TRANSCRIPTION FREQUENCY THERAPEUTICS Q&A WEBCAST:
Audience:
Ok, so this is the Frequency Therapeutics break out session. David, if you want to introduce the panel with you as well as in the room, we can get started.
David Lucchino (CEO):
Sure, so this is David Lucchino, the CEO of Frequency Therapeutics, I'm joined at the Amadeus(?) by Christopher Robert Loose our Chief Scientific Officer and Dana Hilt who is our Chief Medical Officer, also in the room we have Jason Glashow who is Senior Vice President of all communication and corporate strategies, along with Sherry Pierce who runs our IR* program.
* IR = Investor Relations
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Audience:
Maybe I'll just kick off the Q&A here with you presenting the sort of full phase 1/2 data on the local conference towards the end of last year. Maybe you can talk about the feedback you receive on the emerging profile, both kind of on the positive side and what positions kind of maybe we want to see a little bit more of.
David Lucchino (CEO):
I'll take that and then ask Chris and Dana to share their thoughts. I think that what we saw when we presented our data at the big ENT conference in New Orleans back in September. The data was presented by our lead primary investigator Susan King out of San Antonio Texas. It was in a late break-in session. There was a lot of (I think) buzz and excitement about what we're doing and there were a lot of questions of course. The hearing field has never seen data like this previously. Remember, the historical control is nobody's hearing has ever .. doesn't improve. So, it is really being thoughtful and direct about the questions that people have. Rightfully so.
Dana, maybe you want to answer some of those in more detail.
Dana Hilt (Chief Medical Officer):
Right and you asked about the reception in the sort of KOL* community and what people are thinking of the data. So the team has gone around to a variety of the key opinion leaders in the ENT's world and audiology world. Presented the data, had in-depth discussions and to a person, really, they are very enthusiastic about this. They say that, looking at speech clarity, word-in-noise and intelligibility. This is real world hearing. This is what patients complain of as David mentioned in his presentation. So, they are very anxious to work with the company and see if we can replicate the signal and extend it. So, that's what everyone is focussed on.
KOL = Key Opinion Leader
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Audience:
What conclusions were made maybe by the physician community or by you guys looking more granular into the data on the impact between mild and moderate patients?
David Lucchino (CEO):
Chris, you want to take that?
Christopher Robert Loose (Chief Scientific Officer):
Sure, I think what was informative is when you look at word recognition the mild patients typically arrived with better than 45 out of 50 word scores, so very little room to improve. So they really were there and demonstrated that there was no loss of hearing, so real safety affect. So that's why we all were very focussed on the patients that did have that word recognition deficit, typically moderate to moderately severe and that's where all the 6 treated patients that showed improvement for profound. As we move forward we'll continue to make sure to have patients that do have a word deficit, so we continue to refine that.
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Audience:
I have two questions please.
1) Patient two had very severe hearing loss and a modest improvement. What happens when you give sequential injections to a patient like that? Do you see <inaudible> improvement?
2) Where do you stand in the cartilage* space in terms of regeneration, regenerative cartillage in the <inaudible>?
David Lucchino (CEO):
Chris, I'll take question one, maybe you can take question two. So, the first question was, in the data we shared in the presentation today, is that a patient number two showed approximately 7 out of 50 word response. With our drug we essentially doubled that to approximately 14 or 15. So the question is how will repeat dosing affect that. It's a great question and that's something that we're asking as part of our phase 2a study. So, when that's study is unblinded we'll know more.
Christopher Robert Loose (Chief Scientific Officer):
We're dosing up to 4 doses in that study.
Audience:
Cartillage.
Christopher Robert Loose (Chief Scientific Officer):
The question was asked on cartilage. Certainly arthritis is big on regeneration in that space. That is an area that we have looked at. There is a potential for regenerative therapy in that space. We're not prepared now to make any statements about any programs in the space.
