ICOS x CD28

SEATTLE--(BUSINESS WIRE)--Nov. 10, 2017-- Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing treatments for autoimmune/inflammatory diseases and cancer, today announced immuno-oncology preclinical data characterizing the functional activity of molecules Alpine successfully generated from its variant immunoglobulin domain (vIgD) platform. Several novel immuno-oncology molecules were functionally active via multiple mechanisms of action, including the demonstration of tumor suppression in an animal model. The findings will be presented on Friday, November 10, in a poster session titled “Immune Modulation, Cytokines, and Antibodies” [#P343] at the Society for Immunotherapy of Cancer’s (SITC) 32nd Annual Meeting in National Harbor, MD. “Our unique vIgD platform is capable of producing first-in-class immuno-oncology biologics with potentially unique mechanisms of action,” said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. “This promising data highlights the versatility of the platform, showing vIgDs may be implemented in multiple therapeutic formats and may be tailored to modulate multiple molecular pathways according to the desired therapeutic application.” Preclinical Study Design and Results Alpine scientists used the vIgD directed evolution platform to engineer a number of vIgDs with unique binding profiles to proteins relevant to the immune synapse, including PD-1, PD-L1, CTLA-4, TIGIT, CD155, CD28, and/or ICOS. The poster describes the vIgD domains in multiple therapeutic formats, including tumor-localized Fc fusion proteins, multi-checkpoint inhibitors, and vIgDs fused with tumor-specific monoclonal antibodies (V-mAbs). Various in vitro and in vivo tests characterized the functional activity of these potentially novel therapeutics. Data include: Tri-specific vIgDs for treating cancer with a single domain capable of interacting with three different B7 family members. Depending on formatting, tri-specific vIgDs are potentiallycapable of agonizing CD28, blocking PD-L1, blocking CTLA-4, and/or depleting tumor cells and/or regulatory T cells. Initial formats investigated in an animal model of cancer demonstrated activity with tumor growth suppression.A dual ICOS/CD28 costimulatory vIgD fused with the HER2-targeting monoclonal antibody trastuzumab to provide immune stimulation in the tumor microenvironment. These V-mAbs demonstrated in vitroproof of principle for immune cell stimulation and proliferation in response to HER2-positive tumor cells.Multiple vIgD Fc fusions capable of targeting TIGIT and PD-1 while sparing CD226. These multi-checkpoint inhibitory molecules blocked checkpoint activity and improved IFN-γ production by “exhausted” T cells. “The SITC data suggest the versatile vIgD platform has the potential to contribute to the next generation of immuno-oncology therapeutics. Based on these and other encouraging preclinical data, we are continuing to identify and develop appropriate candidates from our vIgD platform for clinical trials for both oncology and inflammation,” said Mitchell H. Gold, M.D., Executive Chairman and Chief Executive Officer of Alpine. About Alpine Immune Sciences, Inc. Alpine Immune Sciences, Inc. is focused on developing novel protein-based immunotherapies using its proprietary Variant Ig Domain (vIgD) platform technology. The vIgD platform is designed to interact with multiple targets, including many present in the immune synapse. Alpine’s vIgDs are developed using a process known as directed evolution, which produces proteins capable of either enhancing or diminishing an immune response and thereby may potentially apply therapeutically to cancer, autoimmune and inflammatory diseases. Alpine has also developed Transmembrane Immunomodulatory Protein (TIP) technology, based on the vIgD platform, to potentially enhance engineered cellular therapies. For more information, visit www.alpineimmunesciences.com.

