LRP5

Low density lipoprotein receptor-associated protein 5/6 (LRP5/6) forms a complex with Wnt protein that triggers cytoplasmic tail phosphorylation of LRP5 or LRP6, which in turn causes Axin to bind to it and inhibit the activity of glycogen synthase kinase (GSK-3β). This process leads to increased phosphorylation of β-catenin, promotes its nuclear translocation, forms complexes with DNA-binding proteins, activates target gene promoters, and ultimately promotes differentiation, proliferation, and survival of osteoblasts. Studies have revealed that Sclerostin secreted by Osteocytes (Osteocytes) interferes with Wnt signaling and stabilizes β-catenin by competitively binding LRP5/6, thus reducing osteogenic activity and triggering osteoporosis. Therefore, blocking the interaction between sclerotin and LRP5/6 can enhance Wnt signaling, increase bone formation, and inhibit bone resorption. By specifically binding to osteosin, osteosinomumab reduces its inhibition of Wnt signaling pathway, thereby promoting osteogenesis and inhibiting osteoclast, and realizing dual mechanism therapy for osteoporosis. Currently, only one drug that targets SOST, Romozolzumab, has been approved for marketing. Romosozumab is the first humanized IgG2 monoclonal antibody targeting SOST osteosclerosis protein, but its road to market has been challenging. In 2017, the FDA rejected romosozumab's U.S. marketing application, citing concerns about an increased risk of cardiovascular events in patients. Subsequently, Amgen and UCB provided additional Phase III clinical data at the FDA request, which was not approved until April 2023. However, the EU CHMP rejected romosozumab's marketing application in June of the same year due to cardiovascular risk concerns, which also limited its projected 2024 sales to only $3.2 billion. Setrusumab is the world's second SOST monoclonal antibody for the treatment of osteogenesis imperfecta (OI). OI is a rare genetic bone disorder characterized by low bone mass and fragility fractures. Setrusumab is a fully human IgG2 monoclonal antibody that treats OI by inhibiting the function of sclerosin, a protein that inhibits the activity of osteoblasts. In June, Ultragenyx Pharmaceutical and Mereo BioPharma announced that setrusumab showed significant results in a sustained reduction in fracture rates in Orbit, the Phase 2 portion of a 2/3 clinical trial for OI patients. Blosozumab is a humanized monoclonal antibody against osteosin developed by Eli Lilly for the treatment of osteoporosis. The company is licensed to develop and commercialize Blosozumab in Greater China. Lilly completed Phase II clinical trials in the United States and Japan, showing favorable safety and efficacy. In May 2023, Transom Group announced Phase I data showing that TST002 (Blosozumab) demonstrated a good safety and tolerability profile in all dose groups, and demonstrated a clinically significant increase in lumbar bone density in terms of efficacy. SHR-1222, China's first SOST monoclonal antibody developed by Hengrui Pharmaceutical, is currently in Phase I clinical trials. Osteoporosis is a systemic bone disease characterized by loss of bone mass and destruction of bone microstructure, resulting in increased bone fragility and susceptibility to fracture. With an aging population, China has the largest number of osteoporosis patients, with about 90 million patients, accounting for 7 percent of the total population, and at least 210 million people with lower than normal bone mass. Therefore, the market potential of osteoporosis treatment drugs is huge. The market size of osteoporosis drugs in China is expected to reach 36.8 billion yuan in 2025 and further grow to 51.2 billion yuan in 2030. The sclerotinomumab represented by Romozomumab provides a new strategy for the treatment of osteoporosis, which is expected to overcome the limitations of traditional drugs and become the focus of future research and treatment.

