Q2 2022 Viridian Therapeutics Inc Earnings Call
Greetings and welcome to the Verde and Therapeutics Conference call. At this time, all participants are in a listen only mode.
A question and answer session will follow the formal presentation.
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As a reminder, this conference is being recorded I would now like to turn the call over to John Jordan, Vice President of Investor Relations. Thank you you may begin.
Thank you Daryl and good morning, everyone and welcome to the Verde Conference call to discuss the initial clinical data for V. R. D. N O one in patients with thyroid eye disease before we begin.
I would like to remind everyone that this conference call and webcast will contain forward looking statements about the company. These statements are subject to risks and uncertainties that could cause actual results to differ.
Please note that these forward looking statements reflect our opinions only as of today.
Except as required by law, we specifically disclaim any obligation to update or revise these forward looking statements in light of new information or future events factors that could cause actual results or outcomes to differ materially from those expressed in or implied by such forward looking statements are discussed in greater detail in our most recent filings.
On Form 10-K, and 10-Q and other reports on file with the SEC I would now like to turn the call over to Jonathan violin, President and Chief Executive Officer of Verde. Thanks, John and good morning, everyone. We're excited to share some remarkable data from our ongoing trial of <unk> hundred one for the treatment of <unk>.
The disease. The results are frankly outstanding and I'm pleased that we can now share our plans for accelerating Dr. Dan <unk> as quickly as possible to phase III with the aim of launching a new best in class intravenous therapy for thyroid eye disease.
We'll also share today, our first data for <unk> <unk> excellent.
Excellent results in this case paving the way for us to develop the best in class low volume subcutaneous product dosed every two or four weeks to launch shortly after our IV product.
We'll share our plans in a moment.
I'm joined today by Dr. Byrd Katz, our Chief Medical Officer, Christian humor, our Chief Financial Officer, and Chief Business Officer, and most gratefully, Dr. Ray Douglas Director of thyroid eye disease program at Cedars Sinai Hospital in Los Angeles, our lead in the U S and internationally recognized clinician scientist and arguably the world's foremost authority on test.
Let's get started and we have much to share with you.
I'll start with a brief overview of the findings and then hand, it over to Barrett and Dr. Douglas to review the data for <unk>, one in more detail after which I'll review some new mechanistic data that we think establishes the RDM below one is unique in its class and provides a clear scientific rationale supporting the impressive clinical efficacy data were reporting today.
I will also review the initial findings from our <unk> two program demonstrating the extended half life, we set out to achieve.
Then I'll provide an update on the acceleration of our 10 strategy based on today's results, including our phase III program for <unk>, one, which we've named thrive, which will be initiated before year end.
I'll also share our plans to develop a best in class subcutaneous therapy.
We now have increased confidence in based on today's data.
Next Christian will review, our second quarter financial results, then we'll open the call for Q&A, So let's dive in.
As you saw on our press release. This morning, we've just unblinded. The first 10 Meg per kg cohorts. After the last patient six week visit and we've seen profound and consistent signs of efficacy on all endpoints measured.
Far exceeding our initial expectations.
Keep in mind that this is after only two infusions of <unk>, one three weeks apart and assessing patients at week six eight.
83% of patients for overall responders, meaning they had at least a two minute millimeter change in proptosis or bulging of the eyes characteristic of Ted and a two point change or greater and clinical activity score cast a composite of Ted symptoms.
83% of patients, where proptosis responders with $2 four millimeter change in practices and the median time to response with just three weeks.
83% achieved maximal are near maximal reductions in cash to a score of zero or one and 75% of patients who've had double vision of baseline diplopia had complete resolution of that to Colombia.
Importantly, <unk> demonstrated all of this will show in a favorable initial safety and Tolerability profile with no reported serious adverse events no hyperglycemia no infusion reactions. This is honestly it's stunning.
And when we look at how Vod NOL, one data compared to potential phase III clinical data, which are higher responses on every single measure and the differences are subtle.
On every relevant endpoint and Ted.
Oh, one shows enhanced efficacy when compared against prior studies at the six week time point.
Doubling the rate the overall the rate of overall responsive to tether, which requires that patients respond on both proptosis in clinical activity score, meaning they improve on both the signs and symptoms of Ted.
83% Proptosis responder rate versus 56%.
Our larger mean change from baseline in Proptosis by half a millimeter.
Four times, the proportion of patients achieving a cast of zero or one with mean change from baseline cash a little more than double that of 2000.
And double the rate of patients with baseline <unk>, who have that diplopia completely resolved.
This isn't something we initially expected, but as you'll see in our presentation. Today recent preclinical evidence showed us that the <unk> has a differentiated mechanism of action.
We learned that the patent and other IGF one our antibodies we tested after only a partial antagonist that means that even a maximal exposures just has it leaves some residual IGF one our activity in contrast, and uniquely the Rd, one acts as a full antagonist and achieves a far more complete inhibition of Egfr I.
I will tell you more about that in a moment, we may have a uniquely powerful therapeutic and the <unk> one.
I'll now hand, the presentation over to our Chief Medical Officer, Barrett Cats, and neuro ophthalmologists with a deep understanding of and appreciation for thyroid eye disease.
Thank you John .
This study was designed to investigate whether V. R. D. N O. One can match the precedent for powerful efficacy and Ted IGF, one hour blockade, but also to enable our development program to advance quickly should we see positive results.
We enrolled patients with active Ted that the clinical activity score of four or higher and onset of Ted signs and symptoms within the preceding 12 months.
These criteria were intentionally similar is it to present phase III trials, so that we could compare our results to those.
Our study was randomized and double masked.
The data today are from our first cohort of eight Ted patients six of whom received 10 milligrams per kilogram of V. R. D. N O one two of whom who received placebo.
Rug was infused twice.
Sunday Zero, then again on day 21.
