Welcome everyone, to this fireside chat with Larimar Therapeutics. My pleasure to host Carole Ben-Maimon, President and CEO of the company. Thanks so much for being with us.
Thanks for having me.
It's been a very exciting time for the company.
Yep.
Some great execution. Help bring us up to speed with your recent accomplishments and priorities for this year.
Okay. We actually put out some information, sorry, it's a couple weeks ago. Basically we had our regulatory meeting that we had talked about in the first quarter was a very positive meeting, and at the same time, we had also applied for Breakthrough Therapy designation. We received Breakthrough Therapy, which was really exciting because that is a clinical piece that has to be component to that, and so it was really the first time that the agency got to see clinical data looking at mFARS and activities of daily living, as well as Nine- Hole Peg Test and a fatigue scale, which this division doesn't really like, but the other three were pretty convincing. The data was all from the September data cut, so we did not do an additional data cut.
That data cut will be, the data from that will be available in the second quarter of this year. We also had a meeting with them, as I said, under the START program, and so just wanted to confirm, given what the environment is in the biotech industry over the last couple of months, just wanted to confirm that they were still in agreement on using, frataxin as a novel surrogate endpoint, which they are. It will be a review issue. They actually changed their stance a bit on the safety data. They had been talking when we released data back last spring, they had been talking about, 30 people at 6 months and 10 at a year. They have backed away from that actually.
They have said that they are anxious to, you know, review the benefit-risk assessment and that the safety data will actually be a review issue as well, where they can put together the benefits, compare them to the risks on the final data set, which will be the data set that will give top-line data to this quarter. Not this quarter, second quarter of this year.
Got it. Okay, great. Now that the FDA has moved away from specifying a fixed minimum safety database and adequacy will be determined during the review, how comfortable are you that your projected exposure levels and enrollment by filing will be able to support a favorable risk-benefit, particularly at the 50-mg dose?
I feel very comfortable, quite honestly. The data will be mostly on the 50 mg because we switched everybody over a year ago. I'm pretty comfortable that it will be, obviously. That's based on the September data cut, obviously, the benefit score or we don't have any additional data. I think the real key piece of information is gonna be can we maintain those in the additional patients that come out a year. Remember, the FA-COMS data set only has patients annually. They only see their patients annually. Although we can look at other time points, you really only have a reference population in patients who complete a year or two years.
There'll be more patients in this data cut who have completed a year, and I think if we see the same types of movement in the clinical outcomes that we saw, as well as the level of frataxin, which we do see regularly, I think it'll be a very strong data package. Remember also, the main adverse event, the most common adverse event, is injection site reactions. Those are limited. They're mild to moderate. They seem to dissipate over time. As patients get out past two, three months, the incidence rate seems to go down, and they seem to be less bothered by them. We have anaphylaxis, as we've talked about before.
That seems to be very much related to patients who take the drug for a period of time, then go off of it for extended periods of time, two to three years sometimes, but definitely longer than three to four months. They, when they restart the drug, they have an event of anaphylaxis. We have been discontinuing those patients from the study. We are looking at whether or not tolerance protocols might be used to see whether we can get them back into the study. As many of you know, we also changed the regimen, but I really think this is related to stopping and restarting. We have started enrolling patients who have not been exposed to the drug.
Also, we should remember that there are 10 patients in the study who had been in a prior study, but they had received placebo, so they had not been exposed to the drug. Only one of those patients actually had an anaphylactic event. It does really seem to be linked to stopping and starting. If all of that stays the same and we continue to see the improvement that we saw in the clinical outcomes, I think we have a very strong data package. Sorry, that was long-winded.
Nope. Perfect. Great color. Thanks. Can you talk a little bit more about the modified dosing regimen-
Mm-hmm
how that works and when we'll see.
Yep
the results of that effort?
Yep. What we do is we give 5 mg in the doctor's office. The first dose is in the doctor's office. That's not a challenge for us because it's a serial PK day, so the patients are in the office anyway. They need to be trained on how to inject themselves as well. We give 5 mg. You may recall that the desired dose, the effective dose, or the dose we believe is effective is 50 mg daily. They get 5 mg. An hour later, if they tolerate it and they've done well, they get a 25 mg dose. They go home on the 25 mg dose, and then at 30 days, they increase to 50 mg.
They do come into the doctor's office for the increase just to be observed, but that seems to be what we do. Now, the intent here is, one, to identify people at a lower dose that might be allergic and hopefully decrease the magnitude or the impact of their allergic reaction. That's not always helpful because dose sometimes is not really related to allergic reactions. The other intent is to stabilize the cell membrane of the mast cells and the basophils so they don't degranulate and release histamine. We'll see if that works. The best thing, I think, is just not to stop your drug for long periods of time, but we'll have to see. There will be patients on that regimen in the data package.
