Summary of Wave Life Sciences FY Conference Call Company and Industry Overview - **Company**: Wave Life Sciences (NasdaqGM: WVE) - **Industry**: RNA editing and gene therapy, specifically targeting alpha-1 antitrypsin deficiency (AATD) and other related conditions Key Points and Arguments 1. Targeting Alpha-1 Antitrypsin Deficiency - Wave Life Sciences is focusing on alpha-1 antitrypsin deficiency as an initial target due to its validation from a single point mutation and measurable biomarkers [2][4][6] - The company is the first to enter the clinic with data on this target, indicating significant progress in the field of RNA editing [2][3] 2. Mechanism of Action - The approach involves correcting mutations on the transcript level, transitioning patients from a ZZ phenotype (high risk of lung and liver disease) to an MZ phenotype (low risk) [5][6] - The editing process aims to increase the production of M protein, which is crucial for patient health during acute phase responses [8][9] 3. Clinical Data and Results - Initial clinical data showed a shift from 0% M protein to 44% after a single dose, with expectations of reaching 65% M protein with multi-dose administration [7][8] - The total protein levels increased to 12 micromolar, with ongoing studies indicating potential for further increases [6][9] - The 400 mg cohort is anticipated to provide insights into the durability and efficiency of the editing process [9][10] 4. Future Steps and FDA Approval - The next steps for the WVE-006 program include further trials with the 200 mg and 400 mg cohorts, focusing on the drug's ability to respond to acute phase events [11][13] - Discussions around FDA approval thresholds suggest that the focus should be on achieving clinically relevant protein levels, particularly the MZ phenotype [16][17] 5. Broader Implications for RNA Editing - The panel discussed the potential of RNA editing technologies to address a variety of genetic conditions beyond AATD, emphasizing the importance of selecting appropriate targets [44][45] - The ability to achieve high levels of editing and the precision of the ADAR enzyme were highlighted as significant advantages over traditional gene editing methods [62][63] 6. Competitive Landscape - Other companies in the RNA editing space, such as ProQR and Arana, are also targeting AATD, indicating a competitive environment [18][26] - ProQR's AX-810 program aims to modulate protein function for cholestatic diseases, while Arana is focusing on optimizing ADAR engagement for therapeutic applications [26][21] 7. Investor Sentiment and Market Expectations - There is a growing interest from investors in the RNA editing space, with discussions shifting from the technology itself to the selection of indications for proof of concept [71][73] - The panel expressed confidence that RNA editing could reach a level of acceptance similar to siRNA therapies, potentially in a shorter timeframe [65][66] 8. Challenges and Considerations - The need for clear biomarkers and therapeutic benefits associated with editing levels was emphasized as critical for advancing the field [59][60] - The panel acknowledged misconceptions about RNA editing capabilities compared to DNA editing, particularly regarding expected editing efficiencies [73][74] Additional Important Content - The discussion highlighted the importance of understanding the pharmacology of RNA editing and its translation from animal models to human clinical data [60][61] - The potential for RNA editing to provide temporary, reversible modifications without long-term consequences was noted as a significant advantage [62][63] This summary encapsulates the key discussions and insights from the Wave Life Sciences FY Conference Call, focusing on the advancements in RNA editing technology and its implications for treating genetic disorders.

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]