The key efficacy endpoints were measured on day 42 that is week six.
We are nearing completion and enrolling our second cohort, which is evaluating two infusions of 20 milligrams per kilogram V or the yen or we continue to remain mask for this cohort and plan to present data at a medical meeting in the fourth.
Quarter of this year.
<unk> has accelerated nicely as we continue to open more sites with the 20 milligram cohort enrolling over three times faster than the 10 milligram per kilogram cohort and we remain on track to deliver data from a third cohort evaluating <unk>.
Two infusions of three milligrams per kilogram in the fourth quarter of this year.
We've incorporated two additional cohorts to the proof of concept portion of this study those to evaluate to V or the yen or one in chronic Ted patients. We plan to begin enrolling this cohort in the fourth quarter of this year and expect to have data in.
In the first half of 'twenty three.
We also plan to incorporate chronic ted patients into our phase III thrive pivotal program as you shall see.
For today, we have a rich and compelling dataset from this first cohort and we will review safety and Tolerability as well as efficacy measures.
Yeah.
To review the data I'll turn the presentation over now to Dr. Raymond Douglas the director of the fire at eye disease program at Cedars Sinai and the key K O L. A thyroid eye disease.
Thank you very much Brent Barrett.
And let's start by reviewing the baseline patient characteristics.
They were quite similar to the dependent phase II and phase III clinical trials with similar levels of baseline proptosis clinical activity score or Cas and rates of diplopia.
Overall, the populations had very similar disease severity.
Time since diagnosis with slightly longer in this study, which is surprising since patients were eligible for the study if their symptoms started no more than 12 months ago.
Age and sex characteristics were also similar.
So overall these are very similar populations and this gives us a good basis for contextualize Ing. The study results within the field, So let's turn to those data now.
Let's start with overall response this is the most stringent assessment of efficacy.
<unk>, both signs and symptoms of T E D and.
An overall responder is defined as a patient who has at least a two millimeter reduction from baseline proptosis and at least a two point change in clinical activity score or Cas.
Now remember Proptosis is the key sign of T E D and was measured in standard fashion with the hotel exophthalmos.
Clinical activity score or Cas is a composite of the presence or absence of seven signs and symptoms characteristics of characteristic of T E D.
As you can see 83% of patients where overall responders five out of six patients while none of the placebo patients exhibited a response.
Data for phase two and phase III trials has a demonstrated overall response rates of 46 and 44% respectively.
Turning now to Proptosis.
As shown on the left there was a 2.4 millimeter change from baseline in Proptosis and the V. R. D N O one group.
In the placebo group, one patient had no change in Proptosis the other placebo patient did.
Which happens about 10% of the time.
Interestingly this placebo patients did not show any improvement on cash and did not report feeling better.
Now turning to the V. R E N O one treated group, which was larger with six patients on the right you can see the patients treated with the Ardian Oh, one experienced significant proptosis response, consistent with this exophthalmos their data.
Morai confirmed Proptosis response in the V Gard yen over one group when available.
Of note. The response in the placebo patient was not confirmed by MRI and in fact slightly worsened by this measure.
83% of treated patients five or six patients had a reduction in proptosis by at least two millimeters 60.
67% had at least two and a half millimeter reduction and half of the patients had a reduction of at least three millimeters.
To put the V. R. D N O one effect on Proptosis in context. So we can compare it to the mean change from baseline Proptosis, where it depends at week six in phase two and phase III, which was one eight and $1 nine millimeters versus 2.4 millimeters for VR again.
Oh one.
Proptosis responder rate defined as the percentage of patients who had at least a two millimeter change from baseline in Proptosis is shown on the right at week six.
83% of patients who received we are again Oh one.
Where proptosis responders at week, six compared to 50, 556%, where it depends at week six.
Let's turn now to clinical activity score or Cas, which is remember a composite scale of assessments of patients experience pain redness and swelling here, we see a 4.3 point change from baseline cash after the ARD yen or one treat.
Hi, Bob.
Far exceeding the placebo response of 1.5, which is similar to the placebo responses 1.1, and the two point in the two trials.
Given a rapid and sizable change in cats.
It's surprising to observe many patients with near total reduction in inflammatory signs and symptoms defined as achieving a cast of zero or one.
<unk> 83 per cent of V. R. D N O on patients met those criteria, while no placebo patients did.
Likewise, two thirds of patients had a five point or a higher reduction in Cas from baseline after the Ardian O one treatment, whereas no placebo patient achieved a four or five point change.
The reduction in cask compared with deposit at the same time point as shown here.
The mean change in past score for V already an old one treatment at the six week time point was robust.
The percentage of patients who achieved a maximal or near maximum therapeutic effect at six weeks was also very robust and shown in comparison to that observed for deposits in phase two and phase III trials.
Keep in mind that the cat seven components scale sport for presence or absence of seven different queries, a pain redness and swelling.
The data tells us that patients are experiencing improvement in a majority of their symptoms and in many cases cases resolution of those symptoms.
The last key efficacy measure I have to share today, diplopia or double vision, which is one of the most disruptive and distressing aspects of Ted to patients.
And now I guess it depends the trial is about two thirds of patients had appropriate at baseline.
And for those that do the most relevant and stringent endpoint is resolution the complete alleviation of double vision.
And the four patients who had baseline diplopia. The average score was two now this is based upon a three point Gorman subjective scale. So this is a rather severe diplopia.
Following BRD and old one treatment, 75% of patients with baseline to poke their experienced complete resolution.
Once again, you wrap it in very meaningful effect for these patients.
The VR, Dan Oh, one data compare favorably to it depends that the same six week time point.
So to summarize we've presented data in six treated patients and two placebo patients demonstrating a positive response for the guardian or want an overall response.
How was this response proptosis reduction cash.
Cash change and cast improving to zero or one and diplopia resolution.
