Forma Therapeutics (United States)

Purpose: Antibody-drug conjugates (ADCs) are a relatively recent advance in the delivery of chemotherapeutics that improve targeting of cytotoxic agents. However, despite their antitumor activity, severe ocular adverse effects, including vision loss, have been reported for several ADCs. The nonspecific uptake of ADCs into human corneal epithelial cells (HCECs) and their precursors via macropinocytosis has been proposed to be the primary mechanism of ocular toxicity. In this study, we evaluated the ability of a novel polymer, poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG), to decrease the ADC rituximab-mc monomethylauristatin F (MMAF) (RIX) uptake into human corneal epithelial (HCE-T) cells. Methods: HCE-T cells were exposed to increasing concentrations of RIX to determine inhibition of cell proliferation. HCE-T cells were treated with PLL-g-PEG, the macropinocytosis inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA), or vehicle. After 30 min of incubation, RIX was added. ADC was detected by fluorescent anti-human immunoglobulin G and fluorescently conjugated dextran as viewed by microscopy. Results: RIX caused dose-dependent inhibition of HCE-T cell proliferation. EIPA significantly reduced RIX uptake and decreased macropinocytosis as assessed by direct quantification of RIX using a fluorescently conjugated anti-human antibody as well as quantification of macropinocytosis using fluorescently conjugated dextran. PLL-g-PEG resulted in a dose-dependent inhibition of RIX uptake with half-maximal inhibitory concentrations of 0.022%-0.023% PLL-g-PEG. Conclusion: The data show PLL-g-PEG to be a potent inhibitor of RIX uptake by corneal epithelial cells and support its use as a novel therapeutic approach for the prevention of ocular adverse events associated with ADC therapy.

Pyruvate kinase (PK) is the enzyme that catalyzes the conversion of phosphoenolpyruvate and adenosine diphosphate to pyruvate and adenosine triphosphate in glycolysis and plays a crucial role in regulating cell metabolism. We describe the structure-based design of AG-946, an activator of PK isoforms, including red blood cell-specific forms of PK (PKR). This was designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency toward PKR while reducing activity against off-targets observed from the original scaffold. AG-946 (1) demonstrated activation of human wild-type PK (half-maximal activation concentration [AC50 ]=0.005 μM) and a panel of mutated PK proteins (K410E [AC50 =0.0043 μM] and R510Q [AC50 =0.0069 μM]), (2) displayed a significantly longer half-time of activation (>150-fold) compared with 6-(3-methoxybenzyl)-4-methyl-2-(methylsulfinyl)-4,6-dihydro-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one, and (3) stabilized PKR R510Q, an unstable mutant PKR enzyme, and preserved its catalytic activity under increasingly denaturing conditions. As a potent, oral, small-molecule allosteric activator of wild-type and mutant PKR, AG-946 was advanced to human clinical trials.

