Wave Life Sciences Ltd. (NASDAQ:WVE) Q4 2022 Earnings Call Transcript

Wave Life Sciences Ltd. (NASDAQ:WVE) Q4 2022 Earnings Call Transcript March 22, 2023

Operator: Good morning, and welcome to the Wave Life Sciences Fourth Quarter and Full Year 2022 Financial Results Conference Call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I’ll now turn the call over to (ph), Wave’s IR Consultant. Please go ahead.

Unidentified Company Representative : Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review Wave’s fourth quarter and full year 2022 financial results. Joining me today are Dr. Paul Bolno, President and Chief Executive Officer; Anne-Marie Li-Kwai-Cheung, Chief Development Officer; Kyle Moran, Chief Financial Officer; and Dr. Chandra Vargeese, Chief Technology Officer. The press release issued this morning and the slide presentation to accompany this webcast are available in the Investors Section of our website at www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements.

These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today, and in our SEC filings. We undertake no obligation to update or revise any forward-looking statements for any reason. Now, I’d like to turn the call over to Paul.

Paul Bolno: Thanks, Kia. Good morning and thank you all for joining us. I’m excited to begin today’s call with a review of recent business highlights and how they position Wave in 2023 and beyond. I’ll then turn the call over to Anne-Marie to discuss our clinical development update with a focus on DMD. Kyle will discuss our financial results and I will end with a summary of upcoming catalysts expected in 2023. We’ll then proceed to the Q&A portion of the call where Chandra will also be available. At Wave, we believe the power of our PRISM platform and the potential of our current and future pipeline has positioned us to become the leading RNA medicines company. PRISM is the most versatile discovery and drug development platform in the industry.

It offers three distinct RNA targeting modalities: editing, slicing and silencing, so that we can design built for purpose molecules that optimally address disease biology. Our platform reflects nearly a decade of investment in proprietary chemistry which are disrupting the existing dogma of oligonucleotides, and are opening up new capabilities. Our chemistry advancements have also enabled us to push into new areas of disease biology that were not accessible or were inadequately addressed with other modalities. And we continue to build a pipeline of innovative first or best-in-class candidates. Importantly, every data point generated by Wave is incorporated into PRISM to accelerate learnings about oligonucleotide structure and optimization, and improve our probability of success with each new target.

Today, we have all the pieces in place to achieve our vision of delivering life changing RNA medicines so that patients and families can realize a brighter future. 2022 was a transformational year for Wave, resulting from focused and deliberate execution. Entering 2023, we have clinical validation of our PRISM platform, a leading position in RNA editing, growing momentum in building a robust pipeline and a strong financial position. Last year, we delivered three positive clinical data sets for our HD, ALS/FTD and DMD programs. Collectively, these data sets highlighted our ability to achieve robust and durable target engagement with our oligonucleotide. Most recently, we announced positive proof-of-concept results from our clinical study of WVE-N531for DMD including the highest level of exon skipping observed in any DMD clinical trial to date after only six weeks.

Anne-Marie will discuss these results and next steps for N531 in more depth later on. The strength of our platform also extended to potent and durable CNS target engagement with only single doses of WVE-003 in HD and WVE-004 in ALS/FTD. Each of these data sets underscore our ability to translate our compelling preclinical data to human and specifically our ability to potently engage targets in the CNS and muscle. Our work in RNA editing is an excellent example of how our proprietary chemistry has established Wave as the leader in this emerging modality. We expect to make history this year when we initiate clinical development of WVE-006 for AATD: Alpha-1 antitrypsin deficiency, which is positioned to be the first RNA editing therapeutic to be evaluated in human.

Additionally, in 2022, we demonstrated proof-of-concept in vivo for new applications of AIMers beyond correction, including modulation of protein-protein interaction and upregulation. Beyond our current clinical programs, we are deepening our pipeline with high value programs across our modalities. One way that we will do this is with our collaboration with GSK, which will provide us with access to unique insights on genetically validated targets with first-in-class potential. We expect that this collaboration, as well as our own target research will help unlock the broad potential of RNA editing as well as our growing RNAi capability and we expect to add several new pipeline programs this year and beyond. I will share more on this later. Lastly, Wave is well resourced to advance our pipeline and support continued growth.