This preliminary data is consistent and compelling which is very encouraging for Ted patients around the world.
Now, let's review safety and Tolerability, there were no reports of hyperglycemia or infusion reactions. Some of the known on target IGF. One off effects were observed we saw two cases of muscle spasm, both mild and did not require intervention.
Also a single case of hearing changes.
Our next visit the AE had resolved hearing was normal by audiogram and she completed this treatment study course.
I will now turn the presentation over to John .
Thank you Dr. Douglas both for your review of the data and your participation in this trial.
I'd like to start by showing the slide again to reemphasize, what we've seen with <unk>.
For every relevant measure and in particular for the more stringent measures. We're consistently across the board seen increased efficacy for Vod and over one versus what was observed for capella.
We believe there is a solid mechanistic rationale for why <unk> may be able to drive deeper and more rapid responses and Ted patients and we'd like to share some of that data with you today.
We've previously shown that <unk>, one binds to the same region of the IGF one of ours.
And that the binding epitopes overlap.
We sought to explore this in more detail because we're a drug binds is only part of the story how it binds matters too.
And we've learned from some of our recent preclinical research that Vod N O L. One is distinct and how it binds and how fully it can inhibit IGF one a function.
The left hand side of this slide illustrates a set of preclinical experiments that the viridian research team undertook to identify which IGF, one our demand and which specific assets are required for binding to a panel and IGF oner antibodies.
Our D N O alone to pause AR and VR DNO to which we'll talk about more in a minute all rely on the same extracellular domains for binding receptor as we expected based on our prior epitope characterization.
Whatsoever, and we argue Oh two are sensitive to changes in the same amino acids, suggesting they bind very similarly, we were surprised to learn that <unk>. One is not sensitive to these same amino acid changes and thus is binding to the same epitope, but differently.
Contrast, these antibodies too long to get them out, which binds to a different unrelated epitope than <unk> to <unk> and are sensitive to different domain divisions as well as different amino acid mutations.
Our research teams has also recently evaluated each of these antibodies and assays measuring IGF, one arm function to understand how changes in binding might affect activity.
The data on the right shows the D. R. D N O L. One fully blocks IGF, one our function and there's a full antagonist of the receptor in contrast to the already on O two and a lot of Judah matter all partial antagonist, each with varying magnitudes of antagonism even at maximal clinical exposures due to antibodies may not fully inhibit IGF one hour.
Function.
We saw very similar responses in other assays.
This suggests that the ardian over one is better at suppressing IGF, one receptor activity than other antibodies and the unique nature of Vod and over one full antagonist may explain the dramatic IGF one increases in healthy volunteers, we presented in May.
It may also explain the rapid and profound clinical improvement seen in Ted patients.
I'd like to point out one more feature of today's the Ardian over one proof of concept data.
Hello, one responses occurred remarkably quickly and suggest faster onset them together on.
On the left is the onset measure used in the phase III trial median time to Proptosis response, which for <unk> was a little over six weeks and for <unk>. It was just three weeks.
On the right is the onset measure used in the test phase II trial meantime to overall response, which as a reminder represents improvement on both Proptosis and cast.
<unk> was $11 two weeks and for Vod and over one just for eight weeks.
These findings are consistent with a higher magnitude of efficacy, we just discussed at week six.
And of course, the faster response to something patients and welcome.
This is something the company has incorporated into its phase III plans by evaluating both a standard eight infusion treatment course like deposit and a shorter five infusion 12 week treatment course, which can be a lot easier for patients.
We now have a clear opportunity to differentiate the Rd. One from together, we believe we have an opportunity to offer patients a shorter course of treatment.
We offer them faster symptom relief and possibly greater efficacy as well as an attractive safety profile.
We already know that the last two infusions of the peso offer little additional efficacy as shown in the left hand panel of the slide.
We just presented data, suggesting BRD and O O one delivers faster more profound efficacy.
Our phase III program will build on these findings.
The program consists of two pivotal efficacy studies thrive and active Ted and thrive too and chronic Ted they will readout in mid year 2024, and by year end 2024, respectively.
Each of these randomized placebo controlled trials will have three arms with 40 patients in each arm as illustrated here in.
And eight infusion regimen Nash into pads are.
A shorter five infusion regimen, which would allow patients to complete their treatment course in just three months, 43% faster than professor NFL.
And a placebo arm.
To further improve the treatment regimen, we plan to use a shorter 30 minute infusion time instead of the 60 to 90 minute deposit infusion.
We'll come back to a detailed review of our phase III program in a moment, but before we do I'd like to share our first clinical data for <unk> two.
Yes.
As some of you may recall.
Again, <unk> a distinct antibody from <unk> designed to recapitulate, the pharmacology to Tesla, but incorporating half life extension to dramatically improved pharmacokinetics and enable lower less frequent dosing.
Shown in the left panel, we've known for some time that the <unk> have very similar PK in non human primates would have lots of about six days and that BRD I know two showed a double ended up half life and head to head non human Primate study.
I decided at the bottom of the slide we also know that in six different oncology trials temperature on that I'm sure. The half life of around 10 to 11 days comparable to VR Genoa. One let's also showed a half life of around 10 to 11 days in oncology trials.
In the Middle panel you can see the <unk> PK in healthy volunteers, we observed a 12 day half life for <unk> similar to the pecan oncology patients today.
Today in the right panel, which is share initial data for <unk> in healthy volunteers. After a single IV dose and it shows a preliminary halfway between 30 and 40 days, which is better than we expected about triple the half life of <unk>.
The safety profile for <unk> has also been favorable to date with no serious adverse events no hearing impairment no hyperglycemia, no muscles, thousands or infusion reactions reported as of the last subject last visit.
We also have today plasma IGF one levels. This is a biomarker for systemic target engagement.
