SPL84-23-1

- 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

Pictured: A collage of medical notes and anatomy/Nicole Bean for BioSpace With all the recent headlines being made in genetic medicine, a presentation from Turn Biotechnologies announcing the first successful in vivo delivery of messenger RNA to the skin with no off-target effects flew largely under the radar. While Turn Bio will still need to prove its platform in the clinic, the news may mark another step toward surmounting the hurdles the industry has faced with delivering RNA therapeutics outside of the liver. The potential for RNA-based medicines is great. As current small molecule and antibody drugs target only around 0.05% of the human genome, RNA therapeutics—including antisense oligonucleotides (ASOs), small interfering RNA interference (siRNA) and mRNA therapeutics—could significantly broaden the range of druggable targets, if they can safely and accurately reach their destinations. The discovery a decade ago that the conjugation of GalNac, an amino sugar moiety, to siRNA and ASO drugs could efficiently target the liver was a significant breakthrough for RNA therapeutics. Alnylam’s Amvuttra (vutrisiran), for polyneuropathy of hereditary ATTR (hATTR) amyloidosis, makes use of GalNac delivery, as does Novartis’ Leqvio (inclisiran), which reduces bad cholesterol. The problem, Iris Grossman, chief therapeutics officer at Eleven Therapeutics, told BioSpace last year, is that very few similar mechanisms have been discovered. Endosomal Escape and Targeting Steven Dowdy, a professor of cellular and molecular medicine at the University of California, San Diego, placed the challenges to extrahepatic delivery into two categories. For mRNA therapeutics, the biggest obstacles are specific targeting and immunogenicity, Dowdy told BioSpace. For RNA conjugates like ASOs and siRNAs, he said, the main challenge is endosomal escape. Steven Dowdy RNA therapeutics are taken up into the cell by endocytosis, but 99% or more of them are entrapped in an acidified endosome and degraded. The human body has developed natural defenses against RNA-based viruses, making the immune system resistant to foreign RNA. “Our therapeutics look to the body, to cells, like invading RNA,” Dowdy said. Most drug developers ensconce mRNAs in a lipid nanoparticle (LNP), which acts as both a protective shield and an endosomal escape device and allows around 5% of the therapy to make it unscathed into cells. Small RNA therapeutics lack such an endosomal escape device, so only 0.3% to 1% of the conjugate escapes the endosome into the target cell. In mRNA delivery, Dowdy said, targeting is the rate limiting step. While the APOE protein binds efficiently to the surface of certain LNPs, carrying them to the liver, he said similarly targeted proteins that enable the RNA to reach, say, the pancreas or cardiac myocytes, don’t exist. While chemists are trying to synthesize different types of lipids to bind proteins that would carry the LNP to other cell types, Dowdy said this has proven a difficult problem to solve for highly specific targeting. The Largest Organ For Anja Krammer, CEO of Turn Bio, the first objective is to effectively deliver the RNA to the cell itself. To solve this challenge, the company is creating tuneable RNA, which involves precisely delivering cargo to the cell and controlling the expression of the genetic information it carries. “Cells throughout the body and in different tissue types have very different responses and require a different level of delivery,” Krammer told BioSpace. Turn Bio’s pipeline includes investigational therapies for skin wounds, cellular exhaustion and frailty. Anja Krammer The second component, she said, is the vehicle that carries the RNA into a specific tissue type. Turn Bio found that carriers used for mRNA vaccine delivery were not effective or efficient enough for therapeutic delivery, so the company developed a proprietary LNP system with its own ionizable lipid. With vaccines, “you need just a very small amount of reaction in the body to be able to trigger that immune response,” Krammer said. But with a large organ like the skin, “you need to be able to hit a lot of cells, need to be able to transfect a lot of cells, and chances are, you’re gonna need to do it more than once.” Current tissue delivery systems create a lot of immunogenicity due to the PEG lipids used to keep them stable, she added. Turn Bio’s proprietary approach uses a stabilization system with a controlled release specific to a particular tissue environment. The preclinical data reported in November showed that “we now can contain that delivery within the skin tissue without the uptake into organs” such as the liver and spleen, Krammer said. The company plans to submit an Investigational New Drug application by the end of 2024. The Central Nervous System RNAi therapies like Alnylam’s Amvuttra and Onpattro (patisiran)—which both target the liver—work by silencing particular genes that cause or contribute to disease. They do so by degrading the genes’ mRNA. Vasant Jadhav Alnylam’s medicines leverage one of two platforms. In the first, siRNA is encapsulated within an LNP and delivered via IV infusion. Onpattro, the company’s first approved drug, for polyneuropathy of hATTR amyloidosis, is delivered in this way. In the second, a modified siRNA is conjugated to a targeting ligand to help it locate a specific cell or tissue within the body. The modifications provide stability against nucleases that would otherwise degrade the siRNA and also help minimize immune recognition of the siRNA, said Alnylam Chief Technology Officer Vasant Jadhav. Alnylam uses two conjugate systems: GalNAc conjugates and central nervous system (CNS)-targeted siRNA conjugates. Having proven its platforms with Onpattro and Amvuttra, Alnylam is turning its attention to the central nervous system. “RNAi is not limited to [the] liver,” Jadhav told BioSpace. “RNAi is a naturally occurring mechanism that’s happening in all cells and tissue types.” Some of these are in the CNS, where he said there are many genetically validated targets. Based on the delivery advances of the past 20 years, “we have highly modified siRNAs that have a targeting or delivery ligand that allows [the therapeutic] to be taken up in CNS,” Jadhav said. In October, Alnylam announced that its Alzheimer’s disease candidate, ALN-APP, showed sustained pharmacodynamic activity up to 10 months after administration in a Phase I trial. The treatment also led to “marked reductions” in two amyloid fragments implicated in Alzheimer’s and cerebral amyloid angiopathy, according to the company press release. “We’re really pleased with what we’re seeing in terms of the conjugates going from liver to now achieving this human [proof of concept] with the CNS molecules,” Jadhav said. The Lungs Clinical progress is also being made in delivering RNA to the lung. Jerusalem-based SpliSense is targeting a cystic fibrosis mutation with its ASO, SPL84. A short, vector-less single strand of RNA delivered directly to the lung via inhalation, SPL84 is designed to restore the function of the CFTR protein. In a recently completed Phase I study, it was shown to be safe and well tolerated in 32 healthy male volunteers. A Phase II trial, which will test the ASO in 18 cystic fibrosis patients carrying the 3849+10 kb C->T mutation, is slated to begin in the first half of next year. In a recently published preclinical study, SpliSense demonstrated the potential superiority of its inhaled approach to standard-size LNPs. In the study, which tested SPL84 in mouse and monkey lungs, the authors wrote that the candidate diffuses more effectively than these LNPs, primarily due to its small size. In comparison to Vertex and Moderna, whose CF program, VX-522, uses a LNP for delivery, SpliSense CEO Gili Hart said her company’s approach is “one hundred times more effective in relation to migration in the lungs.” In an interview last year, Ashley Mahoney, director of external communications at Vertex, told BioSpace that the company had successfully identified an LNP that can deliver the CFTR mRNA to target cells at levels that result in CFTR function levels associated with clinical benefit. While he declined to hazard a guess as to the next organ to see successful RNA delivery, Dowdy said: “If and when we solve the endosomal escape problem in a safe manner, that will open up the ability of RNA therapeutics to selectively treat . . . cancer, COVID and a multitude of other diseases.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn.