Full Antagonist Research Articles

6461 VRDN-003, A Full Antagonist Antibody To The IGF-1 Receptor For Thyroid Eye Disease (TED): Safety And Pharmacokinetic Results Of Subcutaneous Administration In Healthy Volunteers

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. B. Dickinson: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. A. Matthew: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. J. Vijayaraghavan: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. C. Michalsky: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. V. Bedian: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. Introduction: While VRDN-001 is a full antagonist antibody to the IGF-1 receptor (IGF-1R) with phase 2 proof-of-concept data showing clinically meaningful improvements in thyroid eye disease (TED) symptoms after 2 intravenous (IV) infusions, VRDN-003 is a next-generation half-life extended version of VRDN-001. VRDN-003’s half-life extension has the potential to provide sustained pharmacokinetics (PK) and pharmacodynamics (PD) with less frequent administration. We present results from an ongoing study to assess the safety, PK, PD, and bioavailability of VRDN-003 for subcutaneous (SC) administration. Methods: Healthy volunteers (HVs) were randomized to receive a single dose of VRDN-003 or placebo in the following 4 IV or SC dose cohorts: IV 5.0 mg/kg, IV 15.0 mg/kg, SC 300 mg, or SC 600 mg. Preliminary treatment-emergent adverse events (AEs) were assessed through December 12, 2023, and will continue to be assessed through study exit (120 days). Preliminary PK parameters including bioavailability were assessed by noncompartmental analysis, and a 2-compartment Population PK model was employed to simulate exposures following repeat SC dosing. Results: Twenty-eight HVs received either VRDN-003 IV (n=8), VRDN-003 SC (n=12), placebo IV (n=4), or placebo SC (n=4). AEs were reported by 25% (2/8) of participants who received VRDN-003 IV, 25% (3/12) who received VRDN-003 SC, and 13% (1/8) who received placebo. Of the AEs, 3 were deemed treatment related, all occurring in VRDN-003 SC-treated patients and all grade 1/mild as follows: injection site reaction, insomnia, and hepatic enzyme increased. No serious AEs were reported. VRDN-003 half-life was estimated at 40-50 days, 4-5 times longer than VRDN-001; bioavailability is currently estimated to be approximately 60% after SC administration. Simulated dosing regimens show the potential for VRDN-003 to be administered SC Q4W or Q8W and reach exposure levels observed with the VRDN-001 parent molecule in its prior phase 2 study. Conclusions: A single dose of VRDN-003 administered IV or SC to HVs was well tolerated and showed favorable PK for SC administration including a half-life of 40-50 days, 4-5 times longer than its parent molecule, VRDN-001. These results show the potential for VRDN-003 SC dosing regimens with the goal of reducing the treatment burden associated with achieving IGF-1R blockade in TED. Safety and efficacy of VRDN-003 SC will be further assessed in planned clinical studies enrolling patients with TED. Presentation: 6/1/2024

Target-based discovery of antagonists of the tick (Rhipicephalus microplus) kinin receptor identifies small molecules that inhibit midgut contractions.

A GPCR (G protein-coupled receptor) target-based approach was applied to identify antagonists of the arthropod-specific tick kinin receptor. These small molecules were expected to reproduce the detrimental phenotypic effects that had been observed in Rhipicephalus microplus females when the kinin receptor was silenced by RNA interference. Rhipicephalus microplus, the southern cattle tick, cattle fever tick, or Asian blue tick, is the vector of pathogenic microorganisms causing the deadly bovine babesiosis and anaplasmosis. The widespread resistance to acaricides in tick populations worldwide emphasizes that exploring novel targets for effective tick control is imperative. Fifty-three structural analogs of previously identified tick kinin antagonists were screened in a 'dual-addition' calcium fluorescence assay using a CHO-K1 cell line expressing the tick kinin receptor. Seven molecules were validated as non-cytotoxic antagonists, four of which were partial (SACC-0428764, SACC-0428780, SACC-0428800, and SACC-0428803), and three were full antagonists (SACC-0428799, SACC-0428801, and SACC-0428815). Four of these antagonists (SACC-0428764, SACC-0428780, SACC-0428799, and SACC-0428815) also inhibited the tick midgut contractions induced by the myotropic kinin agonist analog 1728, verifying their antagonistic bioactivity. The small molecules were tested on recombinant human neurokinin (NK) receptors, the one most similar to the invertebrate kinin receptors. Most molecules were inhibitors of the NK1 receptor, except SACC-0412066, a previously identified tick kinin receptor antagonist, which inhibited the NK1 receptor only at the highest concentration tested (25 μm). None of the molecules inhibited the NK3 human receptor. Molecules identified through this approach could be useful probes for studying the tick kinin signaling system and midgut physiology. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