Obviously, these are short-term events, so you don't need long-term data in particular on those patients. You just need short-term data. There should be enough data in the data package. Plus, if you look at the dose, right, 5 + 25 is only 30 mg, and we've been starting people on 50 mg. From a safety perspective, that shouldn't have very much impact.
Okay. Very helpful. Let's switch gears and talk about efficacy some more. The FDA is willing to consider frataxin as a novel surrogate endpoint, and they noted that your exposure response analyses are the type that could support a BLA. Are there any incremental analyses or correlations that they will wanna see in order to bridge skin frataxin levels to functional outcomes?
I think they're gonna wanna see more of what we showed them. You know, they're not gonna. I mean, we'll have more patients. What we're doing is we're looking at frataxin levels. This data was not released in September. We will probably put it in the package that comes out since we're doing it for FDA. They wanna look at frataxin levels compared to magnitude of change in the, in the clinical outcomes and see whether or not there is a correlation. What we showed them with the September data cut was that there is, and hopefully we'll be able to demonstrate that again, when we do the data cut in the second quarter.
Okay. What does it mean that frataxin might remain a review issue? Does that have to do with, like, the measurement of it, or what aspects of frataxin?
I think it's all of the above.
Yeah.
They've had our validation package for a long time, but obviously they don't look at things in the detail that they look at it when it's under review. I think it'll be an issue of making sure that they're comfortable with the assay itself. It'll be an issue of whether they see. I mean, we still collect buccal cells. We see the same thing that we see with frataxin in skin as we do in buccal cells, but they're gonna wanna see that there's consistency between all of this. I assume they'll go back and look at all the animal data that was published last summer, and take a look at that and make sure that. Remember, when you send in packages, you don't necessarily send the raw data.
When you send in the BLA, you actually give them the raw datasets for them to analyze themselves and work through. We've actually spent a lot of time on our pharmacology studies putting those datasets into user-friendly fashion. There's certain data, mostly your GLP data, like your tox data, where the agency requires, it doesn't matter. It's called SEND datasets. They're datasets that are user-friendly for the toxicologist to really be able to crunch the PK and all that. Your pharmacology studies, you don't usually do that for because they're supportive studies. They're not critical. We've actually spent a lot of time because we're using it as a surrogate endpoint to make sure that the agency can actually confirm our data analysis and can work through all of those datasets easily. It's just work.
It just costs money and takes up time.
Yeah.
It needs to be done in this case because we really need to make sure that they can get themselves comfortable that the data is representative of what we said.
Very interesting. Okay. A question we get from investors frequently has to do with the actual measurement of frataxin. How is that being done?
Yeah. I want full disclosure, I am not a biochemist. We do have an assay. We've been using it. We developed it way back. The very early animal studies used an ELISA, we've been using this study way before any of our tox studies, it's a ligand binding LC-MS/MS. It basically is able to measure. It first of all can differentiate between the intact CTI-1601 molecule and frataxin that's processed. We've also confirmed that with some Western blots in patients, so we know that the molecule is being processed to the 14 kDa protein. It's been validated and fit for, early on, fit for use, now validated in multiple tissues, in monkeys, rats, mice. I think that may be it. Maybe rabbits, if I remember. It's been validated in all of the tissues that we've used.
Okay, great. The FDA has confirmed that they'd like a global Phase III to be underway and substantially enrolled at the time of BLA submission. Where are you in terms of site initiation and/or site selection and initiation, enrollment, that process?
Yeah. I'll just point out that substantially enrolled is sort of flexible. We'll have to see where they come out. They know what we're doing. I mean, we've submitted the protocol twice now for them to review. That was because we wanted them, after PTC didn't get approval on upright stability, to make sure that that wasn't the problem. They've confirmed that it's not. EMA has also seen the protocol and made comments on it as well. Our CTAs are beginning to go into Europe. We've also filed in Canada as well. We have all our sites identified. Most of them have been qualified. We're going through the IRB process in the United States.
The U.S. sites will start first, and that's intentional because if we get an accelerated approval, we wanna make sure we have as many patients as we can as far along in the study. It's not likely we're gonna get an approval in I mean, in Europe, based on frataxin. It may be on the clinical data. That's possible later on, but it's gonna be later. It's at least a year later. We wanted to make sure that those sites get up and running, but that they can lag a little bit. We've really focused a lot on our U.S. sites. We should start screening in the second quarter of this year in the United States, with the first dose sometime after that. The screening period is four to six weeks.
We'll see when the first dose is, and we will put that out there and let people know that we've dosed the first patient in that study when it happens.
Okay, great. What were the key points that you needed to get aligned with both EMA and FDA in order to feel comfortable that the registrational study.
