Executive Summary [First Quarter 2025 Overview](index=1&type=section&id=First%20Quarter%202025%20Overview) Wave Life Sciences reported Q1 2025 results, highlighting clinical progress and a cash runway into 2027 - Dosing completed in the first two cohorts of the INLIGHT trial for WVE-007 in obesity, with clinical data on track for **2H 2025**[1](index=1&type=chunk) - Dosing is underway in the RestorAATion-2 trial for WVE-006 in AATD, with data expected in **3Q 2025** and **Fall 2025**[1](index=1&type=chunk) - Positive data from the FORWARD-53 trial for WVE-N531 in DMD showed significant functional improvement, with an **NDA submission planned for 2026**[1](index=1&type=chunk) - An **IND submission is expected in 2H 2025** for the potentially registrational WVE-003 Phase 2/3 study in HD[1](index=1&type=chunk) - Cash and cash equivalents of **$243.1 million** as of March 31, 2025, provide a financial runway expected into **2027**[1](index=1&type=chunk) [CEO Commentary](index=1&type=section&id=CEO%20Commentary) The CEO highlighted consistent execution, leadership in RNA medicines, and upcoming clinical data across key programs - Wave Life Sciences is on track to deliver multiple clinical datasets in **2025**, demonstrating broad capabilities in RNA medicines[2](index=2&type=chunk) - WVE-007 in obesity has the potential to transform treatment with **healthy weight loss** and infrequent dosing[2](index=2&type=chunk) - WVE-N531 in DMD delivered the first-ever substantial improvements in **muscle health** with an exon skipping therapy[2](index=2&type=chunk) - WVE-003 in HD has industry-leading CSF mutant lowering and is the only program to demonstrate **allele-selective knockdown** in the clinic[2](index=2&type=chunk) Recent Business Highlights and Expected Milestones [Obesity (WVE-007)](index=2&type=section&id=Obesity) WVE-007 shows preclinical potential for healthy weight loss, with clinical data from the INLIGHT trial expected in 2H 2025 - WVE-007 is a GalNAc-siRNA designed to silence **INHBE mRNA**, an obesity target with strong human genetics evidence[4](index=4&type=chunk) - Dosing has been completed in the first and second single dose cohorts of the **INLIGHT clinical trial**[4](index=4&type=chunk) - Preclinical data showed a single dose of WVE-007 led to weight loss on par with semaglutide but with **no muscle loss**[4](index=4&type=chunk) - Clinical data from INLIGHT, including safety, tolerability, and biomarkers, is expected in the **second half of 2025**[4](index=4&type=chunk) [Alpha-1 Antitrypsin Deficiency (AATD) (WVE-006)](index=2&type=section&id=AATD%20(Alpha-1%20antitrypsin%20deficiency)) WVE-006 demonstrated the first-ever clinical RNA editing in humans, with further data from the RestorAATion-2 trial expected in 2025 - WVE-006 is a subcutaneously delivered RNA editing oligonucleotide (AIMer) designed to address **AATD-related lung and/or liver disease**[4](index=4&type=chunk) - Multi-dosing is ongoing in the first cohort of **RestorAATion-2** (200 mg) and dosing is underway in the second single dose cohort (400 mg)[4](index=4&type=chunk) - Proof-of-mechanism data showed mean circulating wild-type M-AAT protein reached **6.9 micromolar**, with total AAT increasing to **10.8 micromolar**[7](index=7&type=chunk) - Data from complete 200 mg multidose and single dose cohorts is expected in **Q3 2025**, with 400 mg single dose data expected in **Fall 2025**[7](index=7&type=chunk) [Emerging Wholly Owned siRNA and RNA Editing Pipeline](index=3&type=section&id=Emerging%20wholly%20owned%20siRNA%20and%20RNA%20editing%20pipeline) Wave is expanding its pipeline with new siRNA and RNA editing targets, with clinical development for additional programs planned for 2026 - Wave is advancing new targets to expand its pipeline of wholly owned programs in both **rare and common diseases**[7](index=7&type=chunk) - The