The Surrozen Team at San Francisco Bay’s Angel Island/Courtesy of Surrozen, Inc. Surrozen Inc., a 6-year-old Bay-based biotech developing therapeutics through the Wnt pathway, announced Thursday it has partnered with Boehringer Ingelheim to research and develop a therapeutic for the treatment of retinal diseases. The partnership, valued at nearly $600 million, centers on Surrozen's developmental compound SZN-413, a bi-specific antibody targeting Fzd4-mediated and LRP5 Wnt signaling. The alliance will combine this technology with Boehringer's research and development expertise to develop a first-in-class treatment for patients with eye diseases, Surrozen announced. It is the first strategic partnership struck by Surrozen for one of its developmental compounds. Craig Parker, CEO of Surrozen, said this is an exciting time for the company as it prepares to pass along its first in-house developed asset to a partner. Parker told BioSpace Surrozen has been on the lookout for potential partners for a while. Retinal health is a stated focus for Boehringer and the partnership made sense, he said. “Their capabilities and knowledge about the genetics surrounding this indication were impressive,” Parker said. “Retinal health is a new commitment they made. They’re the optimal partner to translate the evidence we’ve generated into potential therapies for people with retinal diseases.” Diabetic retinopathy is a microvascular complication of diabetes. It is a major cause of vision loss and disability. The disease can cause diabetic macular edema and retinal ischemia. Parker said SZN-413 has the potential to allow for the regeneration of healthy eye tissue, which could not only halt retinopathy but potentially reverse the course of the disease. The Hypothesis FZD4-mediated Wnt signaling is known to play a critical role in retinal vascular development and vessel barrier function. Preclinical data showed SZN-413 could potently stimulate Wnt signaling in the eye, which encouraged normal retinal vessel regrowth. Additionally, the data showed treatment with SZN-413 was able to suppress pathological vessel growth and reduce vascular leakage. Diabetic retinopathy can also lead to overproduction of multiple signaling molecules, including VEGF. There are currently multiple anti-VEGF therapies on the market, including Genentech’s Avastin and Lucentis. However, so far none have shown success in treating retinal ischemia, according to Surrozen. That leaves a high unmet need for an approach like SZN-413. Last month, Surrozen published an article in Translational Vision Sciences and Technology highlighting the capabilities of SZN-413 in preclinical models of diabetic retinopathy. The data highlights the potential for SZN-413 to “simultaneously address the retinal non-perfusion and vascular leakage observed in both oxygen-induced and VEGF-induced preclinical diabetic retinopathy (DR) models," the company noted. The paper confirmed that FZD4 and LRP5 are the most abundant and relatively specific receptors expressed in retinal endothelial cells (ECs) and that SZN-413 “induced tight junction proteins in retinal vascular ECs.” Under terms of the deal, Boehringer made an upfront payment of $12.5 million to license SZN-413, as well as other Fzd4-specific Wnt-modulating molecules that could be a treatment for retinal diseases. Following an initial period of joint research, Boehringer will assume all development and commercial responsibilities. Surrozen will be eligible for up to an additional $586.5 million in developmental and commercial milestones. If SCN-413 is approved for commercial use, Surrozen stands to earn mid-single-digit to low-double-digit royalties on sales. Featured Jobs on BioSpace

Results highlight a potential novel treatment for diabetic and other retinopathiesUnique Wnt-mediated mechanism increases vascular integrity, and transforms pathologic regrowth into physiological regrowth of retinal blood vessels SOUTH SAN FRANCISCO, Calif., Sept. 26, 2022 (GLOBE NEWSWIRE) -- Surrozen, Inc. (Nasdaq: SRZN), a company pioneering targeted therapeutics that selectively modulate the Wnt pathway for tissue repair and regeneration, announced today the publication of an article by Surrozen scientists in the journal Translational Vision Science and Technology The results observed with Surrozen’s proprietary FZD4-specific agonist, SZN-413, highlight the potential for this novel mechanism of action to simultaneously address the retinal non-perfusion and vascular leakage observed in both oxygen-induced and VEGF-induced preclinical diabetic retinopathy (DR) models. Diabetic retinopathy is a microvascular complication of diabetes and a serious public health problem as it is a major cause of vision loss and disability in the middle-aged population. The pathogenesis of DR leads to vascular leakage, which causes diabetic macular edema, and capillary occlusion causing retinal ischemia. These areas of retinal non-perfusion can lead to overproduction of multiple signaling molecules, such as VEGF, that contribute to vascular leakage and pathologic angiogenesis. There are currently multiple anti-VEGF therapies available, however these have not been shown to improve retinal ischemia – leaving a high unmet medical need for new mechanisms of action that have the potential to achieve retinal reperfusion and can reduce the production of factors contributing to vascular leakage and pathologic neovascularization. SZN-413, a bi-specific antibody that targets FZD4 and LRP5, induced Wnt signaling and upregulated blood-retinal barrier gene expression in retinal endothelial cells (ECs). FZD4-mediated Wnt signaling is known to play a critical role in retinal vascular development and vessel barrier function in humans and rodent models. The results presented in this paper confirmed that FZD4 and LRP5 are the most abundant and relatively specific receptors expressed in the retinal ECs and SZN-413 induced tight junction proteins in retinal vascular ECs. In a preclinical oxygen-induced retinopathy model, intravitreal injections of SZN-413 significantly reduced