6461 VRDN-003, a Full Antagonist Antibody to the IGF-1 Receptor for Thyroid Eye Disease (TED): Safety and Pharmacokinetic Results of Subcutaneous Administration in Healthy Volunteers

6461 VRDN-003, a Full Antagonist Antibody to the IGF-1 Receptor for Thyroid Eye Disease (TED): Safety and Pharmacokinetic Results of Subcutaneous Administration in Healthy Volunteers

VRDN-003, a full antagonist antibody to IGF-1R for thyroid eye disease (TED): phase 1 results show potential for subcutaneous administration

VRDN-003, a full antagonist antibody to IGF-1R for thyroid eye disease (TED): phase 1 results show potential for subcutaneous administration

Effect of Reduced Dose Spironolactone in Heart Failure With Reduced Ejection Fraction Patients Intolerant of Full Dose Mineralocorticoid Receptor Antagonists

Effect of Reduced Dose Spironolactone in Heart Failure With Reduced Ejection Fraction Patients Intolerant of Full Dose Mineralocorticoid Receptor Antagonists

Building the Glucagon-Like Peptide-1 Receptor Brick by Brick: Revisiting a 1993 Diabetes Classic by Thorens etal.

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor involved in the regulation of blood glucose levels and food intake. Stabilized agonists targeting GLP-1R are used in the treatment of type 2 diabetes and have recently become a breakthrough obesity therapy. Here, we revisit a classic article in Diabetes by Thorens etal. that described the cloning, sequencing, and functional expression of the human GLP-1R. The article also demonstrated that exendin4(1-39) was a full agonist of the human GLP-1R whereas exendin4(9-39) was a full antagonist. We discuss how the knowledge imparted by these studies has gone on to inform multiple strands of GLP-1R biology over the past three decades, including pharmacology, signaling, human genetics, structural biology, and chemical biology.

A window-of-opportunity (WOO) trial of giredestrant +/- LHRHa vs anastrozole+LHRHa in premenopausal women with ER+/HER2- early breast cancer (EBC; IBCSG 67-22; PREcoopERA).

TPS628 Background: Adjuvant endocrine therapy (ET) for premenopausal women with ER+/HER2- EBC often includes ovarian function suppression (OFS) via a GnRH or LHRH agonist (LHRHa) plus an aromatase inhibitor (AI) or tamoxifen. Younger age is associated with lower rates of ET adherence indicating side effects are less acceptable to these women. The development of drug regimens without OFS are clearly an unmet medical need in this setting. New oral selective ER degraders (SERDs) are emerging as potentially useful ETs in the (neo)adjuvant settings. Giredestrant is an efficient and potent SERD and a full antagonist, which translates into better anti-proliferation activity than known SERDs. PREcoopERA is a WOO trial aiming to determine, among premenopausal women with ER+/HER2- EBC: if giredestrant+LHRHa provides greater anti-proliferative activity than anastrozole+LHRHa; and if giredestrant without LHRHa provides similar (non-inferior) anti-proliferative activity to giredestrant+LHRHa. Results would provide rationale for subsequent (neo)adjuvant clinical trials. Methods: PREcoopERA (NCT05896566) is a randomized, open-label, 3-arm, WOO trial evaluating the anti-proliferative activity and safety of the oral SERD giredestrant +/- LHRHa triptorelin, as compared to the AI anastrozole + triptorelin. Eligible are premenopausal women with untreated ER+/HER2- operable stage I-III (excl. T4) EBC, with Ki-67 ≥10%. 220 women will be randomized in 2:2:1 ratio to giredestrant (30 mg/d po for 4 weeks until rebiopsy) + triptorelin (3.75 mg IM on D1); giredestrant alone; or anastrozole (1 mg/d po) + triptorelin. Rebiopsy is planned for D29, either during primary surgery or standalone procedures. The primary endpoint is change in Ki-67 labeling index between pre-treatment diagnostic tumor biopsy and post-treatment rebiopsy, as assessed by the IBCSG Pathology Office. Sample size of 80:80:40 randomized women are planned to test superiority of 4 weeks giredestrant+triptorelin vs anastrozole+triptorelin to reduce Ki-67 (hypothesized percentage changes -80% vs -65%) and to test non-inferiority of 4 weeks giredestrant vs giredesrant+triptorelin (within 10% as non-inferiority margin). The trial was activated on 9 October 2023. The first woman was enrolled on 25 January 2024. Clinical trial information: NCT05896566 .

Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice.

Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu5) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. Partial mGlu5 receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced (R)-ketamine action in mice, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.

Discovery of N-(1,4-Benzoxazin-3-one) urea analogs as Mode-Selective TRPV1 antagonists

A series of 1,4-benzoxazin-3-one analogs were investigated to discover mode-selective TRPV1 antagonists, since such antagonists are predicted to minimize target-based adverse effects. Using the high-affinity antagonist 2 as the lead structure, the structure activity relationship was studied by modifying the A-region through incorporation of a polar side chain on the benzoxazine and then by changing the C-region with a variety of substituted pyridine, pyrazole and thiazole moieties. The t-butyl pyrazole and thiazole C-region analogs provided high potency as well as mode-selectivity. Among them, antagonist 36 displayed potent and capsaicin-selective antagonism with IC50 = 2.31 nM for blocking capsaicin activation and only 47.5 % inhibition at 3 µM concentration toward proton activation, indicating that more than a 1000-fold higher concentration of 36 was required to inhibit proton activation than was required to inhibit capsaicin activation. The molecular modeling study of 36 with our homology model indicated that two π-π interactions with the Tyr511 and Phe591 residues by the A- and C-region and hydrogen bonding with the Thr550 residue by the B-region were critical for maintaining balanced and stable binding. Systemic optimization of antagonist 2, which has high-affinity but full antagonism for activators of all modes, led to the mode-selective antagonist 36 which represents a promising step in the development of clinical TRPV1 antagonists minimizing side effects such as hyperthermia and impaired heat sensation.

Abstract LB166: Discovery of CT3021, a novel potent adenosine A2a/A2b/A1 receptor triple antagonist

Abstract In a CD73-positive tumor microenvironment (TME), ATP released from apoptotic tumor cells converts to adenosine, generating an adenosine-rich immunosuppressive environment. Adenosine activates G-protein coupled receptors expressed on immune cells to achieve immune suppression, with a mechanism of action involving 1) dampening antitumor effector cells (T eff and NK cells) via adenosine engagement on A2a receptor, (2) reducing dendritic cell antigen presentation and promoting MDSC differentiation by activating A2b and A2a receptors, and (3) inducing chemotactic migration of immature plasmacytoid dendritic cells to infiltrate tumor tissue via A1 receptor. Furthermore, A1 receptor expression in certain tumors mediates an adenosine-driven tumor cell proliferation, likely through A1 receptor Gi coupling to the Hippo-YAP signal transduction pathway. Thus, pharmacologic inhibition of A2a, A2b, and A1 receptors by a triple antagonist in the context of adenosine-rich TME may represent an attractive strategy to achieve a better outcome in treating solid tumors. We discovered and characterized a novel adenosine receptor antagonist CT3021. CT3021 exhibits high binding affinity to A2a, A2b, and A1, with a Ki value of 0.37 nM, 1.76 nM, and 1.26 nM, respectively, and is selective against the A3 receptor and other 84 pharmacologically and/or toxicologically relevant targets. Schild analysis demonstrated that CT3021 is a competitive antagonist with a calculated KB value of 0.18 nM on A2a receptor in a whole cell cAMP assay in transfected HEK293 cells. In functional antagonist assays, CT3021 maintains its high potency full antagonism under an adenosine-rich TME-like condition (10-100 µM adenosine) both in transfected HEK293 cells and in isolated human T lymphocytes. CT3021 has a high oral bioavailability, a limited CNS exposure, and a favorable ADME profile. CT3021 is well tolerated in rats after repeat dosing. Further toxicology and efficacy studies are underway to explore the potential of CT3021 as a best-in-class adenosine receptor antagonist immunotherapy for the treatment of CD73 positive and A1 receptor positive solid tumors. Citation Format: Sandong Han, Nam Hee Kim, Hongmei He, Zhi Liang Chu. Discovery of CT3021, a novel potent adenosine A2a/A2b/A1 receptor triple antagonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB166.