With the upfront payment from our GSK collaboration, we extended our cash runway into 2025. We will also receive research funding and we are eligible for additional cash payment as we reach various collaboration milestones. These cash inflows will further support our wholly owned pipeline. With our positive data for WVE-N531, it has been a joy to reconnect with the DMD community over the past few months and discuss the future of this program and our potential to expand beyond Exon 53. Advocates and clinicians alike are encouraged by the unprecedented 53% exon skipping after three consecutive doses. The high muscle concentrations seen in the initial data set and the favorable safety profile, especially since N531 does not require the use of peptide or antibody conjugate and avoid the limitations of other approaches.

With these results early in the course of treatment, we believe that N531 has the potential to restore meaningful levels of functional dystrophin. If we’re successful, then N531 has the potential to meaningfully impact patients, while becoming a significant commercial opportunity for Wave. What excites us most about N531 is the opportunity to expand the success into a broad multi-exon strategy powered by PRISM chemistry. We have already generated in vitro data with our newer PN chemistry modified skipping construct across multiple exons and we would look to accelerate this research following positive dystrophin data for N531 so that we can build a wholly owned DMD franchise. 2022 was a pivotal year for our RNA editing oligonucleotides or AIMers and we continue to be inspired by this modalities credible potential.

AIMers provide unparalleled mechanistic dexterity. We are particularly excited about upregulation with AIMers. Which one should think of as our approach to endogenous mRNA delivery, rather than giving endogenous mRNA therapies, we can increase the expression of mRNA inside the cell using our AIMers. This means that rather than correcting each of the mutations associated with the genetic disease one-by-one, we see opportunities that significantly increase the total addressable market by restoring healthy levels of protein independent of mutation. The potential of this approach is extraordinary. Our AIMer candidate, WVE-006, is on track to be the first RNA editing molecule to enter the clinic. Successful restoration of wild type AAT protein in human would validate this modality not only for AATD but also for the large array of future applications we may pursue.

We are actively working to expand in RNA editing and expect to announce new wholly owned programs with preclinical data this year. Our ongoing discovery work is focused on building GalNAc conjugated hepatic program with plans to expand to other tissues such as CNS and renal with applicability to both rare and more prevalent diseases. Recently RNA editing has become the subject of significant attention given the advantage that it offers over DNA editing and other nucleic acid approaches. Our AIMers are very effective at recruiting ADAR enzymes, are highly stable and demonstrate remarkably durable and highly specific editing in preclinical models. They are compatible with GalNAc conjugation, which is a trusted and established mechanism for delivery to hepatocytes.

And as we’ve shown preclinically, AIMers can also be delivered with free uptake to a variety of cells throughout the body. Our knowledge and experience in silencing, GalNAc conjugation and advancements in PRISM chemistry have enabled the expansion of our platform to the field of RNAi. In 2022, we highlighted our preclinical in vivo data demonstrating that Wave PRISM chemistry leads to enhanced Ago2 loading, resulting in improvements to potency and durability compared with others RNAi capability. Additionally, we shared data using GalNAc conjugated small interferring RNAs in the liver of mice. These data demonstrated unprecedented potency and durability against mouse TTR and human HSD17 Beta 13, and they were among the data that reinforced the broader possibility of our platform to GSK and other potential partners.

Following our compelling data with GalNAc conjugated siRNAs, we next turn to unconjugated siRNAs in the CNS. And we again demonstrated exciting results in vivo. On the right of the slide, you’ll see our initial preclinical in vivo siRNA data in CNS. These unconjugated siRNA demonstrated 70% to 90% reduction in APP, a target that we use to validate this platform capability. These reductions were seen across each of six brain regions in mouse CNS at eight weeks following a single ICV dose of 100 microgram, demonstrating broad distribution in addition to potent silencing. While not shown on this slide, we also observed high Ago2 loading in this experiment, which we believe is being driven by our differentiated PRISM chemistry. It is encouraging to see this level of knockdowns in our first in vivo CNS study.

And this provides a baseline upon which we can continue to optimize for future RNAi CNS programs. We anticipate our activities in RNAi to increase and we expect RNAi to be featured in our GSK collaboration alongside RNA editing and slicing. In January 2023, we closed our deal with GSK and we are now underway with the collaboration, which we expect will yield substantial value to Wave in the coming years. First, we believe that this deal maximizes the commercial opportunity for WVE-006 and AATD. As we consider the evolving treatment landscape, it became clear to us that an important aspect of succeeding in AATD would be to prioritize a partner such as GSK with expertise in global clinical development and commercialization, as well as global and local leadership in respiratory outcome study.