<unk> is blocked plasma levels of IGF, one increased by homeostatic mechanism.
This next plasma IGF, one levels and an excellent pharmacodynamic measure of IGF, one receptor antagonism the more of the receptor is blocked the higher IGF one levels should go.
To present data from an oncology study are shown on the left to further treatment resulted in a two and a half fold elevation and plasma IGF one shown out to day seven.
The middle panel shows IGF one levels after single doses of <unk>, two we see a sustained increase in about two and a half fall similar to the further but staying elevated throughout the 84 day study period, even at the lowest dose a single three Meg per kg infusion.
The similar magnitude of IGF, one increase aligns with the preclinical data, we just discussed the <unk> to closely mimic the effects. It has on IGF, one arm, but was more than threefold longer half life, and therefore duration of action.
Based on internal modeling by our research team Dr. Tien <unk> to support a low volume subcutaneous injection of 300 milligrams either every two weeks or every four weeks.
Peter schedule was supported very strong commercial profile comparable to some of the best selling subcutaneous antibodies such as regeneron depictions.
We plan to evaluate 300 milligrams of <unk> and two millimeters as every two week or every four week dosing and a proof of concept study, which will initiate by year end and we expect to have topline data in the second half of next year.
So let me sum up the lessons we've learned from today's data.
First the <unk> delivers rapid and profound improvements in signs and symptoms of Ted with all efficacy endpoints, surpassing prior to pezza studies, often by twofold or more.
Second the <unk> produces more complete IGF oner inhibition via unique receptor interaction, providing a mechanistic rationale for the remarkable clinical observations we presented.
Thirdly, the ardian over one continues to be well tolerated with a strong safety profile.
Fourth the IGN O two top life extension provides a longer than expected extended activity in humans tripling the half life or first generation IGF, one our antibodies and its PK PD profile paved the way for a proof of concept study of 200 mils of two milliliters containing 300 milligrams subcutaneous injection.
Either every two weeks or every four weeks.
So with these lessons in mind I'd like to share our strategy and Chad our next steps in our development programs.
Chip has launched two years ago, and we'll sell about $2 billion in the U S. This year almost entirely to newly diagnosed patients and.
And peak sales are estimated to be $3 5 billion not including the EU.
There are only so many markets or the size and biotech $2 billion in annual sales growing and not yet, including chronic patients, which at present is restricted or any ex U S patients.
Recall this is not a switch market, where you have to attempt to take a patient off of another therapy. This is a new start only market every single year 20 to 25000 patients in the U S. We'll choose the best product to treat the thyroid eye disease every year think about that.
Exceedingly rare to have a new start market. This big more new patients to the best therapy for themselves each year.
In light of this unique opportunity and the compelling initial clinical profile for Vod on over one presented today, we are accelerating our plans. So the most ted patients can choose one of iridium therapies.
Beyond this established portion of the market there are another 75000 or more patients in the U S with chronic <unk>, who represent the major upsides at this market opportunity because there isn't yet randomized control trial data supporting access and uptake for this population.
Importantly, there is a similar picture in the EU and U K, where there are 35% to 40000 patients diagnosed each year and we estimate more than 150000 chronic patients and no approved therapies.
We're designing our phase III program to support a marketing authorization application for the first approval of <unk> therapy in Europe , which we anticipate to significantly expand our revenue opportunity.
The endpoints or other cash or overall response, where you've seen some differentiating data from us today.
Our Java unable to approaches to satisfy an unmet need and the Ted market, which we're now committing to as corporate objectives.
Our first goal is to sprint to market in the U S and the EU with a best in class IV product in Vod and over one using the trial design, we mentioned a moment ago. We just told you about this large incidents market and new start market and we think we have an advantage.
Our second parallel corporate goal is to develop and launch a durable best in class subcutaneous therapy.
So, let's look a bit closer at a development plans for Vod and over one the thrive program here.
Here are some key features.
As the global registration program will generate robust evidenced in both active and chronic Ted on the Registrational program is designed to enable approval in the U S. The EU and other major and emerging markets.
We have a number of potential improvements over to Panther and accelerated 12 week five infusion course of therapy, 43% shorter and.
Shorter infusion times 30 minutes Vod NOL, one versus 60 to 90 minutes for <unk>.
And as you've seen today, the potential for faster onset and higher efficacy.
And we're in a strong position to execute on rapid timeline to enter this large market.
Our phase III program will initiate by the end of this year, we already have 17 sites active with 30 expected by the end of the year expanding beyond 50 in the first half of next year.
We expect the phase III active Ted data by the middle of 2024 and phase III chronic test data by year end 2024.
In summary, we're designing a development program that we hope will deliver a vod and over one product profile, a superior efficacy faster time to symptom improvement fewer treatment visits and shorter administration time with a highly attractive safety profile. We think these attributes some to a highly differentiated and valuable product profile.
Now, let's turn to our second parallel corporate objective launching the desktop <unk> low volume subcutaneous Ted therapy as rapidly as possible.
Key to this approach is half life extension something no. Other company currently has in development for an IGF one our antibody.
As we just shared the <unk> epitope binding and in vitro profile are very similar to discover the key difference is that O to achieve triple the half life or first generation IGF one our antibodies, we have 30 to 40 days.
We know we have in hand, a compelling profile 300 milligrams and two mills dosed every other week, maybe even every four weeks.
In addition to Vod on O. Two we now have a second opportunity to deliver on our subcutaneous goals.
<unk>, three which is the half life extended version of the <unk> one it retains the unique <unk> binding and antagonist properties, while incorporating the same half life extension technology as the Iridium <unk>.
Based on nonhuman primate data, we expect over three to match VR DNO to PK.
This program isn't new we'd had a three in our corporate presentation for a long time today. We're accelerating this program now that we've seen the Vod and over one Ted proof of concept data.