Purpose: Ensuring consistent healthcare during transition remains challenging for SCD. The Sickle Cell Trevor Thompson Transition (ST3P-UP) study aimed to standardize the transition process for emerging adults with SCD while engaging the community as an equal partner. The ST3P-UP SCD HCT learning collaborative engaged 14 pediatric and adult paired sites (including community participation) using a standardized quality improvement (QI) process. Monthly virtual meetings provided coaching on clinical recommendations, QI methods, and practical implementation of Six Core Elements of HCT (6CE). Materials and methods: Implementation of 6CE was measured across 14 clinical sites who collectively provide care for 1625 individuals with SCD aged 16-25. Each site comprised of both pediatric and adult clinics and a partner community-based organization (CBO). Clinical programs varied: 12 urban, 2 rural; 12 academic, 2 non-academic; 6 small, 8 large. The HCT Process Measurement Tool (HCT-PMT) assessed 6CE implementation adherence using iterative QI strategies at baseline (2018) and every 6 months thereafter through 42 months (2022). Pre and post results were compared for overall group and by type of practice. Results: All 14 sites made substantial progress towards implementing a structured SCD HCT process over the past 42 months. Overall HCT-PMT scores increased over time from 19.4 at baseline to 61.5 at 12 months, 92.1 at 24 months, 96.8 at 36 months and 97.2 at 42 months. Pediatric site scores increased significantly from 24 (baseline) to 71 (12 months) to 96 (24 months) to 99 (36 and 42 months). Adult site scores also increased from 15 (baseline) to 52 (12 months) to 88 (24 months) to 95 (36 and 42 months). Pediatric sites scored higher at each scoring interval from baseline through 42 months versus adult sites. Both large and small sites demonstrated significant increase in PMT scores from baseline over the 42 months of the LC. Only one site – a large adult site – failed to achieve the collaborative goal of a PMT score >90. This site was unique in that they had a change in adult PI three times within the first 18 months of the collaborative however they continue to make progress towards their goal. Conclusion: All 14 pediatric and adult sites reported significant progress with adherence to a structured HCT process aligned with the 6CE within 42 months using quality improvement. Partnering with CBO’s facilitates sustainability and optimal patient engagement.SCD Health Care Transition Process Measurement Tool Trend Over Time Ped & AdultOverall Collaborative PMT Scores Over Time The authors do not declare any conflict of interest

Background: Sickle cell disease (SCD) and thalassemia are hemoglobinopathies characterized by lifelong anemia. In SCD, a single β-globin gene mutation results in sickle hemoglobin (HbS) that polymerizes upon deoxygenation, causes RBCs to sickle and leads to various complications. In thalassemia, α- and/or β-globin gene mutation(s) result in reduced or absent adult Hb, ineffective erythropoiesis, and downstream complications. The resultant anemias, exacerbated by impaired RBC health, are associated with lower ATP levels than in healthy RBCs. Supportive care and agents like hydroxyurea are used most in SCD, with some patients (pts) on regular transfusions. Regular or episodic transfusions, with their own set of complications, are the mainstay of treatment for thalassemia. Etavopivat, an investigational, once-daily, selective, erythrocyte pyruvate kinase (PKR) activator increases ATP and decreases 2,3 diphosphoglycerate (2,3-DPG). In a Phase 1 study, etavopivat 300–600 mg once daily in pts with SCD not regularly transfused was well-tolerated, improved hematologic markers, decreased hemolysis, and improved markers of RBC health [1,2]. Etavopivat 200 and 400 mg once daily (dose levels predicted to provide the desired PD response profiles) are being evaluated in a Phase 2/3 study of pts with SCD not on chronic transfusions (The Hibiscus Study, NCT04624659). Aims: Describe the design of a Phase 2, open-label, multicenter study (NCT04987489) evaluating the efficacy and safety of etavopivat in pts with: SCD on chronic transfusions (Cohort A), transfusion-dependent thalassemia (Cohort B), and non–transfusion-dependent thalassemia (Cohort C). Methods: Up to 20 pts (12–65 y) will be enrolled in each of the 3 cohorts described above. Key eligibility criteria are outlined in the Table. Pts will receive etavopivat 400 mg once daily for 48-wks (Figure). Pts will provide written informed consent. Baseline assessments will include medical, disease, transfusion, and medication histories. Transfusions received during the study (every ~3–5 wks) will be recorded and include Hb values before and ≥15 min after transfusion, transfusion dates, number of RBC units, volume of packed RBCs, and hematocrit of the transfused unit (if available). If a pt has an increase in pre-transfusion Hb of ≥1.0 g/dL versus their baseline pre-transfusion Hb, the investigator may delay transfusion 1 wk or reduce the number of RBC units transfused. In pts with SCD, RBC exchange transfusions may also be performed. The primary endpoints are outlined in the Figure. Secondary and exploratory endpoints include the proportion of pts with a reduction in transfusions over 12 wks of ≥33% and ≥50%, respectively, and a reduction in transfusions over 12, 24, and 48 wks (Cohorts A/B); and Hb response at Wks 24 and 48, and changes from baseline in Hb over 12, 24, and 48 wks (Cohort C). The following additional endpoints will be assessed (all cohorts): changes from baseline in quality of life (using the SF-36 and PROMIS); changes from baseline in serum ferritin levels at 12, 24, and 48 wks; liver iron at 48 wks; 2,3-DPG and ATP; PK; and safety. All primary endpoints will be analyzed using a 1-sided test at α=0.025.Summary: Etavopivat is a novel, investigational, once-daily, selective PKR activator with potential to improve RBC health and lifespan. This Phase 2 study will assess the safety of etavopivat and its impact on Hb levels and transfusion burden in pts (12–65 y) with SCD or thalassemia.