Cariprazine as adjunctive treatment of catatonia in schizoaffective disorder: a case report.

IntroductionCariprazine is one of the most recent innovations in neuropsychopharmacology, with evidence for its efficacy in affective and psychotic spectrum disorders.ObjectivesTo present a case that highlights cariprazine’s potential use outside the regulatory approved indications.MethodsCase report using CARE guidelines and a narrative review.ResultsWe present the case of a 41-year-old male readmitted to a psychiatric inpatient unit due to three months of mutism and withdrawal. At admission, the patient did not communicate verbally or in writing, but he complied with simple orders, and his consciousness remained unimpaired. He scored 11 points on the Bush-Francis Catatonia Rating Scale (BFCRS), indicating immobility, mutism, staring, withdrawal, ambitendency, and automatic obedience. We observed psychomotor retardation and indirect signs of a depressive mood, including the omega sign. His medical history included ongoing psychiatric treatment since the age of 30, with two prior admissions to an acute inpatient unit. At the time of admission, he was treated with olanzapine 20 mg/day, lorazepam 2 mg/day (recently downtitrated), venlafaxine 150 mg/day, and bupropion 150 mg/day. At the start of the current episode, the patient’s diagnosis was uncertain, with previous descriptions of psychotic, affective, and catatonic features. Due to suspicion of catatonia, we administered a high dose of lorazepam (8 mg/day), resulting in a partial response with a 4-point reduction in the BFCRS. We discontinued bupropion, increased venlafaxine to 225 mg, and switched from olanzapine to cariprazine using a taper, washout, and switch strategy. Psychotic symptoms briefly appeared when the patient was not taking a dopamine D2-receptor modulatory drug. We identified mild possible adverse drug reactions, including akathisia, transient insomnia, and daytime sleepiness. At a dose of 6 mg/day of cariprazine, we observed complete remission of catatonia (BFCRS=0) and significant improvement in affective and psychotic symptoms. The patient was discharged home with diagnoses of catatonia and schizoaffective disorder, prescribed 6mg/day of cariprazine, 225mg/day of venlafaxine, and 2,5mg/day of lorazepam. At the 6-month follow-up, the patient continues to exhibit clinical stability.Conclusions This case emphasizes the safety and potential effectiveness of cariprazine in treating catatonia within the context of schizoaffective disorder. We consider that the partial agonist properties of cariprazine could theoretically reduce the risk of exacerbating catatonia, a risk typically associated with full D2-receptor antagonists. Other mechanisms of action, such as D3 partial agonism, may also contribute to the improvement or at least the non-aggravation of catatonic symptoms. Cariprazine’s mood-stabilizing properties make it a promising off-label choice for treating schizoaffective disorder, especially when catatonic features are present.Disclosure of InterestNone Declared

The IL-7R antagonist lusvertikimab reduces leukemic burden in xenograft ALL via antibody-dependent cellular phagocytosis