We're well into IND, enabling studies and expect to file an IND in the second quarter 'twenty three with phase III, enabling healthy volunteer PK PD data in the fourth quarter of 'twenty three.
We'll launch our subcutaneous product with a patient friendly prefilled pen at a minimum something like regeneron to picks up which is two miles 300 milligrams every other week.
Got a lot of confidence in achieving this profile, but we may be able to go further up.
<unk> efficacy data for three weeks per keg, Vod and over one will inform and every four week or longer profile for both the <unk> and the <unk> three.
Overall this approach gives us two shots on goal for our best in class subcutaneous Ted product.
Clinical data in the second half of 'twenty, three will tell us which of the already I know two or three it's best to move forward to phase III, which will be ready to start early in 2024.
We think this puts us in a very strong position to make good data driven decisions to select the best possible molecule well advancing multiple options.
This ensures we have the best in class products to launch as soon as possible after our IV <unk> product launch.
I'd like to close by summarizing wherever readiness headed next on the basis of today's very strong data. We now have plans that advance our mission to deliver better options to patients suffering from Ted and other serious diseases. We have an incredible news flow over the next few years, representing major milestones for the company.
We're excited to execute on these plans and I'd like to thank everyone has contributed to what you've heard today the patients who volunteered for ret trials investigators in our trials, particularly Dr. Douglas for his leadership and the Ted field as productive partnership and for joining us today.
And the Meridian team for all the hard work that driven the progress you've heard today.
Before I open the call for questions Christian who will review our financials.
Thank you John and good morning, everyone.
I'd like to give a brief summary of the Q2 earnings.
Cash cash equivalents and short term investments were 161 million as of June 30th 2022, compared with $197 million as of December 31st 2021.
We believe that our current cash balance in addition to our 75 million credit facility will be sufficient to fund our operations into 2024.
During the second quarter of 2022, we entered into a debt financing agreement with Hercules capital for up to $75 million.
Under the terms of the agreement we drew an initial $5 million at closing.
As of August 12, 2022, Meridian had approximately 43 million shares of common stock outstanding and on an as converted basis, which included 28 million shares of common stock outstanding and an aggregate of approximately 14 million shares of common stock issuable upon the conversion of 194000 and <unk>.
<unk> 3000 shares of series, a and series B preferred stock respectively.
Please refer to our earnings press release for a more detailed Q2 financial update.
With that we can open the call up for Q&A. Thank you.
Thank you we will now be conducting a question and answer session. We would like to ask a question. Please press star one on your telephone keypad.
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Okay.
Our first questions come from the line of Chris Howerton with Jefferies. Please proceed with your questions.
Yeah.
Great. Thank you so much for taking the questions and a hearty congratulations on an excellent data. So I think maybe just two questions from me and then I'll hop back in the queue. So first I know that there was obviously most of the profile extremely clean, but there has been some concerns around hearing loss.
So just curious if you have any more thoughts on that observation and how if anything youre doing to monitor that further and then the second question that I have I think is just more of a clarification in terms of the strategy. So.
So for the subcutaneous formulation.
What information specifically or are you waiting for it and I guess I'd like to make the final decision to move forward. It sounds like it'll be Oh, two information the three big Oh, one IV formulation and then I guess, Jonathan just the little tack on all that on there is are you considering a three meg.
King.
Subcutaneous over one dose group at this point thank you.
Great. Thank you Chris.
Get the questions why don't we start with the adverse events question I'll ask Barry to comment on our observations and maybe Dr. Douglas can provide some additional color and then I'll answer the other two questions.
Thank you for your question I think you've heard Dr. Douglas speak to the safety profile, which really is very strong very tolerable. We did have one patient who described a ringing in their ears and this was transiently are resolved very quickly over a week or so the audio metric analysis of this patients shorten dawn.
Audio metric function at the resolution of this and we believe it is something that we see in clinical practice and does not so terribly uncommon.
And Dr. Douglas, maybe you'd like to provide your views on the hearing loss is.
Yeah.
You know reiterate what Barry said it was you know.
Tomatoes, and typically we've seen those and other ige molecule or molecules to have resolution.
And as Bert also mentioned patients being followed by Audi metric analysis, and I think that that's a very important as we move forward, making sure that we are actually following patients and clarifying our both the pipe and you know potential issues associated with hearing but as noted this did result.
Then I'll answer the question on the subcutaneous strategy.
So the question is what more information do we need the short answer is nothing we already know with VR DNO too that we have that depicts him like profile in hand.
The reason that we're advancing O two and over three in parallel is that we'll owe two seems to really do everything we hoped it would if it matches the deposit profile pharmacologically in every way we've measured it has a phenomenal increased half life. So it gets us to a compelling subcutaneous product profile.
We've learned recently is that over one <unk>.
He has to have a unique and potentially superior pharmacologic profile. So why not take the opportunity to combine the benefits of alon and the benefits of O two and what we're now calling <unk> three.
And because we now know so much about.
The PK and PD of these molecules. We can move these two programs forward in parallel so that by the second half of next year, we will have our subcutaneous proof of concept data for <unk> two.
We'll have a healthy volunteer PK PD for <unk>, III, which is effectively proof of concept again, given everything we know about or one.
And on the basis of that data, we can choose whichever molecule looks best and we're running the programs in a way that we can then start phase III early in 2024. So we really like this strategy. We think it allows us to make data driven decisions on the basis of clinical results.
And then finally you'd asked about that.
Would we consider I actually missed the question about the three minute per cow, it's really not that important I guess I was just like is there any scenario, where a oh one subcutaneous formulation makes sense I guess is the real crystallized question Oh.
Oh I think so you were asking about the upcoming <unk> for kicked out a four <unk>. So so that's gonna be informative in a number of ways.
First we already with high conviction no that we can achieve in every other week sub Q <unk> three if we see that lower doses of <unk> one deliver a similar benefit then that puts every four weeks very much not just on the table, but it would give us confidence in that profile may be even longer.
So that's kind of the key value that we'll get from the three Meg per kg cohort coming up but you're right. There. There is of course still the potential Oh, one itself could achieve sub Q, but honestly with the with.
With the outperformance of half life extension that we saw today, we really think that O two and three our best bet to achieve it's very difficult to beat commercial profile.
Yeah.
I tend to agree and thanks again for just the taking the questions and an excellent David said congratulations.
Thank you.
Thank you our next questions come from the line of Thomas Smith with <unk> Securities. Please proceed with your questions.
Hey, guys. Good morning, Thanks for taking the questions and let me add my congrats on a really strong data early data here.
Just I guess first of all on to follow up on the safety.
With respect to the muscle spasm and hearing impairment can you just kind of remind us of the time course of when these aes are typically seen with the peso treatment and then.
I know, it's not explicitly on the AE slide but can you confirm that there haven't been any cases of hypertension scene in the Ted patient cohorts to date.
Great. Thanks, Tom.
Barrett why don't you.
Address the muscle spasm question and then the the time course of adverse events.
Apparently the mud.
So spasms are common in real life situations in fact, as a way to mitigate them by giving volume in magnesium Dr. Douglas has shown that and shared it with the rest of us they can occur at any time. They occur early the hearing loss is something we thought occurred later, but that is an experienced says.
Increased with success, we recognize that the hearing loss can occur at any time and the truth of the matter seems to be that that hearing impairment is usually reversible. The interesting thing as you talk to these patients and even the ones that complain of hearing impairment, they say Oh gosh I want the drug I'd much rather go.
Death, and change what I'm, having done to me because the efficacy are so strong and that's been our experience as well so far.
Maybe Dr. Douglas can comment a little further.
Yeah. So the hearing impairment occurs in a one or two forms typically tinnitus or plugging of the years and that appears to be 100% reversible typically can occur mid treatment. During this course of therapy, and then resolved either during or after therapy.
And then some notice of audio metric and high frequency hearing impairments.
Impairments are not loss completely but just impairments.
And we're still waiting to see how it goes and its much smaller segment of patients and see if those are also reversible they muscle spasms typically occur and early in the early in the treatment of course, and again are more of a nuisance than anything else typically have not impaired continuation of treatment in.
Asberry suggested can be highly reversible.
Great and maybe so I can then address the adverse event question on hypertension. So.
For <unk> first.
There were only three adverse events or <unk> that were deemed related to treatment. There was a mild transient dizziness.
There was one case of asymptomatic hypertension that resolve the same day without treatment and one case of asymptomatic hypertension resolve the same day without treatment. These are these are.
Just the kinds of things you observed in our phase one study.
And then with respect to <unk>.
Oh one.
There's nothing that we've seen in 10 patients with respect to blood pressure.
Okay, Great. That's super helpful context, Thanks, and then.
So a couple of questions on the phase III plans and then we'll hop back in the queue here, but just can you talk about the need for FDA engagement to confirm how you're thinking about the thrive program and then can you also elaborate a little bit on how you're thinking about enrollment here, specifically with respect to how.
How youre thinking about patient targeting relative to peers.
And some of the other companies who are contemplating 10 pivotal studies.
Specifically gives you confidence in meeting the enrollment timelines, you've laid out and I guess any any early thoughts on the costs anticipated cost of the phase III program.
Okay, great Yeah. Thanks, Tom So first the regulatory question. So we'll formally meet with the FDA later this year, but based on conversations to date, we think our plan will actually exceed what the FDA needs keep in mind that horizon had two studies with a narrow population and only ever studied one dose for approval.
We have a lot more than that right will have acute patients chronic patients. We're studying two different courses of treatment rate different total cumulative dose.
And we've also done some dose ranging.
So we think we're going to have a very very strong package.
And in that first study the study is very much following the precedent.
To put a set so we really don't see a lot of risk here.
And then with respect to enrollment.
<unk> thrive study the active disease phase III is leveraging the flexibility that we built into the current studies, so where we're adding cohorts directed to be registrational using sites. We already have opened we already have 17 sites open we're expanding that quickly.
We've been in the U S and Canada for Phase III, we've long planned to go broader than that will be in the U K and Europe will have 30 sites open by year end.
So this this is a very robust plan to enroll patients.
Interestingly.
We've seen one sites are open we are enrolling at the rate that we had projected.
And that was before we had any clinical data with today's data as you can imagine how excited we are about this data, we think that thats going to be shared by the investigator community as well.
So where we're actually really confident this can move forward quite briskly.
Yeah.
Okay, Great and then just any early thoughts on how you think about cost for the Registrational program.
Yeah, I'm not going to go to details of cost.
But as Christian said, we're very well capitalized and we know we need to do and are poised to execute.
Excellent alright, guys. Thanks for taking the questions I appreciate it congrats again on the data.
Thanks, Tom.
Thank you. Our next question is coming from the lineup Gavin Clark Gartner with Evercore ISI. Please proceed with your questions.
Hey, good morning, Congrats on the great data and thanks for taking the questions. Just had a couple first off on the 20 Meg per kg Oh, one safety data, but you're still blinded to meet those who have been given.
So we are nearly done enrolling.
So.
I guess the answer is most but I don't have the exact number before me.
But the safety data it was as of August 9th So a recent safety read for that cut off and as you saw.
Promising so far.
Data collection is ongoing.
We're pleased that we're not seeing any hyperglycemia, no hearing impairment and muscle spasms, no infusion reactions and of course, no SAE, so really going well so far.
Yeah got it and then do you plan to pursue any studies showing the benefit of re treatment median responders, who have kind of a relapsed a months or years later.
Yeah. The retreat. My question is a really interesting one.
Well not for the <unk>.
First things first for US right. We think we have some really exciting plans to deliver a differentiated product profile I do think the re treatment question is important.
It will take some time to answer it also reflects the state of the field right. This is this is a young and rapidly evolving field of clinical science and we're excited to participate in advancing our knowledge. So so questions like this I think we will.
We'd love to be a leader in figuring out how best to treat patients and build up our commercial product profile as we do so.
Yeah got it and just a last one for me how are you thinking about the pricing.
Given that it could have been.
And then of course, a three minute instead of eight with the peso.
Yeah. So the way the way, we think about our product and its way too early in the pricing, but generally.
We're focused on what value, we can deliver to the market and I mean, you've seen the clinical data you've seen our plans to deliver something that can be highly differentiated in and add a lot of value above and beyond what what exists now so.
We think this will this will be really exciting for us.
And we're focused on delivering that value.
Yeah.
Yeah, No that's really helpful. Congrats again.
Thanks, Jeff.
Thank you. Our next question is coming from the lineup.
Rami cap cuda with lifestyle capital. Please proceed with your questions.
Hey, guys congrats on the data and thanks for taking my questions as well.
Doctor Douglas touched upon this briefly but can you talk to the differences between MRI and hurtful excellence monitor measurements when looking at Proptosis in these patients and how did these measurements kind of compare for the patient in the placebo arm that had the a two millimeter reduction in proptosis as long as those treated with tier one.
Sure why don't I start and then maybe maybe Barrett and Dr. Douglas can comment further.
So the hotel X Ophthalmometer, obviously is a validated measurement where it works great.
We've been very pleased with it but we do know that in a very small sample size like two placebo patients you do sometimes see a patient with a change despite having no active drug onboard so the interest in MRI, but this is an objective measurement right. It doesn't require the kind of device and manual reading of the hotel.
Except the monitor.
We do not have all the data for MRI measurements, but we take these images and then analyze the changes pre and post treatment to get an objective measure of how much the proptosis has changed.
We have.
For patients with MRI measurement pre and post treatments. So at baseline at week six the who receive drug so those for patients who receive drug in every case the.
Millimeter change by Opex up a monitor will slightly exceeded by MRI. So the mris reporting slightly bigger change in Proptosis, a bigger reduction Proptosis and then as you heard that placebo patients.
Where we saw a minus two so two millimeter improvement by the X up a monitor.
Proptosis worsened by five eight millimeters by MRI. So it just underscores why it's so nice to have multiple measurements of the same thing and when we when we think broadly when we think holistically about our data. It's just an incredible consistency in the at the direction and magnitude of response that we are out.
Performing.
Both to pair this phase II and phase III trials across the board and we think the mris as an important piece of that and we'll be excited to have the full datasets in the future.
Bear.
<unk> anything to add if you think about the measurement of Proptosis as we use the excess salometer, we're having the site investigator in each of the sites do that measurement.
Power of the MRI scan or a C. T scan for that matter is that the scan is done with the same section at each site and then sent to a central reading center in Red and a masked fashion. So you have one center reading the entirety of the dataset for these orbital scans and in fact, it should be more.
And what we're seeing interestingly enough is the X ophthalmometer underestimate the Proptosis response of Archrock. The MRI measurements in the CTC measurement trend to suggest that the Proptosis improvement with these superior results are in fact underestimated on except for monitoring.
Okay.
Got it makes sense and then really quickly just to confirm a point you made in the presentation is the more complete antagonism of IGF, one or with your one reason why we saw more robust PD effect and increases in IGF, one levels in healthy volunteers person to person.
Yeah. So.
Obviously, the pathophysiology is not totally understood here, but we can start to connect the dots right. So.
We have a couple of partial antagonists enter pezza VR DNO too they increase IGF, one way about two and a half fold and we know that it has a clinical efficacy results.
One we've got more full antagonism and multiple different in vitro systems.
And then in terms of IGF, one we see almost twice as high in IGF, one increase right a six fold or so increase in plasma IGF, one levels compared to two and a half fold for Japan and then you saw the clinical results right.
The outperformance compared to prior to present that on all these different measurements. So I'm starting to look like a pretty nice correlation.
That we hope to build on and again I think highlights that with <unk>, we might have something truly special on rins.
Okay.
Awesome. Thanks, so much guys and congrats again.
Thanks Rami.
Thank you. Our next question will come from the line of Laura Chico with Wedbush Securities. Please proceed with your questions.
Hi, Good morning, I actually have one or two for Dr. Douglas first Dr. Douglas.
Curious in light of this data could you just remind us in practice with you Ted patients today, how are you evaluating Proptosis response, and do you actually incorporate MRI data and assessing that and also could you speak to kind of defining disease severity in practice are you using primarily Cas scores or.
Or how are you categorized when patients had moderate severe.
And then I will follow that thanks, Laura. Please go ahead Dr. Douglas.
Great. Thanks, so much so in practice.
I think one thing to bear in mind is in practice, it's always a balance between what is practical and what is most robust so impacted us excellent parameter data, but when I treat patients either with surgery, where it depends on I, usually use before and after.
Or scan of some type typically either MRI or C. T scan kind of like the difference between.
You know a very crude point diagram versus and then an entire painting the MRI and <unk> can give you an entire painting of what that looks like in a very objective manner. So I'm very excited about the MRI data and they do it and you know to answer your question very directly do use it as a supplement to.
Exophthalmos tree measurements with hotel.
In regards to severity severity is actually.
Defined as a as the amount of disease burden.
For patients that I use when thinking about treatment for.
Right.
For patients and so for example, if a patient has profound.
Proptosis above normal when it's typically three millimeters or more.
And disease that either is active or as is Korea, I will often opt for dependent therapy and IGF one on therapy, because what we've seen over our data and we have published them both.