Additionally, we have the potential to receive meaningful milestone payments throughout the development process including near term clinical milestone payments, as well as double digit royalties on net sales into the high teens. We retained control of through clinical proof-of-concept in order to leverage our clinical learning and apply them to our future RNA editing programs. Second, with this deal, we expect to unlock and accelerate broad PRISM capabilities and multiple modalities. Both our RNA editing and RNAi capabilities were catalyst for a larger platform focused deal with GSK. We and GSK are excited about opportunities in the liver with GalNAc and outside the liver, given our data showing Wave oligonucleotides can distribute to a variety of cells.

Third, with this deal, we anticipate being able to accelerate our own development of transformative RNA therapeutics. We expect to benefit from GSK’s access II and novel insights on genetic targets to pursue first-in-class treatment approaches. From a capital perspective, we have the opportunity to receive ongoing milestone payments of up to $3.3 billion to support the build out of our differentiated pipeline. A core deliverable for us in 2023 is identifying and advancing the next wave of programs that will expand our pipeline. With our broad capabilities, the universe of addressable targets is vast and we are relying on a set of guiding principles for Wave programs across clinical, technical and commercial dimensions to narrow down prospective targets.

Photo by Akram Huseyn on Unsplash

These include indications of significant unmet medical needs, strong biological rationale supporting clinical validation of genetic targets, efficient path to clinical proof-of-concept and to these relevant clinical biomarkers that could potentially support accelerated registration pathways. Like HD and AATD, DMD is a therapeutic area that is well aligned with our guiding principles of surrogate biomarkers and efficient path to clinical proof-of-concept. It is estimated that more than 80% of the DMD population may be amenable to exon skipping. And as mentioned, we already have in vitro proof-of-concept in other exons. Another area of growing interest to Wave is the inborn errors of metabolism, a class of diseases where the underlying genetic mutation leads to accumulation of toxic metabolites.

Many of these diseases are addressable through GalNAc mediated delivery where we can leverage RNA editing with our AIMers to correct underlying mutation and increase the related protein by stabilizing mRNA. The initial rare disease target indications that we are working on may unlock additional indications within the same pathway or may allow mutation independent strategies that increase the total addressable patient population. GalNAc based RNA editing and RNAi therapeutics are also well suited for cardiometabolic targets, including those in the hepatic kind family of diseases. These are highly prevalent conditions affecting over 10% of adults in the U.S. and Europe and they are associated with significant mortality rates. In the second half of this year, we expect to provide additional updates and data on our initial with the new program with others to follow in 2024 and beyond.

Outside of the liver and muscle, we see a wholly owned pipeline opportunities in a variety of tissues such as CNS, as well as applications for all of our modalities. Our pipeline is differentiated and diversified spending multiple modalities, including RNA editing, slicing and silencing. We have multiple wholly owned programs including WVE-N531 in DMD with more to come. We also have executed strategic partnerships to unlock further value from our platform and program, including our groundbreaking work on AATD. I’m excited by the growing potential of our portfolio. With that, I will now turn the call over to Anne-Marie, who will provide updates related to our clinical programs.

Anne-Marie Li-Kwai-Cheung: Thanks, Paul. In 2022, we delivered key data sets for each of our lead programs, including positive clinical data from our DMD, HD, and ALS/FTD trials. I will review each of these programs today beginning with WVE-N531 for DMD and the next steps we are taking to evaluate dystrophin. Next, WVE-006 shown here in green is rapidly approaching the clinic. We believe 006 may also be best-in-class in the treatment of AATD and our partner GSK is well positioned to maximize the opportunity of 006 around the world. Finally, we continue to advance our CNS silencing program shown on the right of this slide in dark blue under our Takeda collaboration. WVE-003, which is the first allele selective candidate for Huntington’s disease and WVE-004 for C9orf72 associated ALS/FTD.

In 2022, we demonstrated target engagement in the CNS for both programs after patients receive a single dose of 003 or 004 and we’re working towards the next stage . Starting with WVE-N531, in December 2022, we achieved proof-of-concept for N531 with DMD amenable to exon 53 skipping. This study was designed to rapidly evaluate whether N531 as a pharmacological profile, but also comes the limitations of our first generation DMD candidate dystrophin with muscle concentration and safety and tolerability as primary endpoint. Three ambulatory boys participated in this open-label, intra-patient dose escalation clinical trial. The boys received single escalating doses of one, three, six and 10 mg/kg of N531. In the multidose portion of studies, the same boys received three doses of 10 mg/kg every other week.