AbstractAcute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of B-cell precursors (BCP-ALL) or T cells (T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (R/R) disease, high-risk (HR) leukemias and T-ALL, in which immunotherapy approaches remain scarce. Although the interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R–targeting immunotherapy has yet reached clinical application in ALL. The IL-7Rα chain (CD127)–targeting IgG4 antibody lusvertikimab (LUSV; formerly OSE-127) is a full antagonist of the IL-7R pathway, showing a good safety profile in healthy volunteers. Here, we show that ∼85% of ALL cases express surface CD127. We demonstrate significant in vivo efficacy of LUSV immunotherapy in a heterogeneous cohort of BCP- and T-ALL patient-derived xenografts (PDX) in minimal residual disease (MRD) and overt leukemia models, including R/R and HR leukemias. Importantly, LUSV was particularly effective when combined with polychemotherapy in a phase 2-like PDX study with CD127high samples leading to MRD-negativity in >50% of mice treated with combination therapy. Mechanistically, LUSV targeted ALL cells via a dual mode of action comprising direct IL-7R antagonistic activity and induction of macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). LUSV–mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, LUSV may represent a novel immunotherapy option for any CD127+ ALL, particularly in combination with standard-of-care polychemotherapy.

Abstract 6047: Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader

Abstract The estrogen receptor α (ERα) is a clinically validated target for the treatment of estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. However, resistance to early line endocrine treatments due to mutations of the ESR1 gene encoding ERα is associated with poor prognosis and remains an area of unmet clinical need. ERα degradation using heterobifunctional degraders has emerged as a promising approach to tackle endocrine resistance through proteasome mediated degradation of the receptor. Here, we present the preclinical results for the development candidate, PVTX-321, an ERα heterobifunctional degrader. PVTX-321 is a rapid and potent ER heterobifunctional degrader as well as a full ERα antagonist. Both properties translate into potent antiproliferative activity across multiple ER+ breast cancer cell lines bearing either wild-type or clinically relevant ERα mutations (E380Q, Y537S and D538G). PVTX-321 demonstrates favorable oral bioavailability across different species and effectively induces dose-dependent degradation of ERα in vivo. Moreover, PVTX-321 achieves tumor regression as an oral agent at 10 mg/kg in MCF-7 mouse xenograft model. Furthermore, PVTX-321 possesses excellent in vitro and in vivo safety profiles and warrants further development for the treatment of ER+/HER2- breast cancer. Citation Format: Courtney G. Havens, Guozhang Xu, Cass Lowenstein, Debangshu Samanta, Brian Vidal, Elham Behshad, Rakesh Nagilla, Mike Russell, Peter Orth, Winston Wu, Larry Jolivette, Scott Priestley, Helai Mohammad, Zhihua Sui. Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6047.

Structural basis for partial agonism in 5-HT3A receptors.

Hyperactivity of serotonin 3 receptors (5-HT3R) underlies pathologies associated with irritable bowel syndrome and chemotherapy-induced nausea and vomiting. Setrons, a class of high-affinity competitive antagonists, are used in the treatment of these conditions. Although generally effective for chemotherapy-induced nausea and vomiting, the use of setrons for treating irritable bowel syndrome has been impaired by adverse side effects. Partial agonists are now being considered as an alternative strategy, with potentially less severe side effects than full antagonists. However, a structural understanding of how these ligands work is lacking. Here, we present high-resolution cryogenic electron microscopy structures of the mouse 5-HT3AR in complex with partial agonists (SMP-100 and ALB-148471) captured in pre-activated and open-like conformational states. Molecular dynamics simulations were used to assess the stability of drug-binding poses and interactions with the receptor over time. Together, these studies reveal mechanisms for the functional differences between orthosteric partial agonists, full agonists and antagonists of the 5-HT3AR.