The study has taken longer and cost more than Alpine expected. AbbVie has given Alpine Immune Sciences a way out of its delayed, over-budget phase 2 lupus trial. Under the revised deal, Alpine will stop the study early—and accept a significantly reduced option fee if AbbVie chooses to pick up the asset. Alpine gave AbbVie an option on acazicolcept, a dual inhibitor of the CD28 and ICOS T-cell costimulatory pathways, in 2020 as part of a deal worth $60 million upfront. Investigators began enrolling 130 people with systemic lupus erythematosus in a phase 2 trial in June 2021. At that time, the aim was to complete the study in two years. The trial ended up taking longer—and costing more—than planned. Having seen the study overrun, Alpine has amended its deal with AbbVie. Enrollment in the trial will stop within 30 days. Alpine will allow patients who join the trial before enrollment closes to complete dosing, putting it on track to complete the study by the end of 2024. ClinicalTrials.gov has listed the study’s primary and full completion dates as November 2024 and January 2025, respectively, since August. As the timeline slipped from the original target, Alpine warned investors that “expenditures have exceeded our expectations” and that the “increased costs are expected to continue during the course of the phase 2 trial.” The revised deal frees Alpine from the burdens of seeing the study through to its original enrollment goal but deprives it of potential future earnings. AbbVie will now pay $10 million, rather than $75 million, if it chooses to option the asset. Alpine also knocked 25% off the agreed milestones and royalties, reducing its potential development and commercial paydays to $153.75 million, at most. Alpine agreed to the reductions after encountering issues that slowed the lupus trial. The biotech’s plan to open trial sites in Russia was ended by the war in Ukraine. Alpine took contingency measures but the enrollment rate lagged behind its goal, something it blamed on the intravenous route of administration, every other week dosing and available competing trials. The biotech told investors enrollment delays may result in the expiration of previously manufactured lots of acazicolcept, forcing it to produce more of the study drug. Making more would add to costs and “could also contribute to additional delays if such lots are not qualified in a timely manner to avoid a pause in enrollment,” Alpine told investors in a financial filing.  As the acazicolcept study winds down, Alpine will be free to focus on the development of its wholly owned BAFF/APRIL antagonist povetacicept. The biotech plans to move the candidate, which is also a potential treatment for lupus, into “a broad development plan,” CEO Mitchell Gold, M.D., said in a statement.

Pictured: AbbVie sign on a building/courtesy of Adobe Stock, Michael Vi Alpine Immune Sciences has revised its agreement with AbbVie and will stop enrolling patients in a Phase II lupus study of the drug acazicolcept, the companies announced on Thursday. According to the announcement, enrollment in the trial will end within 30 days. Still, patients who are already enrolled can finish the study, as well as patients in the screening process who meet the eligibility requirements. AbbVie will still hang on to the option to have an exclusive worldwide license to acazicolcept. However, the option exercise fee priced at $75 million has been lowered to $10 million and the pre-option development milestone has been removed. So far, Alpine has received $105 million in total upfront and milestone payments in the deal. The company said that any potential future milestones related to sales and development have also been reduced by 25% from the original amounts. “AbbVie has been a tremendous partner, and we appreciate their flexibility in amending our agreement to develop acazicolcept. While enrollment in the Synergy study will be stopped early by Alpine, we still anticipate that sufficient clinical and pharmacodynamic data will be available to enable a thorough evaluation of the study,” Alpine CEO Mitchell Gol said in a statement. “We plan to focus our development resources to advance [wholly owned BAFF/APRIL antagonist] povetacicept into a broad development plan.” Acazicolcept is a dual inhibitor in the CD28 and ICOS T-cell pathways and works by blocking two costimulatory pathways to improve outcomes for patients with autoimmune and inflammatory diseases. According to ClinicalTrials.gov site, the study is estimated to be completed in early 2025. In November 2023, Alpine touted some initial data for acazicolcept, stating that it suppressed the “expression of genes” associated with t-cell activation as well as reducing the “pathogenic hypergammaglobulinemia and glomerular IgG deposition” in mice with lupus. AbbVie has also had its sights set on other modalities as it has made several billion-dollar deals in the past few weeks. In late November 2023, the company paid $10 billion to buy ImmunoGen and its antibody-drug conjugate to treat ovarian cancer. Early this month, AbbVie bought Cerevel for $8.7 billion, gaining access to medicines to treat psychiatric and neurological conditions. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.