wholly owned RNA editing pipeline includes programs for **PNPLA3** (liver diseases) and **LDLR/APOB** (familial hypercholesterolemia)[7](index=7&type=chunk) - Preclinical data for AIMers in lung indications showed increased CFTR mRNA expression **3-fold** and restored up to **50%** of functional protein levels[7](index=7&type=chunk) - New preclinical data is expected in **2025**, with initiation of clinical development for PNPLA3, LDLR, and APOB planned for **2026**[7](index=7&type=chunk) [Duchenne Muscular Dystrophy (DMD) (WVE-N531)](index=3&type=section&id=DMD%20(Duchenne%20muscular%20dystrophy)) Positive 48-week data for WVE-N531 showed significant functional and muscle health improvements, supporting a planned 2026 NDA submission - WVE-N531 is an exon skipping oligonucleotide for Duchenne muscular dystrophy amenable to **exon 53 skipping**[7](index=7&type=chunk) - Positive 48-week data from the FORWARD-53 trial included a statistically significant improvement of **3.8 seconds in Time-to-Rise** vs natural history[7](index=7&type=chunk) - The trial demonstrated substantial improvements in muscle health, including a statistically significant **reduction in fibrosis**[10](index=10&type=chunk) - Dystrophin expression stabilized, averaging **7.8%**, with **88%** of boys above 5% average dystrophin[10](index=10&type=chunk) - The U.S. FDA confirmed the **accelerated approval pathway** using dystrophin expression as a surrogate endpoint remains open[10](index=10&type=chunk) - An **NDA submission for accelerated approval** of WVE-N531 with monthly dosing is planned for **2026**[10](index=10&type=chunk) [Huntington's Disease (HD) (WVE-003)](index=4&type=section&id=HD%20(Huntington's%20disease)) WVE-003 demonstrated allele-selective mHTT reduction correlated with slowing caudate atrophy, with an IND for a Phase 2/3 study expected in 2H 2025 - WVE-003 is a first-in-class, **allele-selective oligonucleotide** for the treatment of Huntington's disease[10](index=10&type=chunk) - SELECT-HD trial data showed the first-ever allele-selective reduction in CSF mHTT protein and a significant correlation with **slowing of caudate atrophy**[10](index=10&type=chunk) - Wave has received supportive initial feedback from the FDA regarding a potential pathway to **accelerated approval**[10](index=10&type=chunk) - An **IND application** for a potentially registrational Phase 2/3 study of WVE-003 in HD is expected in the **second half of 2025**[10](index=10&type=chunk) Financial Highlights [First Quarter 2025 Financial Performance](index=4&type=section&id=First%20Quarter%202025%20Financial%20Performance) The company reported a net loss of $46.9 million for Q1 2025, with a cash runway projected into 2027 First Quarter 2025 Financial Summary (in thousands) | Metric | Q1 2025 | Q1 2024 | Change (YoY) | | :------------------------ | :------ | :------ | :----------- | | Revenue | $9,175 | $12,538 | -26.8% | | Research and development | $40,622 | $33,447 | +21.4% | | General and administrative| $18,357 | $13,549 | +35.5% | | Total operating expenses | $58,979 | $46,996 | +25.5% | | Loss from operations | $(49,804)| $(34,458)| -44.5% | | Net loss | $(46,878)| $(31,558)| -48.5% | | Net loss per share (basic & diluted) | $(0.29) | $(0.24) | -20.8% | - Cash and cash equivalents were **$243.1 million** as of March 31, 2025, which is expected to fund operations into **2027**[10](index=10&type=chunk)[18](index=18&type=chunk) Company Information [Investor Conference Call and Webcast](index=5&type=section&id=Investor%20Conference%20Call%20and%20Webcast) Wave Life Sciences hosted an investor call on May 8, 2025, to review its Q1 2025 financial results and pipeline updates - An investor conference call and webcast was held on **May 8, 2025**, at 8:30 a.m. ET[11](index=11&type=chunk) - The purpose was to review **first quarter 