has been very different relative to the prior FDA as we know it. Do you expect an advisory committee meeting on your application for accelerated approval? On your former question, different as we now it, the division that we're in front of have been exactly the same leadership for the entire two years we've been discussing this with them. So none of the present mishigas or complications that the agency is dealing with have affected clean. We're in front of the same folks the entire time. The head of neurology, the head of DN1, and our clinical reviewer are the same people. And so that's been tremendously fortuitous. I've spoken to a lot of companies that have to go re-litigate in front of new people. We've not had to do that. We've had the same group. So, yes, leadership has changed, but not the people that are the face people with clean. With respect to advisory committee, we are quite prepared to do so. In a normal situation, we would have undeniably expected an adcom somewhere next year in the period of our timing, April or May. The ALS community wants one. They often tell me, we're quite close to them, that they'd love an opportunity to go testify on behalf of this. We have hundreds of people presently on drug and have been, as I've stated just a minute ago, as long as 6.8 years. Now, clean, I mean, does anybody want an advisory committee? The answer is no. I'm not sure the agency proved evidentially in the last two adcoms we watched last week that they want one either. But if there is one, we're happy to take one. But we've heard nothing about that. We have no idea whether or not our program will be asked to do an adcom. And as a note, even though we've started to see new adcoms begin, there's no announced adcom in neurology. Right. Now, just a couple of minutes left, so we'll hit upon the confirmatory trial. You mentioned that this is going to be one of the few in a long while that's going to use survival as an endpoint. What's the burden of proof on that, and what's the timeline you might be looking at to finish a trial like that? And then could you touch upon your MS program? And then a question from Morgan. How are you thinking about what checks need to be signed so that you can get all your plans to fruition? So quickly on the phase three, that's three good questions. The plan there is to evaluate neurofilament and biomarker relationship prospectively with time to event using survival and clinical outcome. But survival is the primary. We're literally going to count survival using both death and an ALS, people who have 22 hours or more of needing breathing support. So if you're on a ventilator and save for the ventilator, you would be dead. That counts in ALS as well. So that's the primary endpoint. To answer your question, 800 subjects, and the way we've designed that is a two-year time-to-event program. So it will commence, and the agency was very clear in their discussion with us in March, that confirmatory study must have patients on drug be enrolling before we will consider an approval. So that's given us a very clear timeline about how we would structure that. So we're going to commence that study in the first half of the year, previous to an approval decision. The second point on your MS, and I'll turn to Morgan. On the MS study, we had a meeting with the agency in August of last year, a year ago. where they agreed, surprising us and some big pharma companies that since have partnered with us on this, that 30 years of expanded disability status scale, which has been the primary endpoint in MS studies for three decades, we can not need for our MS program, but rather look specifically at cognition improvement in MS patients that are progressing with their MS despite being fully controlled by disease-modifying therapy. So that's huge. That is also the first time a small pipsqueak company as clean certainly is at the market cap we have at the team resources etc that we have a possibility of a cognition endpoint in a phase three study is pretty remarkable and so the agency is actually working with us in the define of that cognition endpoint now we've been necessarily focused on als but ms is an opportunity we will turn to in 27 and then on cash yeah just quickly in the few seconds we have left here we've said publicly we have enough cash that takes us into the fourth quarter so based on this timing that rob just described here you know there will be a need to raise some additional capital to get through nda acceptance and an nd approval this year we have been two modest transactions one in january of this year the likes of vivo and coastlands in boxer capital they do have some regulatory warrants so upon acceptance the first tranche warrants would be triggered and we would get another seven million dollars of capital from those parties. And then more recently, we did a transaction, Sumat, in May with the help of Canaccord. Ironically here, we raised $7 million with a single investor. Clean transaction, sold a million shares at $7. So that helps us get to that sort of middle of fourth quarter time period. But yes, we will need to raise some additional capital to get through some of these more important inflection points. And hopefully once we file our NDA, that NDA gets accepted, that that will be reflected in our stock price all right thanks for that and we're looking forward to your filing the nda so and thank you everyone for attending and for tuning into the webcast as well thank you simon thank you