MUC5AC

- Funding secured from CF Foundation and current investors for SPL84 Phase 2 study - - Two additional early-stage candidates expected to commence Phase 1-2a studies over the next 12 months – JERUSALEM, April 3, 2024 /PRNewswire/ -- SpliSense, a clinical-stage biotechnology company focused on the development of transformative RNA-based therapies for pulmonary diseases including cystic fibrosis (CF), muco-obstructive diseases like COPD, asthma, non-CF bronchiectasis (NCFB) and idiopathic pulmonary fibrosis (IPF), today announced that the U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) application for the initiation of a Phase 2 study for SPL84 in CF. SPL84 is the Company's lead antisense oligonucleotide (ASO) product for the treatment of people with CF carrying the 3849+10 kilobase (Kb) C->T splicing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The IND Clearance for the Phase 2 study initiation was granted following SPL84's favorable safety profile, supported by Phase 1 and preclinical toxicological and pharmacological data demonstrating the potential for full restoration of CFTR protein and activity, based on clinically predictive CF models. The Company has also announced today that it has secured funding from the CF Foundation and other existing investors to support the SPL84 Phase 2 study and additional pulmonary programs. This represents the CF Foundation's third investment in SpliSense's SPL84 program. "We are excited to initiate the Phase 2 study for SPL84 in CF with the support of the CF Foundation and other existing investors," said Gili Hart, PhD, Chief Executive Officer of SpliSense. " Although currently available CF therapies have managed to significantly increase life expectancy over the past few decades, there is still a significant unmet medical need for disease modifying treatments. Our lead product, SPL84, has been shown to fully restore CFTR activity in the CF gold standard pharmacological model. With the recent FDA IND clearance, we hope to be able to deliver, a life-changing treatment for people with CF carrying the 3849+10 Kb C->T mutation and expand our unique technology to additional CF mutations where there is a significant unmet need." "In addition, SPL84 serves as proof-of-concept for our platform for the treatment of additional pulmonary diseases, including muco-obstructive diseases and IPF, which are expected to enter the clinic over the next 12 months," added Dr. Hart. About Cystic Fibrosis (CF) CF is a genetic multisystem disorder that originates from various mutations in the CFTR gene, which is responsible for the production of the CFTR protein, a chloride channel expressed in the lungs as well as in other tissues. The past decade has seen a dramatic change in CF care with the approval of new CFTR modulators. However, approved CFTR modulators do not support all people with CF and do not offer a cure for the disease. Thus, new strategies of therapeutic development are essential to address partially responsive and non-responsive people with CF, specifically those carrying the 3849+10 Kb C->T splicing mutation. About SPL84 SpliSense utilizes short, precisely targeted proprietary RNA stretches called Antisense Oligonucleotides (ASOs) to modulate specific mRNA sequences or correct various mutations in the target mRNA. SPL84 binds specifically to the mutated CFTR RNA in the targeted sequence, leading to the modulation of the mutated region in the mRNA, potentially allowing the cell to produce fully functional CFTR proteins. SPL84 is administered directly and preferentially to the lungs via inhalation where it is designed to be taken up by the lung cells and to drive the production of corrected CFTR mRNA and eventually fully functional CFTR proteins. About SPL5AC (Muco-Obstructive Diseases) and SPL5B (IPF) SpliSense is advancing two preclinical ASO assets for the treatment of additional pulmonary diseases, including muco-obstructive diseases and IPF. Patients with muco-obstructive lung disease are susceptible to severe mortality and morbidity, creating an unmet need for the development of an effective and potent agent in the treatment of mucin induced lung disease. SPL5AC is an ASO that specifically lowers the level of MUC5AC expression and production in mucus, decreases mucus viscosity, eliminates accumulation in the airways, and reduces infection and inflammation as demonstrated in three proof of-concept disease animal models. Chronic overexpression of MUC5B is suggested to be the single greatest risk factor for the development of IPF. SPL5B is an ASO that lowers MUC5B expression and production avoiding accumulation of MUC5B mucin and plugs in the distil regions of the lungs. By lowering MUC5B levels and plugs formation, SpliSense aims to slow or delay IPF progression and improve patient's clinical condition and quality of life. About SpliSense SpliSense is a biotechnology company focused on the development of RNA-based treatments for pulmonary diseases. The Company's pioneering platform harnesses ASOs for treatment of unmet cystic fibrosis mutations and large pulmonary diseases including muco-obstructive diseases and IPF. Through its novel ASO pulmonary approach, SpliSense aims to address specific genetic mutations or deficiencies, by restoring or reducing protein function, thus targeting the root cause of the disease. The Company's investors include Cystic Fibrosis Foundation, OrbiMed, Israel Biotech Fund, Integra Holdings and Biotel Limited. For additional information, please visit our website at: Company contact: Tsipi Haitovsky Global Media Liaison +972-52-5989-892 [email protected] SOURCE SpliSense