A biopsy was taken after three bi weekly doses of treatment. We were excited to observe the high muscle concentration of N531, which exceeded our expectations and even more excited to see 53 exon skipping at this time point. It’s particularly notable that all three boys in our study had similar levels of exon skipping despite having different underlying mutations. Additionally, you may recall that our non-human primate date showed muscle concentrations of N531 in the heart and diaphragm that were higher than those in the skeletal muscle, suggesting these results from the deltoid and bicep may be underrepresenting what is happening in other critical muscle tissues impacted by DMD. We also observed a plasma half-life of 25 days which is a tremendous improvement over (ph) plasma half-life of less than 24 hours.

N531 also appeared safe and well tolerated. Treatment related adverse events were generally mild and there were no treatment related SAEs. These data are consistent with our preclinical observations, thus our next generation PN chemistry is increasing muscle exposure and target engagement without needing peptide or antibody conjugate. It’s exciting to see this level of exon skipping after just three doses, especially since skipping may increase with longer dosing. We also expect dystrophin protein to accumulate with continued exposure and dosing. These data strongly support the continued development of N531 to assess dystrophin. Later today at the MDA Clinical and Scientific Conference, Wave’s Dr. Mike Panzara will be sharing these data with clinicians, as well as the next steps for N531, but I’ll also review here in a moment.

Since the data in December, we have been discussing potential next steps for N531 with researchers and key opinion leaders. Each of these discussions was the right time point to assess dystrophin, given its unique biology and the fact that meaningful dystrophin production does take time. On this slide, we provide background as to why that is as explained in the scientific literature. In boys with DMD, nonsense-mediated decay associated with the mutation and the general lack of healthy cellular environment destabilizes the dystrophin transcripts, limiting their low numbers to nearly undetectable levels. In this stage, full length transcript were rare and most transcripts that are produced are short and stable and do not support dystrophin production.

By promoting exon skipping in transcripts, treatments should start producing very low levels of dystrophin. Dystrophin protein has an exceptionally long half-life, even low levels will start to create a healthier cellular environment. This healthier environment in turn improves the cells ability to support transcriptional initiation and increases the number of full-life transcripts available to skin. Then as the number of transcripts rise, dystrophin protein should also start to accumulate at more meaningful levels. For this process to work, persistent exposure in the right compartment of the cells is crucial for creating a feedback loop and rebuilding the system. The data shown high concentrations of N531 in muscle and importantly in the nucleus as well as at 25 day half-life are highly encouraging in this regard.

Over time and with consistent exposure to high levels of exon skipping produced by N531, we expect this feedback loop to support cumulative increases in the expression of dystrophin protein. Dystrophin takes time to accumulate and this has been seen by others. However, with this level of exon skipping, we expect to see more dystrophin with longer treatment. So, I’m excited to share the next step for N531. We plan to initiate Part B of the Wave N531 study with the goal of enrolling up to 10 boys with DMD. This will be a Phase 2 open-label study with doses of 10 mg/kg administered every other week. And we plan to assess dystrophin protein after 24 weeks and 48 weeks of treatment. The primary endpoint will be dystrophin protein restoration and we will also assess pharmacokinetics functional endpoints such as NSAA and others, as well as safety and tolerability.

If the data were supportive, we will discuss regulatory pathways for approval with regulators. We expect to initiate dosing in Part B in 2023 and expect dystrophin data in 2024 and we plan to share more updates on timing once the cohort is underway. Moving on to Wave-006, which is our first AIMer development candidate. 006 is a first-in-class investigational treatment of AATD which has the potential to comprehensively address both liver and lung manifestations of this disease. 006 was designed to correct mutant SERPINA1 transcripts, restoring circulating wild type M-AAT protein. Our preclinical data has demonstrated a significant seven fold change in AAT protein, which is well over 11 micromolar. Importantly, we also demonstrated that restored AAT protein is wild type and that it is functional as demonstrated by the neutrophil elastase inhibition.

