Impact of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Renal Function in Patient with Heart Failure

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor is a recently introduced oral agent to treat renal anemia, but its clinical implications on renal functioning in patients with heart failure remains unknown. We studied an 81-year-old man with heart failure with mildly reduced ejection fraction, chronic kidney disease, and renal anemia. The seven-month HIF-PH inhibitor daprodustat treatment improved the hemoglobin level from 7.4 g/dL to 11.8 g/dL and estimated glomerular filtration ratio from 24 mL/min/1.73 m2 to 35 mL/min/1.73 m2 without any complications, including thromboembolic events. HIF-PH inhibitor might be a promising therapeutic tool to improve renal anemia and renal function in patients with heart failure, although large-scale studies are warranted to validate our findings.

Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19

Molnupiravir is an oral agent a metabolite of which has activity against SARS-CoV-2. In a controlled trial in adults hospitalized for Covid-19 who had symptoms for 10 days or less prior to randomization, patients received placebo (n=75) or varying doses of molnupiravir (n=218) administered twice-daily for 5 days. There was no impact of treatment on death. Median time to sustained recovery was 9 days in all groups, with day 29 recovery rates ranging from 81.5%-85.2%. There were no dose-limiting side effects or adverse events.

A Phase Ib Study of Linperlisib in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Introduction Peripheral T cell lymphoma (PTCL) is an aggressive tumor type with poor survival, where treatment options for relapsed and/or refractory (r/r) disease are very limited. Standard treatments have a median progression free survival (PFS) of only 3-4 months. PI3K inhibitors, blocking tumor cell proliferation, survival, migration, and modulating multiple functions on the tumor microenvironment have previously shown to be active in T cell lymphomas, as well as B-cell lymphomas and chronic lymphocytic leukemia. However, the use of these agents has been hampered by tolerability issues, including toxicities such as diarrhea, colitis, hepatotoxicity, pneumonitis, hyperglycemia, and rash. The PI3Kδ selective inhibitor, linperlisib, is a structurally novel oral agent that has been demonstrated to be clinically efficacious with a favorable safety profile in Phase 1 and Phase 2 trials in B-cell malignancies previously. Here we report updated clinical data with longer follow-up from a Phase 1b clinical trial of linperlisib monotherapy in relapsed or refractory PTCL. Methods The Phase 1b PTCL clinical trial (NCT04108325) was conducted at 10 sites in China. There were 43 patients (pts) with different PTCL histologies enrolled in the study, including PTCL-NOS (17 pts), AITL (16 pts), ALCL (6 pts), NKT (3 pts), and MEITL (1 pt). Tumor assessments are performed every two treatment cycles with 28 days as one treatment cycle using IWG 2007 criteria. Safety was evaluated according to CTCAE v5.0. Linperlisib was dosed at 80 mg QD (RP2D) orally until disease progression, intolerable toxicity or withdrawal from the study. Results In the Phase 1b study of linperlisib monotherapy in r/r PTCL, as of a date cut-off of July 22, 2021, there were 43 pts enrolled with a median age of 58 years, ECOG 0-1 (41 pts, 95.3%), Stage III or IV (39 pts, 90.7%). The pts had a median of 2 prior systemic therapies, and 36 pts (83.7%) were refractory to their last treatment. The majority (83.7%) of pts had prior CHOP or CHOP-like therapy. Thirty-eight out of 43 pts (88.4%) experienced a treatment related adverse event (TRAE), majority (90.3%) of AEs were Grade 1 or Grade 2. The most common TRAEs (≥10%) were neutropenia (60.5%), leukopenia (37.2%), hypertriglyceridemia (37.2%), hypercholesterolemia (32.6%), AST increase (20.9%), ALT increase (23.3%), pneumonia (16.3%), anemia (16.3%), gamma glutamyl transpeptidase increase (16.3%), thrombocytopenia (14.0%), alkaline phosphatase increase (14.0%) and lymphocyte count increase (11.6%). The observed safety profile of linperlisib in r/r PTCL is similar to that observed in r/r follicular lymphoma, with no new toxicities reported. The Grade 3 and above AE occurring in >5% of pts was neutropenia (16.3%). Three pts had dose reductions to 60 mg QD due to AEs, and 5 pts discontinued from the study due to an SAE. Forty-one pts were evaluable for efficacy, 1 pt discontinued from study due to SAE occurred at C1D12, 1 pt discontinued from the study due to withdrawing consent at C1D12, there were no post baseline imaging assessment for these patients. The overall response rate (ORR) was 61.0%, including 34.1% Complete Response (CR), 26.8% Partial Response (PR) and 26.8% Stable Disease, contributing to a 90.0% Disease Control Rate (DCR). CR and/or PR were observed in all PTCL histologies enrolled in this study. Nearly all responses occurred by the first assessment at day 58. AS of a data cut-off of July 22，2021, the median PFS was 10.3 months (95%CI: 4.4-NR) , and the duration of response was not reached (95%CI: 8.5-NR). As of a data cut-off of July 22, 2021, 17 pts still remain on the study treatment, 7 pts had received at least 10 months of linperlisib treatment. Discontinuations were most frequently due to disease progression (18, 41.9%), intolerable SAE (5, 11.6%), or withdrawal consent from the study (3, 7.0%). Conclusions The PI3Kd-selective oral agent, linperlisib, demonstrated promising efficacy and durable responses with a 61.0% ORR and 10.3 months median PFS in patients with r/r PTCL. Additional clinical studies of linperlisib in r/r PTCL, including a Phase 2 registration study, are currently ongoing. Disclosures No relevant conflicts of interest to declare.