- Arrowhead Expands the Reach of RNAi Therapies to Address Diseases in the Lung - Late-Breaking Clinical Data for ARO-RAGE for Treatment of Asthma Demonstrate Deep and Durable Gene Silencing - Promising Preclinical Data Across Multiple Gene Targets Suggest Potentially Broad Applications for Arrowhead’s TRiM™ Platform PASADENA, Calif.--(BUSINESS WIRE)--Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced data on its pipeline of pulmonary targeted RNA interference (RNAi) therapeutic candidates, including clinical results for ARO-RAGE, being presented at the European Respiratory Society (ERS) International Congress 2023 in Milan, Italy. In an ongoing Phase 1/2 clinical trial, ARO-RAGE, Arrowhead’s investigational RNAi therapeutic for the treatment of inflammatory lung diseases, achieved mean target gene knockdown of up to 90% with a maximum of 95% after a single inhaled administration. Interim results from the healthy volunteer portion of the ARORAGE-1001 Phase 1/2 clinical trial show that ARO-RAGE reduced soluble RAGE (sRAGE) concentration in bronchoalveolar lavage fluid (BALF) and serum in a dose-dependent manner. Reduction of serum sRAGE was similar in healthy volunteers and in patients with asthma at the 44 mg dose level. Additional dose cohorts are ongoing. Based on interim blinded safety results from the ongoing study, ARO-RAGE has been well-tolerated to date in healthy volunteers and asthma patients. “Today we announced additional data on multiple programs from our emerging pipeline of first-in-class pulmonary targeted RNAi therapeutic candidates at the European Respiratory Society International Congress. Clinical results from the ARO-RAGE Phase 1/2 study are highly encouraging and demonstrate a significant level of target gene knockdown with a duration of effect that may enable a long dosing interval possibly up to once every two months,” said Javier San Martin, M.D., chief medical officer at Arrowhead. “In addition, the preclinical data presented at ERS suggest that the TRiM™ platform can achieve compelling results across multiple additional gene targets in the lung, including MUC5AC, MMP7, and our newest program against thymic stromal lymphopoietin (TSLP), a clinically well validated target.” Arrowhead Abstracts at ERS 2023 A Clinical-Stage Inhaled RNAi Therapeutic for Pulmonary Inflammation Mediates Durable RAGE Silencing in Nonhuman Primates Poster Session 146, Sept. 10, 2023, 12:30-14:00 CEST A Lung-Targeted RNAi Therapeutics Delivery Platform Compatible with Subcutaneous Administration Mediates Pulmonary RAGE Silencing in Rodents and Nonhuman Primates Poster Session 146, Sept. 10, 2023, 12:30-14:00 CEST Silencing TSLP Expression with a Lung-targeted RNAi Molecule Suppresses Pulmonary Allergic Inflammation Poster Session 146, Sept. 10, 2023, 12:30-14:00 CEST A First-in-human Study of ARO-RAGE, an RNAi Therapy Designed to Silence Pulmonary RAGE Expression Late Breaking Abstract, Sept. 11, 2023, 11:00-12:15 CEST A Clinical-stage RNAi Therapeutic Candidate for IPF Mediates Durable MMP7 Silencing in Nonhuman Primates and Human Lung Tissue Poster Session 383, Sept. 12, 2023, 8:00-9:30 CEST Presentation slides and posters may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website. About Pulmonary TRiM™ Platform Arrowhead’s pulmonary Targeted RNAi Molecule (TRiM™) delivery platform facilitates selective delivery of therapeutic small interfering RNAs (siRNAs) to the lung epithelium via an integrin αvβ6 targeting moiety, mediating durable gene silencing upon inhalation. The pulmonary TRiM™ delivery platform is also compatible with subcutaneous administration and is capable of effectively silencing gene expression in the lung in rodents and non-human primates. While inhaled dosing offers a convenient local delivery solution, systemic administration would offer additional flexibility for some therapeutic applications. Subcutaneous administration in humans is currently being evaluated in a clinical trial. About ARO-RAGE ARO-RAGE is an investigational RNAi therapeutic targeting the receptor for advanced glycation end-products (RAGE) as a potential treatment for inflammatory lung diseases. RAGE is implicated as an upstream mediator of Type-2 and non-Type-2 inflammatory cascades and is involved in the pathogenesis of asthma and numerous inflammatory diseases. Silencing RAGE expression via RNAi is designed to reduce the amount of RAGE protein expressed on pulmonary epithelial cells. Reduced RAGE expression in the pulmonary epithelium may result in reduction of RAGE-dependent inflammatory pathways, leading to decreased exacerbation frequency and improved airflow in patients with asthma. About the ARORAGE-1001 Phase 1/2 Study ARORAGE-1001 (NCT05276570) is a Phase 1/2a, randomized, double-blinded, placebo-controlled study in normal healthy volunteers (NHV), Part 1, and in patients with inflammatory lung disease, Part 2. The single ascending dose portion of the study includes 5 sequentially enrolled NHV cohorts with escalating single-dose levels. The multiple ascending dose portion of the study includes 5 NHV cohorts, 3 asthma patient cohorts, and 1 cystic fibrosis patient cohort. The objectives of the study include the assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of ARO-RAGE in NHVs and patients with inflammatory lung disease. About Arrowhead Pharmaceuticals Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. For more information, please visit , or follow us on Twitter @ArrowheadPharma. To be added to the Company's email list and receive news directly, please visit . Safe Harbor Statement under the Private Securities Litigation Reform Act: This news release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Any statements contained in this release except for historical information may be deemed to be forward-looking statements. Without limiting the generality of the foregoing, words such as “may,” “will,” “expect,” “believe,” “anticipate,” “hope,” “intend,” “plan,” “project,” “could,” “estimate,” “continue,” “target,” “forecast” or “continue” or the negative of these words or other variations thereof or comparable terminology are intended to identify such forward-looking statements. 