ALLOSTERIC SITES AND ALLOSTERIC REGULATORS OF G-PROTEIN-COUPLED RECEPTORS: GRAY CARDINALS OF SIGNAL TRANSDUCTION

Membrane G protein-coupled receptors (GPCRs) are key components of most eukaryotic signaling systems, transducing external signals to intracellular effector proteins. Activation of GPCRs occurs through the specific binding of ligands of different nature to their orthosteric site. However, regulation of the affinity of an orthosteric agonist for the receptor, control of its effectiveness, and selection of the preferentially activated intracellular signaling cascade is carried out using allosteric mechanisms. This is due to the presence in GPCRs of many allosteric sites, which differ in structural and functional organization and topology in the receptor molecule, and are located in all its functional subdomains. The endogenous regulators of these sites are simple ions (Na+, Zn2+, Mg2+, Ca2+, Cl– and others), lipids (cholesterol, phospholipids, steroids), amino acids and their derivatives, polypeptides, as well as signaling proteins that form functionally active complexes with GPCRs (G proteins, β‑arrestins, RAMPs), and autoantibodies to the extracellular regions of GPCRs. Based on pharmacological activity, ligands of allosteric sites of GPCRs are divided into positive, negative or silent modulators of the effects of orthosteric agonists, as well as full and inverse agonists or neutral antagonists, which affect the basal activity of the receptor in the absence of an orthosteric agonist, although combining the properties of a modulator and an agonist is also possible. The multiplicity of allosteric sites and allosteric regulators, complex interactions between them, and the involvement of allosteric mechanisms in the formation of receptor complexes play a key role in fine-tuning the functional activity of signaling cascades, in biased agonism, and predetermine the processes of receptor desensitization and the fate of the receptor complex after hormonal signal transduction. The review summarizes and analyzes current concepts and new trends in the field of studying the allosteric regulation of GPCRs, the localization and functional role of allosteric sites, and their endogenous and synthetic ligands. As an example, synthetic allosteric regulators of the receptors of thyroid-stimulating and luteinizing hormones, as potential drugs for the correction of endocrine disorders, are discussed in detail.

FRI546 VRDN-001, A Full Antagonist Antibody To IGF-1 Receptor In Development For Thyroid Eye Disease (TED): Pharmacodynamic Responses In Healthy Volunteers And Patients With Active TED

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics Inc. B.A. Dickinson: Employee; Self; Viridian Therapeutics Inc. R.M. Summerfelt: Employee; Self; Viridian Therapeutics Inc. A. She: Employee; Self; Viridian Therapeutics Inc. V. Bedian: Employee; Self; Viridian Therapeutics Inc. B. Katz: Employee; Self; Viridian Therapeutics Inc. Introduction: VRDN-001, a full antagonist antibody to IGF-1 receptor (IGF-1R), is in development for the treatment of thyroid eye disease (TED). Clinical and preclinical evidence demonstrate IGF-1R antagonism reduces the inflammation and proptosis that occur in TED. We provide pharmacodynamic (PD) results in healthy volunteers and TED patients from our ongoing phase 1/2/3 clinical trial (NCT05176639) evaluating VRDN-001. Methods: Healthy volunteers (HVs) and patients with active, moderate-to-severe TED were randomized 3:1 to receive 2 intravenous infusions 3 weeks apart (i.e., at week 0 and week 3) of either VRDN-001 (at 3-20 mg/kg) or placebo. PD parameters (IGF-1 serum levels) were assessed through 7 weeks. Results: Thirteen HVs received either placebo (n=3) or VRDN-001, 3 mg/kg (n=3), 10 mg/kg (n=3), or 20 mg/kg (n=4). Additionally, 16 TED patients received either placebo (n=4), 10 mg/kg of VRDN-001 (n=6), or 20 mg/kg of VRDN-001 (n=6). Baseline characteristics were similar across all TED cohorts. All VRDN-001 doses (3-20 mg/kg) elicited rapid, sustained, and similar increases in IGF-1 serum levels, a biomarker for target engagement and IGF-1R inhibition. In HVs receiving VRDN-001 (n=10), IGF-1 serum levels increased within a day of the first infusion for all doses, reaching 4-6-fold above baseline; levels continued to increase after the second infusion, ultimately reaching 4-9-fold above baseline. In TED patients receiving VRDN-001 (n=12), IGF-1 serum levels increased for both doses 2-6-fold above baseline after the first infusion, and further increased after the second infusion, ultimately reaching levels 4-9-fold above baseline. No increases in IGF-1 serum levels occurred for placebo. Conclusions: Two infusions of VRDN-001 in healthy volunteers as well as TED patients elicited rapid and sustained increases in IGF-1 serum levels that were similar across groups, indicating maximal target engagement at all doses tested. Results from an additional ongoing cohort of 3 mg/kg in TED patients will further inform optimal VRDN-001 dosing and potential treatment regimens to balance efficacy and safety and minimize treatment burden in TED. Presentation: Friday, June 16, 2023