205. Evaluating the Time to Oral Step-Down Therapy for Gram-Negative Bloodstream Infections Associated with a Genitourinary Source

Background The transition to oral antibiotics in gram-negative bloodstream infections (BSI) can decrease length of stay, avoid central line access, and improve patient convenience. Some studies suggest that the bioavailability of the oral agent selected can impact outcomes. The purpose of this study was to determine when the most appropriate time to oral step-down is, and assess if the bioavailability of the agent selected impacts outcomes. Methods This retrospective observational chart review evaluated adult patients admitted to Long Island Jewish Medical Center during the study period of January 2019 – December 2019 with a gram-negative BSI from a genitourinary source. The primary objective was to assess if the time to oral step-down therapy impacts clinical success. Secondary objectives included assessment of if continued IV therapy or oral step-down impacts outcome measures including clinical failure, length of stay, and duration of therapy, and to compare high versus low bioavailability agents on treatment outcomes. Results A total of 130 patients were included, with 88 patients in the oral step-down group and 42 patients in the IV therapy only group. Clinical failure occurred in 10 patients in the oral step-down group, with 2 de-escalated in the 1-3 day range and 8 de-escalated in the 4-6 day range (p=0.29). There was no difference in clinical failure when the oral step-down group was compared to the IV therapy group (11 vs. 17%; p=0.41). The length of stay was significantly shorter in the oral step-down group (p< 0.0001), while the duration of therapy was shorter in the IV therapy group (p=0.0015). When comparing high and low bioavailability agents, there was no difference in the rate of treatment failure (p=0.74), length of stay (p=0.08), or duration of therapy (p=0.02). Conclusion There was no significant difference in outcomes if patients were de-escalated to oral therapy early versus late in their treatment course. Step-down to oral antibiotics led to decreased length of stay, and the bioavailability of the oral agent selected did not impact outcomes. This study demonstrates the safety and efficacy of prompt oral step-down for gram-negative bacteremia secondary to a genitourinary source which can have positive impacts on patient care. Disclosures All Authors: No reported disclosures

Pharmacokinetics of Orally Administered GS-441524 in Dogs

Despite being FDA-approved for COVID-19, the clinical efficacy of remdesivir (Veklury®) remains contentious. We previously described the pharmacokinetic, pharmacodynamic and toxicological rationales on the greater suitability of its parent nucleoside, GS-441524, for COVID-19 treatment. Here, we assess the oral bioavailability of GS-441524 in beagle dogs and show that plasma concentrations approximately 24-fold higher than the EC50 against SARS-CoV-2 are easily and safely sustained. These data support translation of GS-441524 as an oral agent for COVID-19.

Clinical Outcomes in Patients with Immune Thrombocytopenia Treated with All 3 Approved Thrombopoietin Receptor Agonists