Yeah
Could be successful ultimately?
Yeah. I think we wanted to make sure that the trial design, so number of patients, type of patients, so these are all ambulatory patients. They are right now 12-40 years of age, with two-thirds of them being under 21. We have actually also a plan to amend the protocol once we have the safety data from the open label study to include kids down as low as two, and that's at the request of EMA through the PIP process. It's 18 months of dosing. They've all agreed to that. Where they haven't agreed is the primary outcome in Europe will be mFARS and in the US will be upright stability. The U.S., as I said, is more comfortable with up.
The reason upright stability is something that we're interested in and we really think is important is because in the younger kids, it's very hard for them to comply with the mFARS. mFARS has a lot of different parameters, upper limb, lower limb, take your finger, touch your nose, your right hand, left hand, and it's hard for kids under eight years old to comply. What that results in is much more variability in the outcome measure. But EMA felt very strongly that upright stability only correlates with ambulation, whereas mFARS is a broader scale, measures upper limb dexterity, measures bulbar function, and so they preferred the mFARS. The protocols are identical with the exception of the primary outcome.
Okay. Interesting. What would be a realistic timeframe for us to have in mind for enrollment and then having the data become available?
There are a lot of studies going on right now. I think you have to figure a year to 18 months for enrollment. It's 130+ patients, and it is double-blind placebo-controlled. If they can get open label studies, patients may choose that. We figuring a year to 18 months for enrollment, 18 months of dosing. Well, now you're already at 2.5 to three years, and then the readout. I would say you're somewhere around three to 3.5 years before the readout of that trial. Now, as I said earlier, there is an interim analysis in that protocol for adjustment of sample size primarily.
There are sites that are coming to us and saying they don't believe it's ethical to keep their patients on placebo, which may have an impact, and FDA is sensitive to that, as is EMA. We are gonna be looking at our data and starting to have conversations through PRIME, because we have PRIME with EMA about whether or not a conditional approval could be an alternative, but based on clinical data, not based on the frataxin data. Those discussions have not even initiated yet. So I just wanna make sure that's clear.
Yep. Very helpful. How would such an interim analysis work potentially?
I don't remember exactly. It's after a certain number of patients are enrolled for a year, if I recall. We'll look at it and make sure our sample size is adjusted, but obviously there'll be a blinded, isolated group that will be able to also look at the efficacy outcomes.
Okay. What have you learned from dosing adolescents and analyzing their results so far? You mentioned that you'll follow up with some adolescents being treated at some point. When is that? Will they be included in the initial label?
Yeah. The PK run-in study had 14 patients in it, some were on placebo. Those patients have already been or are enrolling. There's some that are still not, but they are enrolling in the open label study. We know the PK, we know the dose, the equivalent dose. It's a mg per kg dose for adolescents and children. Whereas for adults it's a fixed dose. For the kids it's capped because some of you know, a 17-year-old can be pretty big. It's capped at 50 mg. They seem to tolerate it well, no differently than the adults. Like I said, they're enrolling in the open label, so some of them started enrolling earlier, like in the fall, I would say. I'm guessing a little bit plus or minus.
There should be substantial data on some of those patients for the agency to review, so I'm very hopeful about the adolescents. We're in the process of amending the protocol for the little ones, for the younger kids. We obviously are going to need some safety and some PK data. It is possible that we will have to amend or supplement the application for the little ones or amend during the review process, because we may not have enough data at the time of filing.
Okay. Another question we obviously get a lot nowadays has to do with the folks at the FDA that you're interacting with. It seems like there's been some good consistency, some good integrity. The division seems like it hasn't been as disrupted as other parts of the agency. Can you give us some insight into that aspect of things?
Yeah. We've had a lot of consistency. DN1 has been very stable. I wish there was some wood here I could knock on, because they've been really. It's Emily Freilich and Teresa Buracchio are the office head and the division head. First of all, they're really nice people. They understand the disease. They've been involved with FA for a long time. They were actually in 2017 at the patient-directed drug development meeting that was held by FARA. They are very cognizant of the unmet need, use those words regularly. In our breakthrough designation, they said used words treatment for the treatment of patients with FA, adults and children. They're very aware. Teresa Buracchio was actually in 2017 at our pre-IND meeting.
She was a reviewer at the time, so she's obviously gotten promoted, but she's been with the program since its inception, even before we filed our IND. I think there, even the reviewers below them have been there for a while, for quite some time. The people who've actually changed intermittently are the translational people, because we work a lot with the translational people because we're using a surrogate endpoint. There's been some turnover there, but even that's distant. It's like four or five years ago, before, you know, this administration. I think that Dr. Makary, many of you probably listened to him yesterday, has been very consistent about diseases with clear mechanisms of action.