avascular area size compared to the positive control, aflibercept. In addition, SZN-413 significantly reduced the pathologic neovascularization area size compared to vehicle and comparable to the positive control. In a VEGF-induced vascular leakage model, SZN-413 reduced retinal vascular leakage from baseline by approximately 80%. “Today Surrozen scientists reported results from studies showing that SZN-413, a bi-specific antibody that binds to FZD4 and LRP5, potently inhibited pathologic neovascularization, restored physiological neovascularization and prevented retinal vascular leakage. These results suggest that this modulation of FZD4 signaling may address important pathologic vascular characteristics of diabetic retinopathy,” said Wen-Chen Yeh, M.D., Ph.D., Chief Scientific Officer at Surrozen. Yang Li, Ph.D., Senior Vice President of Biology at Surrozen, added “The results in this paper further demonstrate Surrozen’s ability to effectively generate selective Wnt surrogates that stimulate tissue repair and renewal, and in this case, in disease models of diabetic retinopathy. SZN-413 has a novel mechanism of action that through FZD4 agonism may simultaneously address the retinal non-perfusion and leakage characteristics of diabetic retinopathy. We look forward to continued development of this lead therapeutic candidate that may offer a new treatment strategy for retinopathies and other diseases of the eye.” About Wnt Signaling Wnt signaling plays key roles in the control of development, homeostasis and regeneration of many essential organs and tissues, including liver, intestine, retina, lacrimal gland, lung, cornea, pancreas, skin and others. Modulation of Wnt signaling pathways has potential for treatment of degenerative diseases and tissue injuries. Surrozen’s platform and proprietary technologies have the potential to overcome the limitations in pursuing the Wnt pathway as a therapeutic strategy. About SZN-413Surrozen nominated SZN-413, a FZD4 tetravalent bi-specific antibody, as a development candidate in the first quarter of 2022 for the treatment of retinal vascular associated diseases. FZD4 mediated Wnt signaling is known to play a critical role in retinal vascular integrity and function. Data generated in preclinical models of retinopathy demonstrated SZN-413 stimulated Wnt signaling and was able to transform pathologic regrowth into physiological regrowth of retinal blood vessels. About Surrozen Surrozen is a clinical-stage biotechnology company discovering and developing drug candidates to selectively modulate the Wnt pathway. Surrozen is developing tissue-specific antibodies designed to engage the body’s existing biological repair mechanisms with potential application across multiple diseases such as inflammatory bowel disease, hepatitis, eye diseases, and diseases of the lacrimal gland, lung and airway, pancreas, skin and many others. For more information, please visit surrozen.com Forward Looking StatementsThis press release contains certain forward-looking statements within the meaning of the federal securities laws. Forward-looking statements generally are accompanied by words such as “will,” “may,” “suggest,” “potential,” “promise,” “look forward,” “expect,” “could,” or the negative of these words and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding Surrozen’s discovery, research and development activities, in particular its development plans for SZN-413, including anticipated clinical development timelines, and the potential for such product candidate to be used to treat human disease. These statements are based on various assumptions, whether or not identified in this press release, and on the current expectations of the management of Surrozen and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on as, a guarantee, an assurance, a prediction, or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Surrozen. These forward-looking statements are subject to a number of risks and uncertainties, including the initiation, cost, timing, progress and results of research and development activities, preclinical or and clinical trials with respect to SZN-413 and Surrozen’s other drug candidates; Surrozen’s ability to identify, develop and commercialize drug candidates; Surrozen’s ability to advance SZN-413 and successfully complete preclinical studies and clinical studies; the effects of the ongoing coronavirus (COVID-19) pandemic or other infectious diseases and natural disasters on Surrozen’s business; volatility in global economic, regulatory and market conditions, which may be adversely affected by the conflict between Russia and Ukraine; and those factors discussed in our Annual Report on Form 10-K for the year ended December 31, 2021, primarily under the heading “Risk Factors,” our Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, and other documents Surrozen has filed, or will file, with the Securities and Exchange Commission. If any of these risks materialize or our assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. There may be additional risks that Surrozen presently does not know, or that Surrozen currently believes are immaterial, that could also cause actual results to differ from those contained in the forward-looking statements. In addition, forward-looking statements reflect Surrozen’s expectations, plans, or forecasts of future events and views as of the date of this press release. Surrozen anticipates that subsequent events and developments will cause its assessments to change. However, while Surrozen may elect to update these forward-looking statements at some point in the future, Surrozen specifically disclaims any obligation to do so, except as required by law. These forward-looking statements should not be relied upon as representing Surrozen’s assessments of any date subsequent to the date of this press release. Accordingly, undue reliance should not be placed upon the forward-looking statements. Media Contact:Ian Stone, Managing DirectorEvoke CanaleTel.: (619) 518-3518Email: ian.stone@evokegroup.com Investor Contact:Email: Investorinfo@surrozen.com