Disney and chronic patients is that they have there.
Magic improvement of their proptosis and their disease, so severe for me.
In guiding my therapeutic use deposits as far as them based upon their disease burden and moderate to severe yourself and three millimeters or more that's was.
It is.
It was a criteria for their disease burden.
Okay. That's helpful and then maybe for the Meridian team.
Could you remind us you briefly touch on the ex U S market and seeking patients outside the U S. Can you remind us on how you're planning to approach.
Actually the nation ex U S. I guess in light of the data you're seeing would this be a market that you can commercialize on your home.
Yes, it's too early to really go into details on our commercial strategy.
Obviously, we're thinking about that but for February for competitive reasons, just don't want to get into it yet.
Congratulations on the data.
Thanks, Laura.
Thank you our next questions come from the line of Calvert puts out with B Riley Securities. Please proceed with your questions.
Yeah, Hey, good morning, Congrats on the data and thanks for taking the question maybe.
Maybe just a quick one for Dr. Douglas and I think you've touched on this a little bit, but how common is it to get greater than three millimeters.
A proptosis reduction in the real world with Televisa.
Yeah. Thanks, Scott Yeah, Dr. Douglas we've got.
Yeah. So you know I think one thing that we've observed with depends on it really speaks to Iga for therapies in general is that what we've seen in the clinical trials is translated exceptionally well to real world experience.
My real World experience.
And we just published a large reviews.
That were achieving on means much greater than three millimeters reduction in proptosis and the majority of patients. So it depends on the disease burden you know when patients present, but what you're seeing I think from the clinical trials.
Optionally Wow, two real world experience.
Thank you Dr. Douglas, maybe I'll, just add to remind everyone that the changes. We're seeing are just two infusions at week six right and it depends of course of treatment eight infusions over 24 weeks. So.
When we think about magnitude effect, where we're looking very early on in the course of treatments just want to make sure everyone keep that in mind.
Yeah.
Okay, and then and then a couple of questions on the design of the Registrational Studies I guess, what went into the decision making for.
Selecting five doses of all one versus maybe four or six for for one of the cohorts.
Sure Yeah, well, we already knew based on the deposit data that the last two infusions of seven and eight are not delivering much of any additional benefit.
And then given the data we've seen today right the speed of onset the magnitude of efficacy, what we know about the PK and PD of the drug.
We landed on five of the sweet spot. So we really like this regimen.
We think that a three month course of treatment is going to be truly compelling for patients.
Okay, and John just to be clear here.
Can you confirm that that's right. Two study will only include that 10 milligram per kilogram dose and results for the other three and 20 milligram per kilogram doses, what will not necessarily inform the design of that trial.
So we're moving forward with 10 megs per keg and the thrive programmed.
We think the data is outstanding.
<unk> have a 50% reduction from the peso dose.
And by testing, both the five infusion and eat infusion.
<unk>, we're still testing two different cumulative doses, where the upside of this dramatically shorter treatment period. So we think this is a really great place to be.
Okay. Thanks, so much for taking the questions.
Thank you.
I just want to point out we are running a little short on time. So we'll try to keep our answers brief and maybe we could ask for just one question from.
However, still in the queue.
Yeah.
Thank you. Our next question comes from the line of Jason Butler with JMP Securities. Please proceed with your question.
Hi, Thanks for taking the question, let me add my congrats I'll keep it brief just on the chronic trial.
Give us some initial thoughts on how you think about patient baseline characteristics here compared to the B acute treatment population and then on a I guess a follow up to that re treatment question would you allow patients who had previously been treated with two pads are into the chronic trial.
Thanks, Jason So the chronic study is we're using 15 months since diagnosis as the cutoff between active and chronic so that means that the thrive program in total will enroll patients regardless of how long ago their symptoms began.
The chronic study we will allow any task score to enter now chronic patients didn't have lower Cas scores. So we expect that population to have lower costs, but it will be quite a broad population.
We will not allow a prior treatment with IGF one.
Jeff one our therapy in this study.
So it'll be naive to idea from ours.
Great. Thanks.
Thank you. Our next question comes from the line of Trevor already with Oppenheimer. Please proceed with your questions.
Hey, guys. Good morning, and my congrats as well so yeah, just real quick for me was mirrored in our one being a full antagonist any thoughts on why you've also shown an apparent safety profile seen thus far.
Yeah, well so what we're learning is that the biology has some subtleties to it right.
What we can say is that between the Ted patients and healthy volunteers.
Expose more than 20.
People too.
One of these doses, even higher doses with 20 minutes per kg in the safety profile looks great.
So we think we're in a really good position.
Yeah.
Alright, thanks, guys.
Thank you. Our next question comes from the line of Michael Higgins with Ladenburg Thalmann. Please proceed with your question.
Thanks, Good morning, guys. Congrats from me as well two world class results.
Question for you on the use of methotrexate in these phase one or before the BLA filing do you have any comments to that you used to do two things.
Thanks, Michael Barrett go ahead. Please we do have inclusion criteria that disallow for any recent such intervention. So it's not part of our plan to change that going forward.
Yeah.
Yeah.
Okay.
Okay.
Okay.
Thank you there are no further questions at this time I would now like to turn the call back over to Jonathan violin for any closing comments.
Great. Thank you everyone and thanks for the good questions.
Data like this really doesn't come along every day and it doesn't happen without the support of a large multi disciplinary team dedicated to the success of these programs I'd like again to thank the investigators worked on our studies the patients who volunteered and the rating employees who've worked diligently and tirelessly and with purpose to build the opportunity we have before.
For us and thanks again to Dr. Douglas fir, joining us we really appreciate it and thank you everyone for joining us this morning with that we'll close the call.
This does conclude today's teleconference. We appreciate your participation you may disconnect. Your lines at this time and enjoy the rest of your day.