* Cartilage is a resilient and smooth elastic tissue, a rubber-like padding that covers and protects the ends of long bones at the joints, and is a structural component of the rib cage, the ear, the nose, the bronchial tubes, the intervertebral discs, and many other body components.
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Audience:
Besides the word score in phase 1/2, did you look at any other secondary end-points that would give you any indication of <inaudible>?
Christopher Robert Loose (Chief Scientific Officer):
The question is, are there any other secondary end-points? So in addition to the word recognition score, which is a test in a quiet background. We also saw improvements in word-in-noise, which is basically repeating that test in a restaurant type of environment, where there are 6 people talking in the background, in a you know much more challenging environment. We saw similar improvers, improvements in that space. We also tested the loudness, test, the pure tone types of test there. We noticed that a number of patients with the biggest losses had improvements in the higher frequencies which is were the greatest amount of drug is present and people have the most loss. So moving forward we are going to be continuing with those three end-points, but we will also be adding ultra high frequencies going forward cause we know that's where the drug is concentrated, as well as quality-of-life, tinnitus and other end-points that we're thinking could give us a full picture of what this medication may potentially do.
Audience:
Just as a follow-up on that. Did you see any improvement in the secondary end-points in the mild hearing loss category?
Christopher Robert Loose (Chief Scientific Officer):
We saw trends across the population.
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Audience:
Yeah, so I was hoping to <inaudible> improvement <inaudible> clinically meaningful.
David Lucchino (CEO):
Sure, Dana?
Dana Hilt (Chief Medical Officer):
When we look at these real word speech tests, such as word-in-noise or word identification, we saw a doubling, as David showed on that histogram. And that test, retest is one or two words is pretty reliable test and a change of 3 to 5 words is, the audiologists tell us, are clinically meaningfully changes. These are changes that patients can then detect in their every day life. And you saw from that, even that worst patient went from 7 to 16, so they had an improvement of 9 words. Patient to the right, patient four had a doubling from 24 to 48 or 47. So we think that, while we have to extend and confirm these data, we think that is consistent with a clinically meaningful effect in patients.
Audience:
Does the fact that 2 of the 6 patients had no response at all mean that for some patients this will not work at all?
Dana Hilt (Chief Medical Officer):
So, out of the six patients that had a deficit. The four that David showed had statistically significant effects, the other two had improvement. Ok? They just weren't quite as robust as the four that we showed. So all 6 had an improvement. Ok? And that's with a single dose at 90 days. So obviously in this next trial we are going up to 4 doses, we are monitoring the patients for six months. So maybe these patients will show a response in this type of treatment program.
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Audience:
Just moving from phase 1/2 to phase 2a, Chris, you talked about how some of the milder patients they, on the word recognition, already had a pretty high threshold. So when we think about the inclusion and exclusion criteria for the phase 2a, are there differences where we may be able to illicit a benefit in milder patients?
Christopher Robert Loose (Chief Scientific Officer):
So the question was asked, can we learn from milder patients in the phase 2a, because they typically can have some smaller deficits. What we have done is, we've put in inclusion criteria requiring that patients entering this phase 2a study do have some more deficit. We are not describing publically what that exact criteria is, because we don't want to create any bias.
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Audience:
Early thoughts about durability of the treatment?
David Lucchino (CEO):
Sure the question was early thoughts about durability of the treatment? You know, obviously, we believe we are having a disease modifying effect and, you know, we continue to believe and theorise that we should see long term durability, but we really have to measure what that is. We saw that for 90 days in our phase 1/2 study and the data suggest that the durability was continuing to be on the upswing in a favorable way. So now we will be measuring approximately 7 months as part of our phase 2a study. We will have to see what the data says, but we remain confident that that trajectory should remain.
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Audience:
You've got in your phase 2a and you talked about this like multiple sort of cohorts and different dosing regiments. So looking to the second half data, given the full cohorts, in an ideal world, what is kind of your win scenario?
