Summary of Wave Life Sciences (WVE) Update / Briefing September 03, 2025 Company Overview - **Company**: Wave Life Sciences (WVE) - **Focus**: Development of therapies for Alpha-1 Antitrypsin Deficiency (AATD) and RNA editing technologies Key Industry Insights - **AATD Overview**: AATD is caused by the aggregation of mutant ZAAT protein in the liver and a lack of functional AAT in the lungs, leading to severe lung and liver diseases, particularly in homozygous PIZZ individuals [1][2] - **Current Treatments**: Existing treatments are limited to weekly IV augmentation therapy, which does not adequately address the acute phase response during exacerbations [1][2] Core Points and Arguments - **WVE-006 Development**: WVE-006 aims to correct the Z mutation, increasing circulating levels of wild type MAAT protein and reducing mutant ZAAT protein aggregation in the liver [4][5] - **Clinical Trials**: The Restoration 2 clinical trial is evaluating the safety, tolerability, and pharmacokinetics of WVE-006 in individuals with AATD [6][8] - **Safety Profile**: WVE-006 has shown a favorable safety profile with no serious adverse events reported across all doses tested [9][10] - **Biomarker Results**: In the single and multiple dose cohorts, mean max total AAT levels reached 12.9 and 11.9 micromolar, respectively, with MAAT protein levels increasing significantly [10][11] - **Dynamic Response**: WVE-006 demonstrated the ability to restore dynamic physiological AAT production during acute phase responses, a first for AATD therapies [15][17] Additional Important Insights - **RNA Editing Technology**: The proprietary RNA editing technology used in WVE-006 allows for efficient and durable editing, which is crucial for achieving therapeutic effects [19][20] - **Partnership with GSK**: GSK's involvement is expected to enhance the development and commercialization of WVE-006, leveraging their expertise in respiratory medicine [18][19] - **Future Programs**: Wave Life Sciences is advancing additional RNA editing programs, including PNPLA3 for liver disease, with a CTA filing expected in 2026 [19][20] - **Long-term Studies**: There are plans for long-term extension cohorts to gather additional data on repeat dosing and acute phase responses [87][88] Conclusion - **Transformative Potential**: WVE-006 has the potential to transform the treatment landscape for AATD by enabling patients to produce protective AAT protein when needed, addressing both lung and liver manifestations of the disease [17][18] - **Next Steps**: The company anticipates sharing further data from ongoing trials in early 2026, which will provide more insights into the efficacy and safety of WVE-006 [22]

WVE-006 Clinical Trial & Results - WVE-006 achieved durable production of serum AAT at levels associated with lower risk of AATD liver and lung disease following repeat 200 mg doses[5] - In the 200 mg cohort, circulating M-AAT reached 64.4% of total AAT protein[6, 31] - The 200 mg MAD cohort showed a 60.3% decrease in Z-AAT protein[6, 35] - A single 400 mg dose of WVE-006 resulted in total AAT reaching 20.6 µM during an acute phase response[7] - In the 400 mg SAD cohort, circulating M-AAT reached 47.2% of total AAT, with a 49.0% decrease in Z-AAT[41] Safety & Tolerability - WVE-006 was safe and well-tolerated in the RestorAATion-1 healthy volunteer study[26] - WVE-006 continues to be safe and well-tolerated in the RestorAATion-2 clinical trial[29] Ongoing Studies & Future Milestones - A 400 mg monthly multidose cohort is ongoing, with data expected in 1Q 2026[7, 43] - The company anticipates milestone payments in 2025 and beyond[49]