OR26-02 VRDN-001, A Full Antagonist Antibody To IGF-1 Receptor In Development For Thyroid Eye Disease (TED), Binds To A Distinct Epitope From Teprotumumab

Abstract Disclosure: V. Bedian: Employee; Self; Viridian Therapeutics Inc. J.C. Tsai: Employee; Self; Viridian Therapeutics Inc. R.N. Newell: Employee; Self; Viridian Therapeutics Inc. Y. Zhao: Employee; Self; Viridian Therapeutics Inc. Introduction: VRDN-001, a full antagonist antibody to IGF-1 receptor (IGF-1R), is under development for the treatment of thyroid eye disease (TED). Clinical and preclinical evidence confirm IGF-1R antagonism reduces the inflammation and proptosis that occur in TED. As different anti-IGF-1R antibodies may have distinct characteristics, we compared the binding epitope and in vitro antagonist properties of VRDN-001 with teprotumumab. Methods: We generated a panel of IGF-1R extracellular domain point mutants of 40 potential IGF-1 interacting residues and 3 N-terminal truncations and assessed the binding pattern of the 2 antibodies to these variants by bio-layer interferometry (Octet). Antagonist characteristics were determined by dose-responses of inhibition of biotinylated IGF-1 binding to IGF-1R expressing FreeStyle™ 293-F cells by flow cytometry and inhibition of IGF-1 mediated signaling in primary human ocular choroidal fibroblasts. Results: VRDN-001 binding was affected by the same domain deletions/truncations as teprotumumab but was not affected by the same point mutations; while teprotumumab binding was reduced or abolished by 2 of the mutations, VRDN-001 binding was not affected by any of the 40-point mutations. These results are consistent with overlapping binding sites but distinct receptor interactions. In antagonism studies, at ≥50 nM, VRDN-001 nearly completely inhibited IGF-1 binding, while teprotumumab only partially inhibited IGF-1 binding through 300 nM. Similarly, VRDN-001 more completely antagonized IGF-1 mediated signaling (phosphorylation of IGF-1R and AKT) than teprotumumab. Conclusion: Despite having overlapping epitopes, VRDN-001 is distinct from teprotumumab in both its mutational signature and its more complete antagonism of IGF-1 mediated signaling. VRDN-001’s unique binding and functional antagonism characteristics may contribute to the robust pharmacodynamic responses observed in healthy volunteers and favorable efficacy signals observed in early clinical trials of TED patients. Presentation: Saturday, June 17, 2023

FRI545 Durability Of Treatment Response With VRDN-001, A Full Antagonist Antibody To IGF-1 Receptor, In Patients With Thyroid Eye Disease (TED): Phase 1/2 Clinical Study