2025 financial results** and pipeline updates[11](index=11&type=chunk) [About Wave Life Sciences](index=5&type=section&id=About%20Wave%20Life%20Sciences) Wave Life Sciences is a clinical-stage biotechnology company developing RNA medicines using its proprietary PRISM® platform - Wave Life Sciences is a clinical-stage biotechnology company focused on unlocking the broad potential of **RNA medicines**[12](index=12&type=chunk) - The company's **PRISM® platform** combines multiple modalities, chemistry innovation, and deep insights in human genetics[12](index=12&type=chunk) - Wave's diversified pipeline includes clinical programs in **AATD, DMD, HD, and Obesity**[12](index=12&type=chunk) [Forward-Looking Statements](index=5&type=section&id=Forward-Looking%20Statements) This report contains forward-looking statements regarding future goals and financial outlook, which are subject to various risks and uncertainties - The press release contains forward-looking statements concerning goals, clinical trial data, regulatory submissions, and **financial runway**[13](index=13&type=chunk) - Actual results may differ materially due to factors such as financing ability, clinical trial outcomes, regulatory actions, and **market competition**[15](index=15&type=chunk) [Contact Information](index=6&type=section&id=Contact) Contact information is provided for investor relations and media inquiries - Contact for investors: **InvestorRelations@wavelifesci.com**[16](index=16&type=chunk) - Contact for media: **MediaRelations@wavelifesci.com**[16](index=16&type=chunk) Unaudited Consolidated Financial Statements [Consolidated Balance Sheets](index=7&type=section&id=WAVE%20LIFE%20SCIENCES%20LTD.%20UNAUDITED%20CONSOLIDATED%20BALANCE%20SHEETS) Total assets decreased to $288.3 million as of March 31, 2025, primarily due to a reduction in cash and cash equivalents Consolidated Balance Sheet Highlights (in thousands) | Metric | March 31, 2025 | December 31, 2024 | Change | | :-------------------------- | :------------- | :---------------- | :----- | | Cash and cash equivalents | $243,075 | $302,078 | $(59,003) | | Total current assets | $257,976 | $320,394 | $(62,418) | | Total assets | $288,343 | $352,207 | $(63,864) | | Total current liabilities | $87,367 | $110,953 | $(23,586) | | Total liabilities | $108,666 | $134,818 | $(26,152) | | Total shareholders' equity | $171,803 | $209,515 | $(37,712) | [Consolidated Statements of Operations and Comprehensive Loss](index=8&type=section&id=WAVE%20LIFE%20SCIENCES%20LTD.%20UNAUDITED%20CONSOLIDATED%20STATEMENTS%20OF%20OPERATIONS%20AND%20COMPREHENSIVE%20LOSS) The company reported a net loss of $46.9 million for Q1 2025, an increase from $31.6 million in the prior year quarter Consolidated Statements of Operations Highlights (in thousands) | Metric | Three Months Ended March 31, 2025 | Three Months Ended March 31, 2024 | | :---------------------------------- | :-------------------------------- | :-------------------------------- | | Revenue | $9,175 | $12,538 | | Research and development | $40,622 | $33,447 | | General and administrative | $18,357 | $13,549 | | Total operating expenses | $58,979 | $46,996 | | Loss from operations | $(49,804) | $(34,458) | | Net loss | $(46,878) | $(31,558) | | Net loss per share (basic and diluted) | $(0.29) | $(0.24) |