David Lucchino (CEO):
I think and then I'd like Chris, Dana and I and Carla Labelle(?) who is not here today, who has spoken about this. I'll kick off and then I'll ask Chris to comment. I use the word cohesiveness. I think what we've already demonstrated in the phase 1/2 study is profound and clinically meaningful and I think if we can continue to build upon that in a scientific way, in a biological way, I think that continues to be a real success for us.
Christopher Robert Loose (Chief Scientific Officer):
I think that is the keyword, is cohesiveness of the data. What we'll see in this larger study, it's four times larger. We'll get to understand the dose schedule and how that impacts outcome. And as David said we will be following patients twice as long after the last dosage as in the previous study what will give us information on durability. That's what we're looking for.
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Audience:
But, do you have preclinical models that would suggest that the repeat dosing could have more meaningful benefit? I can't remember.
Christopher Robert Loose (Chief Scientific Officer):
So the question is, do we have preclinical models on repeat dosing? That is not possible in the standard models, which are mouse models. You can't go in and continue to violate the ear drum of the mouse without creating effects. So that's a question we will have to answer in the clinic.
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Audience:
So you demonstrated that you can regenerate hair cells. The patient population are going to have a list of <inaudible> ... biology, including cochlear synaptopathy. Is there any evidence that your drug impacts the synapses?
Christopher Robert Loose (Chief Scientific Officer):
The question is, could there be an impact on cochlear synaptopathy? First, I would say of hearing loss is 90% of hearing loss is sensorineural as we've looked across patients that have donated their cochleas to science after they died. When you have a declining audiogram, it is very common to have hair cell loss. So we think that is really a driving feature. Part of a hair cell being born, it's job is to connect to neurons and create those synapses. So, one could theorise that you could be aiding in that process as well, but our focus is to regenerate hair cells and have them go through the process they go through when they develop and integrate.
David Lucchino (CEO):
And then Chris, there's a follow-up on that question. Would you mind talking a little bit sort of about asymmetric division and the approach that we use as we think about delivering our drug?
Christopher Robert Loose (Chief Scientific Officer):
Sure, the approach in our technology. When it was discovered that there were progenitors in the ear, there have been approaches that have tried to directly force the differentiation of those progenitors into a hair cell directly. Turning one cell type into another cell type. That is not how hair cells are traditionally formed in utero. By following regeneration in the gut in other tissues where the core breakthroughs for our technology were made by looking at regenerative systems. What you see is an asymmetric division where a progenitor copies itself and leaves behind a progenitor and then turns on the right genetic programs to make a fully formed dotter cell, in this case a hair cell. So, we are really steering in a unique direction compared to the prior competitors in the space who have been doing a forced differentiation. We are trying to get a step back with these progenitors to divide, replace the progenitors and kick on all of the genes to form a fully formed, fully integrated hair cell.
David Lucchino (CEO):
And now, we remind everyone, Dr Langer* at MIT who was an institute professor and Jeff Karp* who was a full professor at Harvard medical school. When they had this break-through, it happened in the GI system. They weren't looking to start a company that was focussed on hearing regeneration. That's when they had this insight patent(?) and that's when Chris and I got involved, because at the same time they realized there was a cousin of the type of the progenitor who they had success in the GI track, was in your cochlea. And that really led us to starting to investigate looking at frequency and really understanding the sort of deep biological (sort of) translatability and justification for this.
* Robert Langer
* Jefrrey Karp
* GI = Gastro-intestinal
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Audience:
Where are the regulators kind of in this involving space of novel endpoints? I guess, it feels like they're going to be learning just as much about the data that you guys bring.
David Lucchino (CEO):
So, the question is, where are the regulators? What I can share and then I'll ask Dana to also give his input, is that we had a very constructive and transparent interaction with the FDA. We had a face to face meeting. They've been very open. I think what they've clearly said was that, 'though this is not a life-threatening disease, it is a life-altering disease' and they take this just as seriously. So what I think they've said to us, and they've reviewed our phase 2a study, is 'let's see where the data takes us'. We sort of understand the historical ways how the FDA looked at this, as it relates to hearing aids. So now, let's see where the data takes us for a therapy that can regenerate hearing.