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a platelet count < 100 x 109 / L due to accelerated platelet destruction and impaired platelet production (McMillan 1981). At present, there are 3 available thrombopoietin receptor agonists (TPO-RAs) approved for treatment of chronic ITP in adults. All three agents have high response rates, 40-90%, depending on the criteria used to define response (Ghanima et al 2019). Previous studies illustrate efficacy of Romiplostim and Eltrombopag having surprisingly high response rates when switching from one to the other, particularly if there was a response to the first TPO-RA (Gonzalez-Porras et al 2015; Lakhwani et al 2017; Cantoni et al 2018) but no studies have compared all 3 approved TPO-RA. Herein we describe 7 patients with difficult to treat chronic ITP who received all 3 TPO-RA and assess responses of the 7 to each of Eltrombopag, Romiplostim and Avatrombopag. Methods This was a retrospective review of all patients with chronic ITP seen at the Platelet Disorders Program at Weill Cornell Medicine-NY Presbyterian Hospital between July 2019 (following FDA approval of Avatrombopag) and June 2020 who had been treated with Eltrombopag, Romiplostim and Avatrombopag. Seven patients were identified (most had been followed for many years) and information collected on demographics, laboratory results, and clinical data including response and tolerance to ITP treatments, in particular the 3 TPO-RA. Results There were 4 females and 3 males with median age of 64 years (range 33-77). All had primary ITP with median 3 (range 2-13) separate ITP treatments, including investigational therapies, preceding treatment with their first TPO-RA (Table 1). All 7 patients had difficult to treat ITP with episodes of severe thrombocytopenia despite chronic treatments, requiring periodic rescue with IVIg and/or steroids. Three patients received Eltrombopag as their first TPO-RA and 4 patients Romiplostim. All 7 patients received Avatrombopag as their third TPO-RA and all also received other therapies either in conjunction with or in between TPO-RAs (Figure 1). No patient went directly from one TPO-RA to another without intervening treatment. All 7 patients (100%) responded to their first TPO-RA. For the 3 initially on Eltrombopag, duration of treatment ranged from 1 week to 8 years. When these 3 were switched to Romiplostim as a second TPO-RA, they responded with median time on treatment 27 months (range 21-48 months). Reasons prompting the switch from Eltrombopag to Romiplostim included: lost response (1), allergic reaction (1), insurance/financial issues (1). The 4 patients who started with Romiplostim had a median duration on treatment of 18 months (range 4-96 months). Two of these 4 who switched to Eltrombopag as their second TPO-RA responded to Eltrombopag with median time on treatment 5.5 months. Reasons for switching from Romiplostim to Eltrombopag included: unstable platelet response (2), patient preference for an oral agent (2). Prior to taking Avatrombopag, 5 patients returned to a TPO-RA they had previously responded to with 3 requiring higher doses on re-exposure. These patients (4, 6, 7) had switched from that initial agent due to patient preference (1), financial issues (1) and unstable platelet response (1). Five/7 patients (71%) responded to the third TPO-RA, Avatrombopag. Reasons prompting the switch to Avatrombopag from the previous TPO-RA included: patient preference (4), lost response (2), unclear/suboptimal response (1). The 5 responders remain on only Avatrombopag with durations of 3 months to 11 months. Conclusions: All 7 patients responded initially to TPO-RA whereas response rates of around 70% were seen when patients are switched to a second and subsequent third TPO-RA; response was very good to all 3 agents without clear preference of one over the others. Responders to distinct second and third TPO-RAs included patients who switched due to lack of response to a preceding TPO-RA as well as those who switched due to preference (for an oral agent without dietary restrictions) or intolerance/side effects. Loss of response to one TPO-RA should not preclude trying another. Patients may not respond as well on re-exposure to a previously seen TPO-RA; hence, ideally treatment would be maintained if possible with the initial agent. Disclosures Bussel: RallyBio: Consultancy; Momenta: Consultancy; Dova: Consultancy; 3SBios: Consultancy; Regeneron: Consultancy; Principia: Consultancy; Rigel: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Argenx: Consultancy; UCB: Consultancy; CSL Behring: Consultancy; Shionogi: Consultancy.

1290. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial and Gram-Negative Infections: A Multicenter Evaluation

Background Omadacycline (OMC) is an aminomethylcycline antibiotic in the tetracycline class that has been Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. OMC has been shown to have potent in vitro activity against a broad-spectrum of Gram-positive and Gram-negative organisms, as well as Nontuberculous Mycobacteria (NTM). Due to it’s unique activity and availability as an oral agent, off-label use of OMC has been increasing. We evaluated the real-world effectiveness and safety of OMC for a variety of infections. Methods This was a multicenter, retrospective, observational study that was conducted from January 2020 to June 2020. We included all patients ≥ 18 years of age that received OMC for ≥ 72 hours for any indication and/or pathogen. The primary outcome was clinical success, defined as a lack of 30-day (non-NTM) or 90-day (NTM) mortality or microbiologic recurrence and absence of therapy escalation or alteration. Reasons for OMC utilization and incidence of potential adverse effects attributable to OMC were also analyzed. Results A total of 18 patients were included from six geographically distinct academic health systems (median age: 56 (IQR, 49-60.5) years; 61% male; 72% Caucasian). The majority of OMC use was in NTM (61%; 100% Mycobacterium abscessus) and in Acinetobacter baumannii (22%) for bone/joint (39%) and respiratory tract (33%) infections. OMC was used primarily in the outpatient setting alone (83%) and most isolates did not have OMC susceptibility conducted (89%). Clinical success was reported in 83% of the total population (71% non-NTM and 91% NTM). The majority of patients were prescribed OMC due to antimicrobial resistance to previous antibiotic(s) (61%) and/or due to OMC’s availability as an oral agent (44%). Three patients experienced side effects while on therapy (serum creatinine elevation, AST/ALT increase, and gastrointestinal distress). Conclusion OMC appears to be effective and well-tolerated for a variety of infections caused by various pathogens, including M. abscessus and A. baumannii. Disclosures Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)

Selinexor: a first-in-class SINE compound for treatment of relapsed refractory multiple myeloma

The progression of multiple myeloma is accompanied by complex cytogenetic and epigenetic alterations that include mutation or functional inactivation of tumor suppressor proteins and overexpression of oncoproteins. Patients whose myeloma is refractory to the three major classes of drugs including immunomodulatory agents, proteasome inhibitors and anti-CD38 monoclonal antibodies have a very poor prognosis. Drugs with novel mechanisms of action that can bypass resistance mechanisms are sorely needed for this group of patients. Selinexor represents a novel, oral agent with an innovative mechanism of action that offers a significant therapeutic advance in this group of heavily treated patients. Moreover, this novel mechanism may provide additional options for patients with less refractory disease.