Core Insights - Wave Life Sciences Ltd. has made significant progress in its clinical trials, including the completion of dosing in the INLIGHT trial for obesity and positive data from the FORWARD-53 trial for Duchenne muscular dystrophy (DMD) [1][2][3] - The company is on track to deliver multiple clinical datasets in 2025, which will showcase its capabilities in RNA medicines [2] - Financial results for Q1 2025 indicate a net loss of $46.9 million, with cash and cash equivalents of $243.1 million, expected to fund operations into 2027 [6][7][14] Obesity - WVE-007, a GalNAc-conjugated siRNA, aims to induce healthy weight loss by silencing INHBE mRNA, with dosing completed in the first two cohorts of the INLIGHT trial [3][4] - The trial assesses safety, tolerability, pharmacokinetics, and metabolic health, with clinical data expected in the second half of 2025 [3][4] - WVE-007 has shown potential for significant weight loss without muscle loss, and when combined with semaglutide, it doubled weight loss [4] Alpha-1 Antitrypsin Deficiency (AATD) - WVE-006 is being evaluated in the RestorAATion-2 trial, with ongoing dosing in both single and multiple cohorts [1][3] - Data from the 200 mg multidose and single dose cohorts are expected in Q3 2025, while data from the 400 mg cohort is anticipated in fall 2025 [1][4] - The trial aims to demonstrate the safety and efficacy of WVE-006 in individuals with the PiZZ mutation [4] Duchenne Muscular Dystrophy (DMD) - WVE-N531 has shown statistically significant improvements in muscle health and function in the FORWARD-53 trial, with a 3.8-second improvement in Time-to-Rise [7] - The drug has received Orphan Drug Designation and is expected to file for accelerated approval in 2026 [7] - All participants in the trial have opted to continue into the extension phase, receiving monthly doses [7] Huntington's Disease (HD) - WVE-003 is positioned as a first-in-class treatment for HD, demonstrating allele-selective reduction of mutant HTT protein while preserving wild-type HTT [7] - The company is preparing for a potentially registrational Phase 2/3 study, with an IND submission expected in the second half of 2025 [7][5] Financial Overview - Revenue for Q1 2025 was $9.2 million, down from $12.5 million in the same quarter of the previous year [6][14] - Research and development expenses increased to $40.6 million from $33.4 million year-over-year, while general and administrative expenses rose to $18.4 million from $13.5 million [6][14] - The net loss for the quarter was $46.9 million, compared to a loss of $31.6 million in the prior year [6][14]

Core Viewpoint - Wave Life Sciences (WVE) is anticipated to report a year-over-year decline in earnings despite an increase in revenues for the quarter ended March 2025, which could significantly influence its stock price based on actual results compared to estimates [1][2]. Company Summary - The consensus estimate indicates a quarterly loss of $0.27 per share for Wave Life Sciences, reflecting a year-over-year change of -12.5%. Revenues are projected to be $13.97 million, representing an 11.4% increase from the previous year [3]. - Over the last 30 days, the consensus EPS estimate has been revised 0.43% lower, indicating a reassessment by analysts regarding the company's earnings prospects [4]. - The Most Accurate Estimate for Wave Life Sciences is lower than the Zacks Consensus Estimate, resulting in an Earnings ESP of -1.89%. The company currently holds a Zacks Rank of 3, making it challenging to predict an earnings beat [10][11]. Earnings Surprise History - In the last reported quarter, Wave Life Sciences was expected to post a loss of $0.17 per share but instead reported earnings of $0.17, resulting in a surprise of +200%. However, the company has only beaten consensus EPS estimates once in the last four quarters [12][13]. Industry Context - Rhythm Pharmaceuticals, another company in the Zacks Medical - Biomedical and Genetics industry, is expected to report a loss of $0.69 per share for the same quarter, indicating a year-over-year change of +70.6%. Its revenues are expected to be $40.18 million, up 54.7% from the previous year [17]. - The consensus EPS estimate for Rhythm Pharmaceuticals has been revised 0.7% lower in the last 30 days, leading to an Earnings ESP of -12.84% and a Zacks Rank of 3, complicating predictions for an earnings beat [18].