Dana Hilt (Chief Medical Officer):
Just to comment that, as we know, hearing aids are approved as amplification devices, so they are really looking at audiometric thresholds. What we're doing here, and we certainly have some effects on that, but more importantly we are having effects on intelligibility and speech comprehension. So to clarify, all of the scales we are using are validated scales. They are robust. They are accepted by the medical community. The FDA recognizes the medical applicability of these scales. And as David said, they are open to discussion as bringing the results forward and talking about what would the endpoints be in a registration trial and as you know the FDA's focus is factually(?) changing into what impacts the patient's life, what patient reported outcomes, what sort of measures can we use to register drugs that really impact what the patient appreciates. So I think this is a very positive direction.
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Audience:
How do you document the stability of the hearing loss <inaudibile> in patients?
Dana Hilt (Chief Medical Officer):
So the question is about documenting the stability of the hearling loss in the patients. So these are patients that had to have previously documented audiograms. So we are not just asking clinically 'are you stable?'. We are actually showing that have not any changes in their audiometric measure of hearing. So they are completely stable.
Audience:
<inaudible>
Dana Hilt (Chief Medical Officer):
That really includes the audiometric profile, primarily. That is really the focus for stability, because that's the one that is done most often.
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Audience:
Are there any safety issues that Frequency Therapeutics or the agency is focussed on?
David Lucchino (CEO):
The answer is no.
Dana Hilt (Chief Medical Officer):
We really haven't seen any pattern of significant adverse effects, certainly not any serious adverse effects. This is very important. It's still early in the development program, so we have to monitor that. But to repeat what David said, the ENT physician does this procedure many times. They administer steroids. They administer antibiotics. This is something the nurse preps the patient. It's a local anesthetic cream. The physician does it in 5 minutes and then moves on to the next patient. So this is something, I'm a neurologist, I would say it's simpler than a lumbar puncture. It's a very straight-forward and simple procedure. It is done, as David said, thousands and thousands of times over here.
Christopher Robert Loose (Chief Scientific Officer):
As you expect on that point, I guess, because this is locally delivered, the systemic concentrations of the drug are more than a thousand fold below pharmacological levels. So really you are just looking at a local exposure in the patient. And we know this is short course of therapy. Maybe up to one dose and maybe up to four doses we're exploring now, but it is not something that is chronically given to patients and both of those really help with the safety profile.
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Audience:
In the clinical trials you saw very rapid concepts(?) in two weeks. Is that surprising?
Christopher Robert Loose (Chief Scientific Officer):
The question is we saw reponse in about two weeks within our clinical work. That is very similar what we see preclinically. Over the course of a number of weeks, we see the responses there. When you look at regenerative species that's what's seen there. I think, what is important to keep in mind is here we have a hair cell that is gone missing and a progenitor nextdoor that need to divide one time. That is the extent of the biology that needs to happen. One division, a naturation and a reconnection. Hours of pushing this cells to get into this mode, to start the program. About weeks makes sense.
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Audience:
How does the treatment compare to an intratympanic injection of steroids? I guess that's probably standard care?
Dana Hilt (Chief Medical Officer):
So the question is how does this compare to intratympanic injections of steroids. Just to clarify steroids aren't really useful for people with hearing loss, but the physicians, the ENT physician of course give steroids hundreds of times. It is a very common procedure. This is really identical, it is pretty much the same sort of procedure that a physician, an ENT physician would use to do an intratympanic injection of steroids. I don't want to trivialise it, but it's an extremely straight-forward procedure.
Christopher Robert Loose (Chief Scientific Officer):
And I add briefly. Steroid can be used right after some kind insult to slow down some kind of inflammation, but obviously are not being used for restoration of hearing downstream. So, same procedure for applying the medicine, but very different population that we are looking at to get that restoration.
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