You know, I got excited about this almost 10 years ago, probably 10 years ago at this point, because there aren't a lot of neurodegenerative diseases where you actually know the root cause, and there's not even a protein that's abnormal here. 2% have a mutation on one allele, but they're not in these trials. It's really you've got a disease where you actually know the root cause and you're giving back frataxin, which is, to me, very exciting. I think the agency sees that. I think they understand it. Obviously, we need a double-blind placebo-controlled trial to confirm it, but I think they understand, and they've stayed. These people have been there, and I think will stay.
Let's fast-forward, and assuming all goes well and nomlabofusp is on the market, how do you see it addressing the patient population? Are there obvious segments that make the most sense to adopt it earlier than others or deeper than others? Is Skyclarys even a competitor? Help us think through those things.
Yeah. The obvious one are the kids. I mean, Skyclarys is not approved in anybody under 16 years old, so those patients have nothing. They're also the fastest progressing patients. The earlier you're diagnosed, the faster the progression of the disease. I think it is also the place where we are most likely to see the most effect because they have the least amount of damage, permanent damage at that point. I think it's just more easily reversed or prevented from progressing. We hear anecdotes from our site. On the East Coast, we're using a site called Uncommon Cures. The CEO is, you may have heard of him, Dr. Marshall Summar.
He ran, he was the chairman of NORD for a long time, has been very active in the rare disease space, is a geneticist, ran a clinic out of GW for many years, a professor. He's supposed to have retired, but he's running Uncommon Cures, which only does children. They'll go up to age 25, but they only do children. I was actually down there a couple of weeks ago. Beautiful brand new site, great recreation room. The nurses are ER nurses who were all on a team. Anyway, it's a beautiful site. He is actually enthralled with the drug. Like, he really thinks that they're seeing activity. It's anecdotal. Whoops, sorry. It's anecdotal. There's He's doing the open label study. There's no placebo in that study, so we'll see.
I think that's the first population that we wanna get into. When it comes to the older patients who are on OMAV, we do have data on OMAV. We allow patients in our study, both the open label and the Phase III on OMAV. We have safety data. We know they can take it. The question, obviously, is gonna be third-party payers. I do believe that some people will stop. We have a couple of patients in the study who actually stopped their OMAV during the trial. I don't know for what reason, but they did. I think there are some patients who will be willing to switch given the mechanism of action of the disease and some physicians who will suggest that they switch.
I do think there may be, for later stage patients, some reason to take both drugs, and the question's gonna be, what will third party payers say? I also think, though, that the physician population understands that frataxin is the root cause of the disease, and if you're not restoring frataxin, you're treating much further down the disease pathway. I do think physicians and the market research we have suggests physicians will start with nomlabofusp with patients either who are not doing well on omaveloxolone or who, you know, they think could benefit from something that gets to the root cause of the disease.
Okay. Yeah. Makes sense. It works at the top of the.
Chain
mechanism versus the bottom for Skyclarys.
Yep. Yep.
Um, so-
I would add that we saw a greater magnitude of change. I mean, in one year, granted eight patients, in one year, we had a 2.25 point improvement on mFARS compared to 1.5 points on Skyclarys at one year, which is a significant difference. I mean, that's, you know, if 1.5 points is clinically meaningful, going from 1.5 to 2.25 over the same period of time is actually a significant difference.
In fairly advanced patients.
In very advanced patients, yeah.
Yeah.
Absolutely.
Okay. What's the plan for Larimar to bring this to market? Is independent collaboration the base case? Does partnership make sense in any form? What are your goals?
We have two goals. The first is to get this to patients as fast as we can, and in the best, most efficient way we can. We don't wanna get slowed down and bogged down with a lot of bureaucracy and a lot of decision-making. We also know how hard it is to launch a drug. I've been around a long time, longer than I want to admit, and it's very hard, and we don't wanna make mistakes. We want this drug to get to patients. We do talk to people. We would consider the right partner if it was the right time.
We also have shareholders that we care very much about and that have been with us for a very long time and taken a lot of risk with us, and so we wanna make sure that they get treated appropriately. Those are the two criteria. That said, we are planning to launch the drug by ourselves so that we don't get caught without a plan. We, as many of you may have seen, we did launch a disease awareness campaign back in the fall of last year, and we are continuing to advance that disease awareness campaign. We obviously are not hiring sales reps and things like that, but we're continuing to do market research, continuing to look at market access. We have an internal person who works for us full-time that's looking at market access.
We're going down the road as if we're going to go it alone, and we will be prepared to go it alone. If the right opportunity presented itself, we would be happy to keep an open mind.
Makes sense. Well, thank you so much for the update, Carole.
Thanks for having me.
Keep up the great work.
Thanks. Thanks for having me. Thanks, everybody.