Company Overview - Wave Life Sciences Ltd. is a clinical-stage biotechnology company focused on RNA medicines to transform human health [3] - The company utilizes its RNA medicines platform, PRISM®, which integrates various modalities and chemistry innovations to address both rare and common disorders [3] - Wave's pipeline includes clinical programs targeting Alpha-1 antitrypsin deficiency, Duchenne muscular dystrophy, Huntington's disease, and obesity, along with several preclinical programs [3] Upcoming Events - Wave Life Sciences will host a live webcast and conference call on May 8, 2025, at 8:30 a.m. ET to review Q1 2025 financial results and provide business updates [1] - The event can be accessed via the "Investor Events" section on the company's website [2] - An archived version of the webcast will be available on the company's website following the live event [2]

Group 1 - The article discusses Wave Life Sciences Ltd. (NASDAQ: WVE) and its recent positive data for WVE-006 related to Alpha-1 Antitrypsin Deficiency (AATD), which is expected to lead to a catalyst in 2025 [2] - The author operates the Biotech Analysis Central service, which provides in-depth analysis of various pharmaceutical companies and includes a model portfolio of small and mid-cap stocks [2] - The service offers a subscription model with a promotional two-week free trial and a discounted annual plan [1] Group 2 - The article does not provide any specific financial data or performance metrics related to Wave Life Sciences or the broader biotech industry [3][4]

Company Overview - Wave Life Sciences (WVE) shares increased by 6.1% to $10.02, following a significant trading volume, contrasting with an 8.9% decline over the past four weeks [1] - The company is focused on developing treatments for Duchenne muscular dystrophy (DMD) [2] Clinical Study Results - The stock's rally was driven by positive results from the phase II FORWARD-53 study, which assessed WVE-N531 for DMD treatment [2] - The study met all objectives, showing sustained exon skipping, muscle concentrations, and dystrophin restoration over 48 weeks, with a 61-day tissue half-life supporting monthly dosing [2] - Treatment with WVE-N531 was reported to be safe and well-tolerated [2] Financial Expectations - The upcoming quarterly report is expected to show a loss of $0.26 per share, reflecting an 8.3% year-over-year decline, while revenues are projected at $13.26 million, a 5.8% increase from the previous year [3] - The consensus EPS estimate for the quarter has been revised 9.8% higher in the last 30 days, indicating potential price appreciation [4] Industry Context - Wave Life Sciences operates within the Zacks Medical - Biomedical and Genetics industry, where another company, Agios Pharmaceuticals (AGIO), has seen a 12.6% decline over the past month [4] - Agios Pharmaceuticals' EPS estimate has decreased by 5.4% over the past month, indicating a challenging outlook compared to the previous year [5]

Core Insights - Wave Life Sciences announced positive results from the Phase 2 FORWARD-53 trial of WVE-N531, demonstrating significant improvements in muscle health and function in boys with Duchenne muscular dystrophy (DMD) [1][4][10] Group 1: Trial Results - The FORWARD-53 trial achieved all goals, showing a statistically significant and clinically meaningful improvement of 3.8 seconds in Time-to-Rise (TTR) compared to natural history, the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks [1][3][12] - A 28.6% reduction in muscle fibrosis was observed between weeks 24 and 48 (p<0.01), alongside a 50% decrease in serum creatine kinase (CK) levels (p<0.001) [3][12] - Dystrophin expression stabilized between 24 and 48 weeks, averaging 7.8%, with 88% of boys achieving over 5% average dystrophin [1][8] Group 2: Safety and Tolerability - WVE-N531 was reported to be safe and well-tolerated, with no serious adverse events and all treatment-related adverse events being mild to moderate [1][8] - The trial included 11 boys, all of whom advanced to the extension portion of the study receiving monthly doses of WVE-N531 [7][8] Group 3: Regulatory and Future Plans - Following feedback from the FDA, Wave plans to file a New Drug Application (NDA) in 2026 for accelerated approval of WVE-N531, supported by data for monthly dosing [1][5][6] - Wave expects to submit multiple clinical trial applications (CTAs) for other DMD candidates targeting different exons in 2026, aiming to establish a best-in-class exon skipping franchise [1][6][10] Group 4: Market Opportunity - WVE-N531 and other exon skipping programs could address approximately 40% of the DMD population, representing a market opportunity exceeding $2.4 billion in the United States alone [6][10]