Core Insights - Wave Life Sciences announced positive data from the ongoing Phase 1b/2a RestorAATion-2 study for WVE-006, a treatment for alpha-1 antitrypsin deficiency (AATD), demonstrating durable production of serum AAT protein at levels associated with lower risk of liver and lung diseases [1][3][4] Group 1: Clinical Data and Efficacy - WVE-006 achieved a total AAT level of 11.9 µM and M-AAT level of 7.2 µM in the 200 mg multidose cohort, with M-AAT levels significantly increasing from 4.8 µM during the single dose portion [5][6] - A single 400 mg dose resulted in total AAT of 12.8 µM and M-AAT of 5.3 µM, with M-AAT levels reaching 47.2% of total AAT [8] - The treatment demonstrated the ability to dynamically increase AAT production during acute phase responses, as evidenced by a total AAT level of 20.6 µM observed in one individual during a kidney stone incident [6][10] Group 2: Safety and Tolerability - WVE-006 has shown a favorable safety profile, with all adverse events reported as mild to moderate, and no serious adverse events or discontinuations [9] Group 3: Market Potential and Licensing - Approximately 200,000 individuals in the US and Europe are affected by AATD, with current treatment options limited to weekly IV augmentation therapy, representing over $1.4 billion in worldwide sales in 2023 [2][15] - GSK holds the exclusive global license for WVE-006, with Wave eligible for up to $525 million in milestones and tiered royalties on net sales [11][17] Group 4: Future Developments - Wave plans to share new preclinical data from additional RNA editing programs at a Research Day in fall 2025 and initiate clinical development of new programs in 2026 [12][18]

Core Insights - Korro Bio, Inc. is progressing well in its Phase 1/2a REWRITE clinical trial for KRRO-110, with an interim readout expected in the second half of 2025, indicating potential best-in-class status for the treatment of Alpha-1 Antitrypsin Deficiency (AATD) [1][2][4] - The European Medicines Agency (EMA) has granted Orphan Drug Designation to KRRO-110, which provides various development incentives [1][5] - The company ended Q2 2025 with $119.6 million in cash, cash equivalents, and marketable securities, which is expected to fund operations into 2027 [6][19] Clinical Development Updates - Over 80% of planned healthy volunteers have been dosed in the REWRITE trial, with no serious adverse events or dose-limiting toxicities reported [1][5] - The REWRITE trial consists of two parts: Part 1 (single ascending doses) and Part 2 (multiple ascending doses), with completion of the trial anticipated in 2026 [4][10] - The interim data from Part 1 is expected to provide insights into the pharmacologically relevant dose levels for PiZZ patients [5][10] Financial Performance - Collaboration revenue for Q2 2025 was $1.5 million, a significant increase from no collaboration revenue in Q2 2024, attributed to the partnership with Novo Nordisk [7] - Research and Development (R&D) expenses rose to $21.0 million in Q2 2025 from $17.1 million in Q2 2024, driven by increased personnel and research costs [8] - General and Administrative (G&A) expenses increased to $7.6 million in Q2 2025 from $7.0 million in Q2 2024, primarily due to higher personnel-related expenses [9] Strategic Initiatives - The company is executing its 3-2-1 strategy, aiming to establish three clinical-stage development programs targeting two tissue types by leveraging its OPERA® platform [2][5] - A development candidate for a rare metabolic disorder program is expected to be announced by the end of 2025, which will be administered subcutaneously [1][13] - Korro continues to advance its collaboration with Novo Nordisk, focusing on cardiometabolic diseases with high unmet clinical needs [5][13]

