Core Insights - Korro Bio, Inc. has provided updates on its Phase 1/2a REWRITE clinical trial for KRRO-110, reported third-quarter financial results, and outlined strategic business decisions [1][5]. Clinical Trial Update - KRRO-110 successfully generated functional M-AAT protein in patients with Alpha-1 Antitrypsin Deficiency (AATD), although the protein levels were below preclinical projections [2][5]. - The REWRITE trial has completed all six planned single ascending dose cohorts in healthy volunteers, with no dose-limiting toxicities observed [4][7]. - The trial is currently evaluating KRRO-110 in two AATD patient cohorts at doses of 0.6 mg/kg and 0.8 mg/kg [4][7]. Development Candidates - Korro has nominated KRRO-121, a GalNAc-conjugated construct aimed at treating hyperammonemia, marking an expansion of its RNA editing platform [3][5]. - The company plans to advance KRRO-121 and a GalNAc version for AATD patients into clinical trials in the second half of 2026 and 2027, respectively [3][5]. Financial Results - As of September 30, 2025, Korro reported cash, cash equivalents, and marketable securities totaling $102.5 million, down from $163.1 million at the end of 2024 [12][26]. - Collaboration revenue for the third quarter of 2025 was $1.1 million, compared to no revenue in the same period of 2024 [13]. - Research and development expenses decreased to $13.8 million from $16.0 million year-over-year, while general and administrative expenses also saw a decline [14][15]. Strategic Restructuring - The company is implementing a strategic restructuring that will reduce its workforce by approximately one-third to focus on generating clinical data and advancing GalNAc-conjugated programs [3][18]. - This restructuring is expected to extend Korro's cash runway into the second half of 2027, with one-time restructuring charges estimated at $2.4 million [18]. Regulatory Milestones - KRRO-110 has received Investigational New Drug clearance from the FDA, along with Fast Track and Orphan Drug Designations [7][19]. - The company is prioritizing high-potential GalNAc-conjugated programs targeting the liver, including KRRO-121 [7][8].

Summary of Wave Life Sciences FY Conference Call Company Overview - **Company**: Wave Life Sciences (NasdaqGM: WVE) - **Industry**: RNA medicines, focusing on oligonucleotides, RNA editing, and genetic targets [3][4] Core Points and Arguments RNA Medicines and Pipeline - Wave Life Sciences is positioned at the forefront of RNA medicines, utilizing a proprietary chemistry engine to accelerate the development of oligonucleotides, including siRNA and RNA editing [3] - The company has successfully progressed from identifying genetic targets to generating meaningful human therapeutic data within 24 months, exemplified by their INHBE program for obesity [3] Alpha-1 Antitrypsin Program (WVE-006) - WVE-006 is the first RNA editing program to enter clinical trials, targeting alpha-1 antitrypsin deficiency [5] - The program achieved approximately 65% editing on protein levels, with a notable increase in protein response during acute exacerbations, demonstrating the potential for effective treatment [6][10] - The treatment paradigm is shifting from traditional IV protein replacement therapy to a more sustainable editing approach that can generate protein during acute events [9][10] - The FDA has not set a specific threshold for treatment efficacy, but the original approval for protein replacement therapy was based on an 11-micromolar threshold [19][20] Competitive Landscape - Wave Life Sciences is the only non-LNP derived therapy in the RNA editing space, differentiating itself through safety and durability by avoiding LNPs, which can cause liver injury [21][22] - The company emphasizes the specificity of its RNA editing approach, avoiding off-target effects and aberrant proteins, which are common in DNA editing [22][23] Obesity Program (INHBE - Program 007) - The INHBE program targets inhibin E, leveraging human clinical genetics to address obesity without inducing starvation or lean mass loss [28][29] - Wave has demonstrated significant reductions in activin E protein, correlating with weight loss similar to semaglutide, while maintaining lean muscle mass [30][31] - The potential for a once or twice yearly maintenance therapy is highlighted, with ongoing studies to assess fat loss and metabolic health [36][38] Future Studies and Market Strategy - Wave plans to conduct phase two studies on obese patients to evaluate fat reduction and sustainability of weight loss, with a focus on reducing reliance on GLP-1 therapies [42][43] - The company is exploring strategic collaborations while maintaining a wholly owned asset approach, aiming for clear registrational paths in the obesity landscape [42][43] Other Important Content - The company is optimistic about the potential for its therapies to transform patient outcomes in both alpha-1 antitrypsin deficiency and obesity [23][30] - Wave Life Sciences is focused on delivering data that demonstrates the efficacy and safety of its treatments, with upcoming data releases expected to provide further insights into their therapeutic potential [44][45]