Financial Data and Key Metrics Changes - Revenue for Q4 2024 was $83.7 million, compared to $29.1 million in Q4 2023, while full-year revenue was $108.3 million versus $113.3 million in 2023, indicating a significant quarter-over-quarter increase primarily due to deferred revenue recognition from the Takeda collaboration [34][35] - R&D expenses increased to $44.6 million in Q4 2024 from $34.1 million in Q4 2023, and for the full year, R&D expenses rose to $159.7 million from $130.0 million in 2023, driven by new program spending [34] - The net income for Q4 2024 was $29 million, a turnaround from a net loss of $16.3 million in the prior year, while the full-year net loss was $96.7 million compared to $57.5 million in 2023 [34][35] - Cash and cash equivalents at year-end 2024 were $302.1 million, up from $200.4 million at the end of 2023, primarily due to financing proceeds and milestone payments [35] Business Line Data and Key Metrics Changes - The company advanced its WVE-007 program for obesity, with initial data expected in the second half of 2025, indicating progress in clinical trials [6][10] - WVE-006 for AATD showed a mean increase of 6.9% micromolar circulating AAT and 10.8% micromolar total AAT two weeks post single dose in the first patient study, demonstrating the potential for effective treatment [11][12] - In DMD, the company is on track to deliver 48-week data from its forward 53 clinical trial, with previous data showing a mean muscle content adjusted dystrophin of 9% [14][16] Market Data and Key Metrics Changes - The obesity treatment market is highlighted as having over 1 billion people globally, with WVE-007 positioned as a potential best-in-class treatment due to its unique mechanism of action [8][9] - The Huntington's disease market impacts over 200,000 people in the US and Europe, with the company emphasizing the importance of early intervention and allele-specific therapies [17][19] Company Strategy and Development Direction - The company is focused on RNA medicines, with a commitment to advancing its pipeline, including WVE-007 for obesity and WVE-006 for AATD, aiming to address significant unmet medical needs [5][6] - The strategy includes leveraging unique mechanisms of action to differentiate from existing therapies, particularly in obesity and genetic diseases [28][29] - The company plans to initiate clinical development of additional RNA editing programs in 2026, expanding its therapeutic reach [13][30] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the company's trajectory in 2025, anticipating multiple value-accretive milestones across clinical programs [37] - The management highlighted the importance of addressing the limitations of current obesity treatments and the potential for WVE-007 to provide a sustainable weight loss solution [9][28] - There is a strong focus on regulatory engagement and the potential for accelerated pathways for DMD and Huntington's disease therapies [56][62] Other Important Information - The company has seen increased demand for participation in its clinical studies, particularly for WVE-006, indicating strong interest from both clinicians and patients [12] - The management emphasized the importance of tracking M-protein levels as a key indicator of therapeutic efficacy in AATD treatments [41][45] Q&A Session Summary Question: Can you provide more information on WVE-006's baseline protein levels? - Management indicated that the baseline was below the lower limit of detection, and emphasized tracking M-protein levels as a key metric for therapeutic impact [39][41] Question: How will DEXA scanning be used in the WVE-007 study? - Management confirmed that DEXA scans will be used to assess fat loss versus muscle mass changes, with the goal of demonstrating healthy weight loss [46][47] Question: What are the expectations for the upcoming DMD data readout? - Management confirmed ongoing discussions with regulators regarding the 48-week data and emphasized the importance of understanding dystrophin kinetics over time [51][55] Question: How does the company view the potential for mutant huntingtin lowering as a surrogate endpoint in Huntington's disease? - Management expressed that if the FDA accepts mutant huntingtin lowering as a clinical surrogate, it would be beneficial for the field and the company [60][62] Question: What has changed regarding the prevalence of Huntington's disease? - Management explained that recent research has shown that Huntington's disease begins before symptom onset, leading to a higher estimated prevalence [63][65] Question: How should we think about dosing for RNA editing versus DNA editing? - Management highlighted that dosing should be viewed in terms of efficacy and durability, with ongoing exploration of optimal dosing regimens [91][97]