Financial Data and Key Metrics Changes - Revenue for Q2 2025 was $8.7 million, a decrease from $19.7 million in the prior year quarter, attributed to the timing of revenue recognized under the collaboration agreement with GSK [28] - Research and development expenses increased to $43.5 million from $40.4 million in the same period in 2024, driven by spending in the inhibin E program and RNA editing programs [28] - General and administrative expenses rose to $18 million from $14.3 million in the prior year quarter, primarily due to share-based compensation and other external expenses [28] - The net loss for Q2 2025 was $50.5 million, compared to a net loss of $32.9 million in the prior year quarter [28] - Cash and cash equivalents at the end of Q2 2025 were $208.5 million, down from $302.1 million as of December 31, 2024, with expectations to fund operations into 2027 [29] Business Line Data and Key Metrics Changes - The AATD clinical program is advancing with promising data from the RESTORATION trials, showing significant increases in circulating AAT levels [7][9] - The Enlight clinical program for obesity has expanded its second cohort from 8 to 32 participants due to favorable safety and tolerability results [10][11] - FORWARD 53 clinical results for DMD demonstrated a statistically significant improvement in time to rise, marking it as a best-in-class therapeutic option [13][14] Market Data and Key Metrics Changes - The company is actively engaging with the DMD community, highlighting the importance of their FORWARD 53 clinical results [12][13] - The obesity market is being targeted with the Enlight program, which is positioned to offer a differentiated approach compared to current standard care [22][24] Company Strategy and Development Direction - The company aims to unlock the potential of RNA medicines through proprietary oligonucleotide chemistry, focusing on both rare and common diseases [4][5] - Plans to initiate clinical development of new programs in 2026, with a focus on expanding their wholly owned discovery pipeline [12][25] - The strategy includes preparing for regulatory filings and engaging with the FDA for accelerated approval pathways [15][16] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the ongoing clinical programs and the potential for upcoming data readouts to inform the therapeutic pipeline [31] - The company is encouraged by the engagement from the community and clinicians regarding their AATD program, indicating a strong need for effective therapies [6][9] - Future data from the RESTORATION and Enlight trials are expected to serve as key inflection points for the company [12][25] Other Important Information - The company welcomed Dr. Chris Wright as Chief Medical Officer, bringing extensive experience in drug development [5] - The company is focused on addressing both hepatic and extrahepatic targets with their RNA editing and siRNA programs [25][26] Q&A Session Summary Question: Can you elaborate on your reasons for expanding cohort two over advancing to cohort three sooner? - The decision to expand cohort two was based on safety data indicating the ability to dose escalate, and cohort two was modeled to align with weight loss similar to semaglutide [34][36] Question: Should we expect a linear dose response, or does the preservation of lean mass offset the weight loss aspect? - The expectation is that weight loss will be driven by fat without impacting muscle, but human data will clarify the translation of these effects [38] Question: What is your guidance on the different expectations from the two data readouts for the AATD program? - The focus will be on the multidose data, which is expected to show larger liver exposure and higher protein levels compared to single doses [44][46] Question: What is the desirable knockdown level for inhibin E? - The goal is to replicate preclinical data, aiming for a knockdown that aligns with therapeutic weight loss, and the company is open to continuing dose escalation beyond cohort three [51][52] Question: Can you provide specifics on the dosing completion for the two hundred milligram multidose? - All patients in the cohort have received their seven doses, and the study remains on track for data readout in the third quarter [58][59] Question: Is there anything qualitatively about the consistency of effect for the AATD program? - The company is encouraged by the consistency observed in preclinical models and early clinical data, indicating substantial protein production [65][66]

Core Viewpoint - Korro Bio, Inc. has received orphan drug designation from the European Medicines Agency (EMA) for its investigational medicine KRRO-110, aimed at treating Alpha-1 Antitrypsin Deficiency (AATD), marking a significant milestone for the company and highlighting the urgent need for innovative therapies in this area [1][2]. Company Overview - Korro Bio is a clinical-stage biopharmaceutical company focused on developing genetic medicines through RNA editing for both rare and prevalent diseases [6]. - The company utilizes its proprietary RNA editing platform, Oligonucleotide Promoted Editing of RNA (OPERA), to create differentiated programs that allow for precise and transient single base edits [6]. Product Development - KRRO-110 is currently undergoing evaluation in the Phase 1/2a REWRITE clinical study, with an interim readout expected in the second half of 2025 [2][4]. - The REWRITE study will assess the safety and tolerability of KRRO-110 in up to 64 participants, including healthy adults and AATD patients [4]. Orphan Drug Designation - The EMA grants orphan drug designation to medicines for life-threatening or chronically debilitating diseases affecting fewer than 5 in 10,000 people in the EU, providing various development incentives such as protocol assistance and market exclusivity upon approval [3]. - KRRO-110 also received orphan drug designation from the U.S. FDA in March 2025, further supporting its development [2]. Disease Background - AATD is a genetic disorder caused by a mutation in the SERPINA1 gene, leading to pulmonary emphysema and hepatic cirrhosis among affected adults [5]. - KRRO-110 aims to repair the SERPINA1 RNA to restore normal AAT protein secretion, potentially improving liver function and preserving lung function [5].