Financial Data and Key Metrics Changes - Revenue for Q3 2025 was $7.6 million compared to a net loss of $7.7 million in the prior year quarter, attributed to the timing of revenue recognized under the collaboration agreement with GSK [22] - Research and development expenses increased to $45.9 million from $41.2 million year-over-year, driven by advancements in the inhibin E and RNA editing programs [22] - General and administrative expenses rose to $18.1 million from $15 million in the prior year quarter, primarily due to share-based compensation [22] - Net loss for Q3 2025 was $53.9 million, an improvement from a net loss of $61.8 million in the prior year quarter [23] - Cash and cash equivalents at the end of Q3 2025 were $196.2 million, down from $302.1 million as of December 31, 2024, but extended cash runway into Q2 2027 with additional proceeds [24] Business Line Data and Key Metrics Changes - The company highlighted significant advancements in the WVE-007 program, showing dose-dependent reductions in activin E levels, with reductions of 56%, 75%, and 85% for different dosing cohorts [8][9] - WVE-006 demonstrated the potential to restore physiological AAT production, achieving AAT levels of up to 13 micromolar and a 60% decrease in mutant ZAAT protein [13] - The DMD program, WVEN531, showed a statistically significant improvement in time to rise, with a 3.8 seconds improvement compared to natural history [18] Market Data and Key Metrics Changes - The company is addressing a significant market need with an estimated 9 million homozygous individuals living with PNPLA3I148M liver disease in the US and Europe, who are at a nine-fold higher risk of dying from their liver disease compared to non-carriers [16] - The obesity market is highlighted as having over 1 billion individuals living with obesity, many of whom lack access to current GLP-1 therapies, presenting a unique opportunity for the company's treatments [55] Company Strategy and Development Direction - The company is focused on advancing its pipeline, particularly in RNAi and RNA editing, with a strategy to leverage proprietary chemistry and platform innovations [5] - There is a strong emphasis on developing non-incretin treatment approaches for obesity, with WVE-007 positioned as a potential maintenance therapy to prevent rebound weight gain [6][11] - The company aims to build on its momentum in the obesity space, with plans for further studies and potential partnerships to enhance development [43] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the progress made in clinical trials, particularly with WVE-007 and WVE-006, and the potential for these therapies to transform treatment paradigms [25] - The management team acknowledged the competitive landscape in the obesity market and the need for innovative solutions that provide durable results without the side effects associated with current therapies [55] - There is confidence in the ability to meet regulatory requirements and achieve clinical milestones, with ongoing discussions with the FDA regarding imaging endpoints for Huntington's disease [29][30] Other Important Information - The company is preparing for a global potentially registrational phase 2-3 study of WVE-003 in adults with Huntington's disease, using caudate volume as a primary endpoint [19] - The company has received positive feedback from key opinion leaders regarding the potential of its RNA editing programs to address unmet medical needs [14] Q&A Session Summary Question: Inquiry about cholesterol fat mobilization post-inhibin knockdown - Management confirmed no observed changes in increased lipids and deposits in the liver from preclinical studies, indicating positive findings regarding fat mobilization [26][27] Question: Pre-IND meeting with FDA regarding Huntington's imaging endpoints - Management confirmed alignment with the FDA on using MRI as an imaging endpoint, emphasizing the importance of well-designed clinical trials [29] Question: Changes in gene expression timing in obesity studies - Management noted that while gene expression changes occur over time, early engagement of targets and sustained suppression of proteins are observed [34] Question: Insights on acute phase response in AATD patient - Management indicated that the patient responded as expected, with no new insights beyond the initial findings [48] Question: Future studies beyond NYTE for obesity program - Management expressed interest in exploring further studies and potential strategic partnerships, while noting that the GSK collaboration would not hinder these opportunities [62]