Financial Data and Key Metrics Changes - Revenue for Q4 2024 was $83.7 million, compared to $29.1 million in Q4 2023, while full-year revenue was $108.3 million, down from $113.3 million in 2023 [35] - R&D expenses increased to $44.6 million in Q4 2024 from $34.1 million in Q4 2023, and for the full year, R&D expenses rose to $159.7 million from $130.0 million [35] - Net income for Q4 2024 was $29 million, compared to a net loss of $16.3 million in Q4 2023, while the full-year net loss was $96.7 million, up from $57.5 million in 2023 [35][36] - Cash and cash equivalents at year-end 2024 were $302.1 million, compared to $200.4 million at the end of 2023, primarily due to financing proceeds and milestone payments [36] Business Line Data and Key Metrics Changes - The company advanced its pipeline with WVE-007 for obesity, which is expected to provide a unique mechanism of action with dosing just once or twice a year [7][10] - WVE-006 for AATD demonstrated a mean 6.9% micromolar circulating AAT and 10.8% micromolar total AAT two weeks post single dose in the first patient study, indicating a favorable safety profile [12] - In DMD, WVE-531 showed a mean muscle content adjusted dystrophin of 9%, with a well-tolerated profile, and the company is on track to deliver 48-week data by the end of the month [15][17] Market Data and Key Metrics Changes - The obesity treatment market is highlighted as having over 1 billion people affected globally, with WVE-007 positioned to address limitations of current GLP-1 therapies [9][10] - Huntington's disease impacts more than 200,000 people in the US and Europe, with the company emphasizing the need for early intervention therapies [18][64] Company Strategy and Development Direction - The company is focused on RNA medicines, with a commitment to advancing its pipeline and addressing high unmet needs in various therapeutic areas [6][14] - WVE-007 is positioned as an alternative to GLP-1 therapies, focusing on peripheral action to avoid disadvantages associated with centrally acting drugs [29] - The company plans to initiate clinical development of additional RNA editing programs in 2026, expanding its therapeutic offerings [14][32] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the progress made in 2024 and the potential for multiple value-accretive milestones in 2025 across all clinical programs [38] - The management highlighted the importance of engaging with the obesity community and clinicians to combat disease stigma and improve treatment outcomes [8] - The company anticipates that its current cash reserves will fund operations into 2027, excluding potential future milestone payments [36] Other Important Information - The company has seen a surge in enrollment and demand for its clinical studies, particularly for WVE-006, indicating strong interest from both clinicians and patients [13] - The management emphasized the unique aspects of their RNA editing technology compared to traditional DNA editing, highlighting the safety and efficacy of their approach [12][85] Q&A Session Summary Question: Can you provide more information on WVE-006's baseline protein levels? - Management noted that the baseline was below the lower limit of detection, and emphasized tracking M-protein levels as a key indicator of therapeutic impact [40][42] Question: Regarding WVE-007, how will DEXA scanning be utilized in the study? - Management confirmed that DEXA scans will be used to assess fat loss versus muscle mass changes, with the goal of demonstrating healthy weight loss [47][48] Question: What are the expectations for the upcoming DMD data readout? - Management indicated that discussions with regulators are ongoing, and they expect to provide updates on both the 24-week and 48-week data [52][56] Question: How does the company view the potential for mutant huntingtin lowering as a surrogate endpoint in Huntington's disease? - Management expressed that if the FDA accepts this as a clinical surrogate, they would be positioned to file based on existing data showing significant mutant huntingtin reductions [61][62] Question: What has changed regarding the prevalence of Huntington's disease? - Management explained that recent research has shown that the disease begins before symptom onset, leading to a higher estimated prevalence than previously thought [64][66]

Financial Performance - The company reported net losses of $97.0 million, $57.5 million, and $161.8 million for the fiscal years ended December 31, 2024, 2023, and 2022, respectively, with an accumulated deficit of $1,121.9 million as of December 31, 2024[275]. - The company has not generated any product revenue to date and does not expect to do so in the foreseeable future, leading to continued significant operating losses[276]. - The company has received approximately $1,578.4 million in net proceeds from sales of securities and collaborations through December 31, 2024, including $977.8 million from public offerings and $511.3 million from collaborations[280]. - The company anticipates that its existing cash and cash equivalents will be sufficient to fund operations for at least the next 12 months[277]. - The company has never declared or paid cash dividends on its ordinary shares and does not anticipate doing so in the foreseeable future[460]. Capital Requirements and Funding - The company filed a shelf registration statement for the sale of up to $250.0 million in ordinary shares, allowing for potential future capital raising[281]. - The company’s future capital requirements are uncertain and will depend on various factors, including monthly spending levels and the progress of drug discovery and clinical development[279]. - The company relies on third parties for raw materials and clinical trials, which may be disrupted by local or global health epidemics, affecting