Abstract Background: Prostate cancer is the 2nd leading cause of cancer-related deaths among men in the US. CREB binding protein (CBP) and paralog p300 are co-activators of androgen receptor (AR) relevant to metastatic castration-resistant prostate cancer (mCRPC) progression and AR therapy resistance. FT-7051 is an oral, potent and selective inhibitor of CBP/p300 bromodomain with activity in preclinical prostate cancer models, including those resistant to enzalutamide. Methods: The Courage Study (NCT04575766) is a first-in-human, multicenter, phase 1, open-label study to examine the safety, PK/PD, and preliminary anti-tumor activity of FT-7051 in mCRPC patients (pts) who have progressed despite prior therapy, including at least one AR pathway inhibitor. The study uses a Bayesian optimal interval (BOIN) design with an accelerated titration phase. FT-7051 is dosed on a 28-d cycle (21-d on/7-d off). Following accelerated titration, dose escalation/de-escalation decisions are made by comparing the observed dose-limiting toxicity (DLT) rate at the current dose with pre-specified dose escalation/de-escalation boundaries. The primary objectives are to evaluate safety and tolerability of FT-7051 and determine the recommended phase 2 dose. Key secondary endpoints include PSA at 12 wks, time to PSA progression, time to radiographic progression, overall response rate, and PK parameters. Biomarker analyses include PD assessments of CBP/p300 inhibition in surrogate tissues and genetic analyses in circulating tumor cells (AR, AR-v7) and peripheral blood. Results: As of 18-June-2021, a total of 5 pts were enrolled with exposure data entered into the database, with 2 pts ongoing and 3 pts discontinued (disease progression, n=1; no longer clinically benefitting, n=1; subject withdrawal, n=1). Pts had a median age of 71 yrs (range: 66-82) with a median time since first mCRPC diagnosis of 2.3 yrs (0.4-4.7) and a median of 3 (1-5) prior lines of mCRPC therapy. Mutations reported by the investigator for 3 pts included MYC, p53, RB1, AR, and PTEN loss. Preliminary PK analyses indicated that FT-7051 exposure increased with dose in a greater than dose-proportional manner. Importantly, observed FT-7051 exposures were consistent with the predicted efficacious exposure threshold derived from PK/efficacy modeling in preclinical studies. TEAEs were reported in 4 (80%) pts. Most TEAEs were mild (Gr1) or moderate (Gr2), ≥Gr3 TEAEs included one event of possibly related Gr3 hyperglycemia and one event of unrelated Gr5 disease progression. Conclusions: Preliminary safety and PK data from the accelerated titration phase of this BOIN study support the continued investigation of FT-7051 in men with mCRPC. Initial PK data confirm that FT-7051 exposure is consistent with the predicted efficacious exposure threshold determined by PK/efficacy modeling. Additional analyses of PSA, PD assessments, and genetic analyses, including AR-v7 status, will be reported. Citation Format: Andrew J. Armstrong, Michael S. Gordon, Melissa A. Reimers, Arif Hussain, Vaibhav G. Patel, Elaine T. Lam, Alex Sedkov, Von Potter, Neal Shore. Initial findings from an ongoing first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P202.