Abstract Disclosure: R. Douglas: Consulting Fee; Self; Horizon Therapeutics, Viridian Therapeutics. Research Investigator; Self; Viridian Therapeutics Inc., Horizon Therapeutics. S. Ugradar: Consulting Fee; Self; Viridian Therapeutics Inc. K. Cockerham: Advisory Board Member; Self; Viridian Therapeutics Inc., Horizon Therapeutics. Research Investigator; Self; Viridian Therapeutics Inc. Speaker; Self; Horizon Therapeutics. R.E. Turbin: Advisory Board Member; Self; Horizon Therapeutics. Research Investigator; Self; Viridian Therapeutics Inc. Stock Owner; Self; Viridian Therapeutics Inc. R. Tang: Consulting Fee; Self; Viridian Therapeutics Inc. Research Investigator; Self; Viridian Therapeutics Inc., Horizon Therapeutics. N. Nijhawan: Research Investigator; Self; Viridian Therapeutics Inc. D.J. O’Shaughnessy: Employee; Self; Viridian Therapeutics Inc. R.M. Summerfelt: Employee; Self; Viridian Therapeutics Inc. A. She: Employee; Self; Viridian Therapeutics Inc. B. Katz: Employee; Self; Viridian Therapeutics Inc. Introduction: Clinical and preclinical evidence demonstrate IGF-1 receptor (IGF-1R) antagonism reduces TED-related inflammation and proptosis. VRDN-001, a subnanomolar affinity, full antagonist antibody to IGF-1R, is being evaluated in a phase 1/2 double-masked RCT (NCT05176639) at 3, 10, or 20 mg/kg administered intravenously. Results from the first cohort of TED patients (10 mg/kg) are presented here. Methods: Adults with active moderate-to-severe TED and clinical activity score (CAS) ≥4 were randomized to 2 infusions 3 weeks apart of either 10 mg/kg VRDN-001 or placebo (3:1). Safety, tolerability, and efficacy through 12 weeks were assessed. Endpoints included overall responder rate (% of patients with ≥2 mm reduction in proptosis and ≥2 point reduction in CAS), proptosis responder rate (% of patients with ≥2 mm reduction), change from baseline in proptosis and CAS, proportion of patients with CAS decrease to 0 or 1, and diplopia resolution. Results: Baseline characteristics were similar between VRDN-001 (n=6) and placebo (n=2). After 2 infusions, at 6 weeks, the overall responder rate was 83% (5/6; VRDN-001) vs. 0% (0/2; placebo). Proptosis responder rate was 83% (5/6; VRDN-001) vs. 50% (1/2; placebo). Mean proptosis decreased by 2.4 mm (VRDN-001) vs. 1.0 mm (placebo). MRI analysis of proptosis, available for 4 of 6 drug-treated patients, confirmed proptosis improvement in each; MRI analysis showed slight worsening of proptosis in both placebo patients. CAS decreased to 0 or 1 for 83% (5/6; VRDN-001) vs. 0% (0/2; placebo), with mean decreases of 4.3 (VRDN-001) and 1.5 (placebo). In patients presenting with diplopia, complete resolution occurred for 75% (3/4; VRDN-001) vs. 0% (0/1; placebo). Durability of response in the 5 VRDN-001 treatment responders at 6 weeks persisted through 12 weeks: 80% (4/5) maintained overall responder status and 80% (4/5) maintained proptosis responder status, with mean reduction in proptosis at week 12 of 2.2 mm for all 6 drug-treated patients; MRI analysis confirmed the maintained response for all 4 of the drug-treated patients for whom scans were available. Mean CAS reduction remained consistent (4.2 at Week 12 vs. 4.3 at Week 6) and 80% (4/5) maintained a CAS of 0 or 1. All 4 patients with baseline diplopia had diplopia resolution at Week 12. VRDN-001 was well-tolerated through 12 weeks. AEs were mostly mild, with no severe or serious AEs reported. Conclusions: Two infusions of 10 mg/kg VRDN-001 were well tolerated in this cohort of TED patients, and the rapid, clinically meaningful improvement across all efficacy measures by 6 weeks was sustained through 12 weeks. Further, these results were achieved with a lower dose and fewer treatments than in prior RCTs of other anti-IGF-1R antibodies. Results from the additional 3 mg/kg and 20 mg/kg cohorts may extend these findings and define potential VRDN-001 treatment regimens. Presentation: Friday, June 16, 2023

VRDN-001, a full antagonist antibody to IGF-1 receptor: in vitro pharmacology and phase 1/2 results in patients with thyroid eye disease (TED)

VRDN-001, a full antagonist antibody to IGF-1 receptor: <i>in vitro</i> pharmacology and phase 1/2 results in patients with thyroid eye disease (TED)

Antagonistic Insulin Derivative Suppresses Insulin-Induced Hypoglycemia.

Insulin derivatives provide new functions that are distinctive from native insulin. We investigated insulin modifications on the C-terminal A chain with insulin receptor (IR) peptide binders and presented a full and potent IR antagonist. We prepared insulin precursors featuring a sortase A (SrtA) recognition sequence, LPETGG, at the C-terminal A chain and used a SrtA-mediated ligation method to synthesize insulin derivatives. The insulin precursor exhibits full IR agonism potency, similar to native human insulin. We explored derivatives with linear IR binding peptides attached to the insulin C-terminal A chain. One insulin derivative with an IR binder (Ins-AC-S2) can fully antagonize IR activation by insulin, as confirmed by cell-based assays. This IR antagonist suppresses insulin-induced hypoglycemia in a streptozotocin-induced diabetic rat model. This study provides a new direction toward insulin antagonist development.