Core Viewpoint - ProQR Therapeutics has submitted a Clinical Trial Application (CTA) to the European Medicines Agency (EMA) for its lead program AX-0810, which targets NTCP to address cholestatic liver diseases, marking a significant milestone in advancing its Axiomer RNA editing platform into clinical development [1][2][8] Company Overview - ProQR Therapeutics is focused on developing transformative RNA therapies using its proprietary Axiomer™ RNA editing technology platform, which utilizes ADAR-mediated RNA editing to create specific nucleotide changes in RNA [4][5] - The company aims to address unmet medical needs in both rare and prevalent diseases through its innovative RNA repair platform [5] Product Details - AX-0810 is an investigational RNA editing oligonucleotide designed to treat cholestatic liver disease by targeting NTCP, which is involved in bile acid transport [3] - The mechanism of AX-0810 is supported by human genetics data indicating that certain NTCP variants can reduce bile acid reuptake, suggesting potential benefits in improving liver health [3] Clinical Trial Information - The proposed Phase 1 study for AX-0810 will evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult volunteers, with initial data expected in Q4 2025 [2][8] - The study will also explore biomarkers to assess early signals of target engagement, and is set to commence at a single site in the Netherlands pending regulatory clearance [2]

Summary of Wave Life Sciences Conference Call Company Overview - **Company**: Wave Life Sciences (WVE) - **Event**: 2025 Jefferies Global Healthcare Conference - **Date**: June 04, 2025 Key Points Industry and Pipeline - Wave Life Sciences is focused on RNA editing, aiming to establish a new category of medicine with its unique chemistry [5][6] - The company has multiple pipeline programs, with a lead program targeting alpha-one antitrypsin deficiency (ATD) [3][4] Alpha-One Antitrypsin Program - Upcoming data sets include a 200 mg cohort in Q2 and a 400 mg cohort later in the year [4][8] - Initial data showed therapeutic levels of alpha-one antitrypsin protein, with 11 micromolar total protein and 7 micromolar of the edited M protein [5][6] - The program aims to demonstrate the potential for monthly dosing based on the observed protein production [6][8] - The collaboration with GSK includes over $520 million in milestones and $2.3 billion in total milestones related to the RNA editing pipeline [18][19] Obesity Program - The obesity program (HIBE) is in Phase 1, with data expected later this year [21][22] - The study includes subtherapeutic and therapeutic cohorts, with a focus on weight loss mechanisms and safety [22][26] - Inhibin E is highlighted for its potential to drive fat loss without muscle loss, showing a favorable metabolic profile in heterozygous patients [25][26][28] DMD and Huntington's Disease Programs - For Duchenne Muscular Dystrophy (DMD), discussions with the FDA are ongoing regarding accelerated approval based on dystrophin expression and muscle health data [39][40] - The company is also preparing for a pivotal trial for Huntington's disease, utilizing natural history data to measure patient progression [42][43] Regulatory Environment - The regulatory landscape for Huntington's disease is evolving, with potential changes in endpoints that could benefit Wave Life Sciences [43][44] - The company is positioned to adapt to changes in regulatory expectations, particularly regarding mutant huntingtin as a clinical surrogate endpoint [44] Additional Insights - The focus on RNA editing and the unique delivery mechanisms may differentiate Wave Life Sciences from other companies in the siRNA space [31][32] - The potential for once or twice a year dosing in obesity treatment could significantly expand market opportunities [36][37] - The emphasis on safety, tolerability, and target engagement in clinical trials is critical for advancing the pipeline [28][30]