We see the transition of 06 to the clinic — 006 to the clinic as an important catalyst for Wave and for the field. Success in the first in-patient study would provide proof-of-concept for 006 in AATD and for RNA editing broadly. We will measure success in this study as restoration of functional M-AAT protein. Additionally, while 006 uses a new therapeutic modality, we have the benefit of following a well understood path laid out by regulators. There are now multiple programs approved or in late stage development that use GalNAc. And additionally, regulators are well versed in the use of oligonucleotides to recruit endogenous cellular machinery, like slicing machinery in DMD and Ago2 for RNAi. IND enabling studies for 006 are nearing completion and we remain on track of file CTAs in the second half of 2023.

We have also started to work with GSK to map out our development pathway for 006. And we’re looking forward to sharing more about the first in human study later this year. I’ll touch briefly on the current status of WVE-003, the first allele-selective candidate for HD and WVE-004, our variant selective candidate for C9orf72 associated ALS/FTD. In September 2022, Wave became the first company to demonstrate the feasibility of selectively silencing a mutant allele with our single dose data for 003. We remain convinced of the importance of preserving as much wild type protein as possible in the in Huntington lowering. And 003 remains the only allele selective approach in clinical development for HD. This could be particularly important in pre and early manifestation.

We’ve always believed that we needed to achieve between 20% to 30% lowering of needs in Huntington to impact disease progression. So it is encouraging that our single dose 30 and 60 milligram data suggests we may already be within this range. Based on these data, we adopted to select HD trial to expand the single dose cohort to better define the treatment effect and decide on optimal doses, the multidose phase of the study. We expect to share biomarker and safety data from these cohorts in the first half 2023. In April 2022, our FOCUS-C9 study of WVE-004 became our first to show successful translation of our preclinical data in the clinic. For the remainder of 2022, we have completed the single dose cohort, made progress on the multidose cohort and initiated the open label extension trial, also in consultation with the independent data safety monitoring committee.

We completed enrollment of the multidose cohort shown here on the slide, which keeps us on track for data in the first half of 2023. This will be a substantial data set consisting of several single and multidose cohorts, which will inform our next step, including discussions with Takeda. In summary, we have an exciting year ahead with multiple important clinical catalysts. These programs all underscores the promising breadth of our best-in-class multimodal RNA medicines platform, as well as our commitment to advance first or best-in-class therapies for patients. I will now turn the call over to Kyle Moran, our CFO for our financial update.

Kyle Moran: Thanks, Anne-Marie. Turning to the financial. Our net loss for the three months ended December 31, 2022 was $43.7 million as compared to $34.8 million in the same period in 2021. The increase in net loss year-over-year was primarily driven by increased spend on our clinical program, as well as increased compensation-related expenses. We recognized approximately $1.2 million in revenue from our Takeda collaboration for the fourth quarter of 2022 as compared to $1.8 million in the same period in 2021. R&D expenses increased $5.3 million to $31.1 million in the fourth quarter of 2022 as compared to $25.8 million in the same period in 2021. This increase was primarily due to increased external expenses related to our AATD, C9 and DMD program and compensation related expenses, partially offset by a decrease in spending in our HD program.

General and administrative expenses increased $1.6 million to $13.7 million for the fourth quarter of 2022 as compared to $12.1 million last year, primarily due to increases in professional and service fee expenses. We ended the fourth quarter with $88.5 million in cash and cash equivalents as compared to $150.6 million as of December 31, 2021. Additionally, in Q1 2023 where strategic collaboration with GSK became effective and provided upfront cash of $170 million to Wave. Accordingly, we expect our cash and cash equivalents will be sufficient to fund operations since 2025. As a reminder, we do not include future milestones or opt in payments under our GSK or Takeda collaboration in our cash runway. I’ll now turn the call back over to Paul.

Paul Bolno: Thanks, Kyle. I am proud of how the team continues to execute with resolute focus on unlocking program value through our ability to align the right target with the best oligonucleotide approach, be that editing, slicing or silencing with antisense or RNAi. In the year ahead, we expect to deliver on multiple pipeline and platform candidates. With our clinical silencing programs, we’re advancing two candidates for which we expect additional data in the first half of this year. WVE-003 and HD is the only clinical stage mutant Huntington lowering wild Huntington sparing approach, while WVE-004 offers a variant selective approach to C9orf72 associated ALS/FTD. We’ll have substantial data sets to determine the next step for these programs and if successful would initiate discussions with our partner Takeda.