Core Insights - ProQR Therapeutics reported its financial and operational results for Q3 2025, highlighting significant advancements in its RNA editing technology platform, Axiomer, and the initiation of a first-in-human study for its lead program AX-0810 [1][2]. Financial Highlights - As of September 30, 2025, ProQR held cash and cash equivalents of approximately €106.9 million, a decrease from €149.4 million at the end of 2024 [4]. - The net cash used in operating activities for the nine-month period ended September 30, 2025, was €39.4 million, compared to €27.0 million for the same period in 2024 [4][6]. - The net loss for the nine-month period was €33.3 million, or €0.32 per diluted share, compared to a net loss of €18.5 million, or €0.23 per diluted share, for the same period last year [7][16]. Recent Progress and Upcoming Events - The company received CTA authorization for the Phase 1 trial of AX-0810, targeting NTCP for cholestatic diseases, and is initiating the study in healthy volunteers [4][5]. - Initial safety, tolerability, and pharmacokinetic (PK) data from Cohort 1 are expected by year-end 2025, with target engagement data anticipated in the first half of 2026 [5]. - ProQR's Axiomer pipeline includes programs targeting various diseases, such as AX-2402 for Rett syndrome and AX-2911 for fatty liver disease, with updates expected in the coming months [5]. Collaboration and Milestones - The company achieved certain milestones in its collaboration with Eli Lilly, amounting to $2.0 million (~€1.8 million) [6]. - ProQR continues to execute its partnership with Eli Lilly, with potential data updates and milestone income from the ongoing collaboration [5]. Research and Development Costs - Research and development costs for the nine-month period ended September 30, 2025, were €34.8 million, compared to €25.7 million for the same period last year [6]. - General and administrative costs were €11.2 million for the same period, up from €9.7 million in 2024 [6].

Company Overview - ProQR is pioneering ADAR-mediated RNA editing with its Axiomer platform, moving from invention to clinical trials [11, 17] - The company has a strong intellectual property estate and strategic partnerships with Eli Lilly and Rett Syndrome Research Trust [17, 135] - ProQR's cash and cash equivalents were €119.8 million as of the end of Q2 2025, providing a runway into mid-2027 [18, 136] Pipeline and Clinical Development - AX-0810, targeting NTCP for cholestatic diseases, has received CTA authorization and is entering a Phase 1 clinical trial [17, 21] - The Phase 1 trial aims to establish safety, PK, and target engagement in healthy volunteers [21] - AX-2402, for Rett syndrome, is rapidly advancing, positioning ProQR at the forefront of neurological RNA editing medicines [21] AX-0810 and Cholestatic Diseases - Cholestatic diseases, including Primary Sclerosing Cholangitis (PSC) affecting approximately 80,000 adults and Congenital Biliary Atresia affecting approximately 20,000 pediatrics, have high unmet medical needs [24, 38] - AX-0810 is a first-in-class RNA editing therapy designed to modulate the NTCP channel, limiting bile acid uptake while preserving other channel functions [31] - The therapeutic goal of AX-0810 is to reduce inflammation and fibrosis, alleviate symptoms in PSC and BA, and prevent or delay cirrhosis, organ failure, and transplant [36] AX-0810 Clinical Trial Design - The Phase 1 trial is a multiple ascending dose (MAD) study with N=33 participants (24 on treatment, 9 on placebo) across three cohorts: 3mg/kg, 6mg/kg, and 9mg/kg (TBC) [103, 104] - The trial will assess safety, tolerability, and PK of AX-0810, and confirm target engagement as measured by changes in bile acid levels, bile acid profile, and TUDCA challenge [107] - Initial Cohort 1 safety, tolerability, and PK data are expected toward the end of 2025, with target engagement data on all cohorts anticipated in H1 2026 [107, 131]

Core Insights - Wave Life Sciences is hosting its 2025 Research Day, focusing on RNA editing and RNA interference (RNAi) technologies [2]. Group 1: Event Overview - The event is being recorded and is accessible for future reference [1]. - The presentation materials will be available on the company's website in the Investors section after the call [2]. Group 2: Management Statements - Management may provide forward-looking statements during the presentation, which are subject to various risks and uncertainties [3].

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]