Summary of Cora Bio Conference Call Company Overview - **Company**: Cora Bio - **Industry**: Biotechnology, specifically focusing on genetic medicines for chronic diseases [1][2] Core Points and Arguments - **Mission and Strategy**: Cora Bio aims to develop genetic medicines targeting complex chronic diseases by leveraging pharmacology and genetic insights. The focus is on creating a toolbox for biological pathway activation that is not available with small molecules [3][4] - **RNA Editing Technology**: The company utilizes RNA editing through oligonucleotides to modify specific genes, aiming for high levels of editing (above 50%) to restore normal protein function in patients [4][5] - **Pipeline Development**: Cora Bio has a three:two:one strategy, planning to advance three candidates into clinical trials across two tissue types. The third indication is expected to target the central nervous system (CNS) for ALS [6][7] - **Regulatory Environment**: The company has engaged with the FDA, receiving orphan drug designation and conducting pre-IND meetings. There is concern about the increasing regulatory bar but confidence in the data driving approval processes [10][12][13] - **Preclinical Data**: Cora Bio presented promising preclinical data showing significant editing efficiency (60-65%) in animal models, which translates well to protein levels in circulation [18][20] - **Lipid Nanoparticle Delivery**: The company uses lipid nanoparticles for drug delivery, which have shown safety in patients with liver conditions. The focus is on optimizing dosing to achieve therapeutic protein levels [21][23][25] Important but Overlooked Content - **Patient Population Insights**: The company discussed the baseline liver function levels in patients with ZZ mutations, indicating that many have normal liver function, which may mitigate concerns about toxicity from lipid nanoparticles [22][23] - **Dosing Strategy**: Cora Bio aims for a dosing frequency of every three to six weeks, with the goal of achieving therapeutic protein levels that are comparable to normal individuals [26] - **Regulatory Pathway Confidence**: The company believes that demonstrating protein levels close to normal and achieving significant editing levels could support discussions for accelerated approval with regulators [39][40] - **Financial Position**: Cora Bio has a cash runway into 2027, with $139 million on the balance sheet and potential milestones from collaborations, indicating a solid financial foundation for ongoing development [47]

Summary of Beam Therapeutics Conference Call Company Overview - **Company**: Beam Therapeutics (Ticker: BEAM) - **Event**: 2025 Global Health Care Conference - **Date**: May 20, 2025 - **Key Speaker**: John Evans, CEO Industry and Core Technology - **Industry**: Biotechnology, specifically focusing on gene editing and therapies - **Core Technology**: Base editing, a next-generation CRISPR technology that allows precise single base changes in genes without double-stranded breaks [3][4] Key Developments and Progress - **Clinical Progress**: - Multiple franchises in the base editing portfolio are clinically derisked with clear paths toward registration [2] - Successful data for sickle cell disease (B101) showing a differentiated profile compared to competitors [3] - First in vivo data for alpha-one antitrypsin deficiency (BEAM-302) demonstrating therapeutic thresholds [4] - First patient dosed for glycogen storage disease 1A (BEAM-301) [4] - **Financial Position**: Well-financed with successful capital financing, providing cash into 2028 to support ongoing projects [5] Regulatory Environment - **FDA Dynamics**: - New leadership at the FDA may impose a higher bar for approvals, but there is optimism about working with the FDA to bring effective therapies to market [7][10] - The company feels aligned with FDA's goals of addressing root causes of diseases [10][11] - Received RMAT designation, allowing for early engagement with the FDA regarding accelerated approval pathways [41][42] Safety and Efficacy - **Safety Profile**: - The company emphasizes a strong safety profile for its lipid nanoparticles (LNPs), differentiating from competitors [31][32] - Minimal liver toxicity observed in lung patients, allowing for future trials involving liver-involved patients [61][63] - **Efficacy Measures**: - Focus on total alpha-one antitrypsin levels and functional measures as endpoints for approval [47][48] - Plans to conduct biopsies and bronchoscopies to measure disease progression and treatment effects [49][50] Competitive Landscape - **Market Position**: - Monitoring competitors like Vertex and CRISPR, but confident in the differentiation of their data and therapies [66][68] - Plans to invest in next-generation therapies while maintaining the current pipeline [68] Future Outlook - **Next Steps**: - Engaging with the FDA over the next 6-12 months to refine the path to market and explore accelerated approval options [55][56] - Anticipating increased patient enrollment in trials to gather more data and demonstrate demand [57] Conclusion - Beam Therapeutics is positioned strongly within the biotechnology sector, leveraging its innovative base editing technology to address significant medical needs. The company is navigating a complex regulatory environment while maintaining a focus on safety and efficacy, with a clear strategy for future growth and market expansion.