research and development activities[289]. - The company faces risks related to macroeconomic conditions, including inflation and volatility in interest rates, which could impact its ability to raise additional funding[284]. Research and Development Challenges - The company has not yet demonstrated the ability to successfully complete pivotal clinical trials or obtain marketing approvals necessary for product commercialization[287]. - The company’s RNA medicines platform, PRISM, aims to target genetically defined diseases but has not yet completed successful clinical development of an oligonucleotide therapeutic[291]. - The company has invested significantly in the development of its RNA medicines platform, PRISM, and has no products currently on the market, with revenue generation expected to be many years away[295]. - The company has a diverse pipeline including clinical programs in AATD, DMD, HD, and obesity, but the success of these programs is uncertain[294]. - The company experienced a discontinuation of the WVE-004 program after Phase 1b/2a study results showed no clinical benefit, highlighting the high failure rate in drug development[312]. Regulatory and Compliance Risks - Regulatory approval processes for product candidates are extensive and costly, with unpredictable timelines that can materially impair revenue generation[319]. - The company must submit a diversity action plan for future Phase 3 trials, which may affect planning and recruitment of diverse patient populations[315]. - Regulatory authorities may suspend clinical trials if unacceptable health risks are identified, impacting the approval process for product candidates[307]. - The company is subject to ongoing regulatory oversight for marketed drugs, which includes compliance with U.S. and foreign requirements, and failure to comply could result in penalties or withdrawal of approvals[325]. Manufacturing and Supply Chain Issues - Manufacturing capabilities are being developed at a 90,000 square foot facility in Lexington, Massachusetts, which began cGMP manufacturing in early 2018[299]. - The company faces risks related to the complexity of oligonucleotide manufacturing, including potential delays and quality control issues[301]. - The company’s ability to manufacture product candidates may be hindered by supply chain disruptions, particularly for raw materials sourced from international suppliers[300]. - Increased competition for raw materials necessary for oligonucleotide production could severely impact manufacturing capabilities[376]. Market and Competitive Landscape - The pharmaceutical industry is highly competitive, with many large companies and research organizations targeting the same diseases, which could affect the company's ability to commercialize its drugs successfully[330]. - Competitors may have advantages such as greater financial resources, more extensive experience, and established products, which could adversely affect the company's competitive position[333]. - Market acceptance of the company's product candidates may be hindered, as key participants in the pharmaceutical marketplace may not adopt new technologies based on oligonucleotides[328]. Intellectual Property and Legal Risks - The company faces risks related to obtaining and enforcing market exclusivity for its technologies and product candidates, which is critical for maintaining commercial value[400]. - Legal issues regarding the patentability of biopharmaceuticals may create uncertainty and affect the company's ability to protect its intellectual property rights[401]. - The company may face challenges from third parties regarding its patent rights, which could adversely affect its ability to develop and commercialize its products[407]. - The company relies on trade secrets and confidential information for competitive advantage, but breaches of confidentiality agreements could harm its position[422]. International Operations and Taxation - The company faces risks associated with international operations, including regulatory changes and geopolitical instability, which could adversely affect its business[360]. - The company is subject to income and other taxes in the United States and foreign jurisdictions, and future changes in tax laws may adversely affect its business and financial condition[395]. - The company may be classified as a passive foreign investment company (PFIC), potentially resulting in adverse U.S. federal income tax consequences for U.S. holders[437]. Collaboration and Dependency Risks - The company commenced a collaboration with GSK in January 2023 to research, develop, and commercialize oligonucleotide therapeutics, including WVE-006, its first-in-class A-to-I(G) RNA editing candidate for AATD[365]. - Future revenues may heavily depend on the success of third-party collaborators, such as GSK, which is responsible for later clinical development and commercialization of the AATD program[369]. - The company relies on third-party collaborators for the development and commercialization of certain product candidates, which may limit control over resources and timelines[366].