With slicing, WVE-N531 is demonstrating the potential to be a best-in-class approach in the DMD space. We plan to initiate dosing in Part B in 2023 and announce data in 2024. If successful, these data would unlock high value DMD franchise. In addition to DMD, we see future expansion opportunities for slicing in other muscle diseases as well as CNS. With editing, WVE-006 is the most advanced candidate and potentially a best-in-class approach for AATD. We expect transition of this program to the clinic in the second half of this year, if successful, WVE-006will unlock the broad potential of AIMers. With RNAi, our preclinical data suggests that we have best-in-class potential with this modality and is shaping up to be a powerful silencing component our RNA medicines platform with applicability in the liver, CNS and beyond.

We are rapidly advancing discovery activities in RNA editing and beyond and expect to announce new programs and share preclinical data this year. Finally, we are already advancing collaboration activities with GSK with potential for additional cash inflows over the course of this year and beyond. 2023 promises to be another great year of PRISM innovation and progress towards bringing medicines to patients. With that, I’ll now turn it over to the operator for Q&A.

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Q&A Session

Operator: The first question comes from Salim Syed with Mizuho. Your line is now open.

Mike Linden: Hi, good morning. This is Mike Linden on for Salim. Thanks so much for taking our question. I guess just on WVE-N531. So for Part A, we saw this three patients at the six weeks starting after the 10 milligram dose. What are the plans to follow-up on these patients? Is there any update you can provide maybe on the protocol going forward here for the first three patients? And then I guess to follow-up with that on Part B, maybe how should we be thinking about the regulatory pathway going forward and potential timeline for that?

Anne-Marie Li-Kwai-Cheung: Thanks. So the Part B that we announced today looking at up to 10 boys includes boys who were originally enrolled in our Part A, so they have the opportunity to also enroll in this Part B extension. With regards to regulatory pathways, as you’re alluding to, there are well trodden regulatory paths for accelerated approval on the basis of dystrophin. And obviously, when we have our data, we will be assessing and discussing with the regulators what the best pathway is for us.

Mike Linden: Got it. Thanks.

Operator: Please stand by for our next question. Our next question comes from Joon Lee with Truist. Your line is now open.

Joon Lee: Hi, thanks for the updates and for taking our questions. The FDA is hosting a couple of Adcoms that directly impacted programs. One is happening today to discuss the neurofilament light chain as a potential surrogate endpoint. And the other is sometime next month to discuss dystrophin as a biomarker for DMD. How likely do you think the Adcom will be supportive of these biomarkers? And how would these decisions impact your clinical development strategy for your programs? And I have a quick follow-up.

Anne-Marie Li-Kwai-Cheung: Sure. So obviously, we’ll be watching the outcome of these Adcoms very closely. And I can’t of course state what the outcome will be, but I would say that any indications that the FDA is still supporting the use of biomarkers to aid the approval of new therapies, the rare diseases is highly encouraging and supported, of course, by us. And when we see the outcome of those ADcoms we will be assessing how it impacts our own therapy.

Paul Bolno: I think the added nuance to, Joon, your second point on the direct the Adcom on micro dystrophin. I mean, I think it will be an interesting discussion, one on the continued support of dystrophin as a regulatory endpoint potentially for accelerated approval. But I think what we think consistently in the exon skipping field is, approvals based on dystrophin level. So I think, again, it’s encouraging to see the agency continue to leverage these clinical biomarkers as potential registration info.

Joon Lee: Great. And regarding the Huntington’s program, are you looking to — what exactly are you looking to achieve with the additional SAD study before you feel confident enough to advance to MAD study? Correct me if I’m wrong, but the 30, 60 and 90 milligrams were already studied in the prior SAD study? Thank you.

Paul Bolno: Yes. I think that’s the follow-up of the expansion cohorts are going to help with them read that I think establish the dosing regimen for multi dose in the progress?

Anne-Marie Li-Kwai-Cheung: Yes. So that original cost that we reported was underpowered and so we wanted to further explore those doses before we move into the multi dose cohort. Obviously, when you move into the multi dose, you want to be sure that you are selecting the right dose for a continued study. So it’s the logical and normal way to follow the drug development.

Joon Lee: Thank you.

Operator: Please stand by for our next question. The next question comes from Paul Matteis with Stifel. Your line is now open.