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These forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of our preclinical studies and clinical trials, and our research and development programs; our expectations regarding the potential benefits of the partnership, licensing and/or collaboration arrangements and other strategic arrangements and transactions we have entered into or may enter into in the future; our beliefs and expectations regarding milestone, royalty or other payments that could be due to or from third parties under existing agreements; and our estimates regarding future revenues, research and development expenses, capital requirements and payments to third parties. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of numerous factors and uncertainties, including the impact of the ongoing COVID-19 pandemic on our business, the safety and efficacy of our product candidates, decisions of regulatory authorities and the timing thereof, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, the future success of our scientific studies, our ability to successfully develop and commercialize drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, the enforcement of our intellectual property rights, and the other risks and uncertainties described in our most recent Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q and other documents filed with the Securities and Exchange Commission from time to time. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances. Source: Arrowhead Pharmaceuticals, Inc.

Korean researchers have shown that meclofenamate is a promising drug for controlling mucin levels in the respiratory mucus SEOUL, South Korea, July 26, 2023 /PRNewswire/ -- Our respiratory system is lined with a thin fluid layer called mucus on the inside. The mucus protects us from inhaling harmful and unwanted airborne agents from germs to pollutants; it achieves this feat due to its unique gel-like texture imparted by proteins called mucins. By extension, over- or under-secretion of mucins can lead to abnormal respiratory mucus—a pathological manifestation in many respiratory diseases like chronic bronchitis, cystic fibrosis, and asthma, among others. Although multiple clinically approved drugs are available that can combat abnormal respiratory mucus, many of them cause unwanted and potentially serious side effects. This calls for an alternative solution to provide relief to patients having respiratory diseases. Continue Reading Korean researchers repurpose a nonsteroidal anti-inflammatory drug called meclofenamate to treat the culprit in many respiratory diseases, namely abnormal mucus. In a recent study, a group of researchers from Korea repurposed an available drug called meclofenamate to understand its effects on the respiratory mucus. Meclofenamate had been traditionally used as a nonsteroidal anti-inflammatory drug for treating arthritis, parasitic infections, and prostate cancer, among other diseases. The researchers have now found that meclofenamate can also treat abnormal respiratory mucus by controlling mucin secretion. Their study was made available online on April 7, 2023, and was published in Volume 31 Issue 3 of the journal, Biomolecules & Therapeutics, in March 13, 2023. Speaking about the clinical potential of the results of the study, Dr. Hyun-Jae Lee, who is an associate professor at Smith Liberal Arts College and Department of Addiction Science, Graduate School, Sahmyook University, and one of the lead researchers exclaims, "Compared to conventional drug development strategies, our strategy of discovering new therapeutic effects from existing drugs saves a lot of time and costs." How indeed did Dr. Lee and his team go about this landmark study? The researchers tested the meclofenamate in a cell line called NCI-H292 that mimicked the respiratory cells, replete with the secretion of mucus with mucins. Specifically, they checked for the expression of a gene responsible for secreting a key mucin, MUC5AC. Further, they explored the molecular pathways involved in the action of meclofenamate on the mucin. Their findings hit the bull's eye, to say the least. Their results suggested that meclofenamate markedly reduced the gene and, additionally, the protein expression of MUC5AC. The drug was found to achieve this by influencing a biomolecular pathway that is extensively involved in the immune response, namely the nuclear factor kappa light chain enhancer of activated B (or NF-kB) cell signaling pathway; it reduced the degradation of a biomolecular component called 'inhibitory kappa Bα' and the movement of another such component called 'p65' into the nucleus of the respiratory cells. The gist of these findings is clear—meclofenamate is capable of controlling mucin secretion, and in turn, the characteristics of respiratory mucus. Without doubt, meclofenamate has emerged as a novel therapeutic agent for abnormal respiratory mucus, with this study. These findings not only succeed in repurposing a readily available and clinically approved drug for a new disease condition, but also sets an example for ongoing efforts related to drug development and research. Reference Title of original paper: Meclofenamate Suppresses MUC5AC Mucin Gene Expression by Regulating the NF-kB Signaling Pathway in Human Pulmonary Mucoepidermoid NCI-H292 Cells Journal: Biomolecules & Therapeutics DOI: About Sahmyook University Website: Contact: Eunyoung Eom 02-3399-3928 [email protected]com SOURCE Sahmyook University