Infrequent Administration Research Articles

Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a)

Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities. To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a). Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023. Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval. The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations. Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, -30% (IQR, -51% to -18%) for the 300 mg of zerlasiran group, and -29% (IQR, -39% to -7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, -17 to 28) nmol/L for the placebo group, -258 (IQR, -289 to -188) nmol/L for the 200 mg of zerlasiran group, -310 (IQR, -368 to -274) nmol/L for the 300-mg dose group, and -242 (IQR, -343 to -182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, -4% to 21%), -97% (IQR, -98% to -95%), -98% (IQR, -99% to -97%), and -99% (IQR, -99% to -98%), respectively, attenuating to 0.3% (IQR, -2% to 21%), -60% (IQR, -71% to -40%), -90% (IQR, -91% to -74%), and -89% (IQR, -91% to -76%) 201 days after administration. Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration. ClinicalTrials.gov Identifier: NCT04606602.

Inhibition of Spontaneous Hepatocarcinogenesis by 4,5-Didehydrogeranylgeranoic Acid: Effects of Small-Dose and Infrequent Administration

Inhibitory effects of 4,5-didehydrogeranylgeranoic acid (dGGA) on the development of tumors were investigated in spontaneous hepatoma mice, C3H/HeNCrj. Experiment 1: Male mice at 8 weeks of age were raised on a basal diet, and then provided with a diet containing 0.02% dGGA from 32 to 91 weeks of age. Experiment 2: dGGA was administered to the animals only once at different time points, from 2 months to 17 months after birth, respectively. Experiment 3: dGGA was administered twice to the mice at different time points: at 5 months and 11 months, and at 8 months and 11 months, respectively. When the inhibitory effects on tumor development were evaluated with the incidences of tumors, average numbers, and weight of tumors per mouse, there was a marked relationship between the time of single or dual dosing and the inhibitory effects of dGGA. The greatest inhibitory effects were observed in Experiment 3 in the group of animals given dGGA at the ages of 8 and 11 months, which were far superior to the results with a large dose of the compounds for a long time. These results might indicate that dGGA administered at the right time in the right amount effectively prevents the development of cancer.

THU447 Hungry Bone Syndrome Secondary To Denosumab Use In A Patient With Sleeve Gastrectomy

Abstract Disclosure: A. Prabha Kumar: None. M. Shakir: None. B. Sharma: None. O. Syed: None. S. Natarajan: None. M. Dominic: None. Our patient is a 60-year-old woman with significant past medical history of morbid obesity, requiring laparoscopic sleeve gastrectomy, converted to Single Anastomosis Duodeno-Ileostomy (SADI) 4 months ago. Her comorbidities included Crohn’s disease, chronic lower extremity lymphedema treated with torsemide, spironolactone & metolazone, psoriatic arthritis (PsA) & osteoporosis secondary to prolonged use of steroids for suppression of PsA. She was also chronically on proton pump inhibitors (PPIs). Since the SADI, patient had diarrhea, an expected complication & was symptomatically managed. She received Denosumab (Prolia) injections for osteoporosis. Her 1st shot was nearly 6 months ago & 2nd was 5 days prior to her presentation at the hospital. She presented with symptoms of tingling over bilateral lower extremities and generalized weakness causing dizziness and fall at home. Vitals were positive for orthostasis. Labs revealed serum calcium 6.7 mg/dL (8.4 - 10.2 mg/dL), magnesium 1.3 mg/dL (1.5 - 2.6 mg/dL), potassium 3.1 mmol/L (3.5 - 5.1 mmol/L) phosphorus 1.7 mg/dL (2.5 - 4.8 mg/dL), 25-Hydroxy Vit D 39 ng/mL (30 - 50 ng/mL) & serum PTH 152 pg/mL (15 - 65 pg/mL). Physical examination and EKG were unremarkable. She received aggressive resuscitation of fluids & electrolytes & was discharged on calcium carbonate 600 mg TID, Vit C 500 mg BID, Vit D 1000 units daily and calcitriol 0.5 mcg BID. PPI was discontinued as it is known to reduce calcium & magnesium absorption. Metolazone was discontinued to prevent electrolyte depletion. Serum calcium normalized to 8.4 mg/dL. She was advised to taper off steroids to avoid further progression of osteoporosis, thereby eliminating the need for Prolia. Prolia is a RANK-L inhibitor given as a subcutaneous injection every 6 months. It works by inhibiting the action of osteoclasts, thereby, preventing bone remodeling & bone loss. It has shown to improve bone mass, microstructure & strength, thus reducing fractures. As a result, regular calcium turnover is affected & serum calcium is housed within bones, causing hypocalcemia & state of “hungry bones”. Risk is especially high in patients with reduced renal function, have recently undergone thyroid surgery, are concurrently on meds like loop diuretics which cause calcium loss. Malabsorptive diarrhea after SADI is an understood complication and can result in Vit D deficiency, hypocalcemia with secondary hyperparathyroidism. Daily calcium & Vit D is recommended after gastric bypass & in patients receiving Prolia, if indicated. Another take away for physicians is to pay special attention to medication reconciliation on admission as medications like Prolia could easily be missed given the infrequent administration. Careful risk stratification & prophylactic supplementation is required in such patients to prevent hypocalcemia. Presentation: Thursday, June 15, 2023

An Exploratory Pilot Study of Neuropsychological Performance in Two Huntington Disease Centers of Excellence Clinics.

To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance between premanifest and manifest HD patient groups (compared with each other and normative expectations). Clinical data from 76 adult genetically confirmed patients referred for neuropsychological evaluations was retrospectively collected from two HDSA COEs. ANOVA and Chi-square tests were used to compare variables between pre-manifest (n = 14) and manifest (n = 62) groups for demographic, cognitive, neuropsychiatric, and disease severity variables. Our clinics serviced a disproportionate number of motor manifest patients. Six measures were excluded from analyses due to infrequent administration. The full WAIS-IV Digit Span was disproportionately administered to the manifest group. The premanifest group showed stronger cognitive performance with effect sizes in the large range on subtests of the WAIS-IV Digit Span, HVLT-R, SDMT, and verbal fluency. This is the first study to assess an empirically supported neuropsychological research battery in a clinical setting with a relatively large sample size given the rarity of HD. The battery adequately captured areas of impairment across the disease spectrum. Application of the current battery with larger premanifest samples is warranted.

Targeted Nanotherapy of Hematologic Malignancies Using Gold Nanoframework-Based Delivery of a Novel NF-Kb Inhibitor

Hematologic malignancies account for one third of all cancers worldwide. Traditional chemo- or radiotherapy of these often highly aggressive cancers is limited by poor bio-selectivity and a narrow safety window, correlating with a risk for serious side effects and the development of refractory disease. Precision molecular therapeutics and highly targeted nanotechnological approaches can be employed as an alternative to overcome these challenges and successfully produce targeted anti-tumor responses, especially in the setting of disseminated disease. Herein, we report the formulation of a therapeutic nanocomposite comprising of a hyaluronic acid (HA)-coated gold nanoframework delivery system and encapsulated IT848, a novel small molecule with potent anti-lymphoma and -myeloma properties that targets the transcriptional activity of nuclear factor kappa B (NF-κB). We show that IT848 inhibits NF-κB activity through inhibition of DNA binding of all five NF-κB subunits. IT848 treatment of lymphoma and myeloma cell lines and patient samples inhibited proliferation and induced caspase-dependent and independent apoptosis. In addition to direct NF-κB inhibitory effects, IT848 treatment altered the redox homeostasis of cancer cells through depletion of the reduced glutathione pool, selectively inducing oxidative stress in cancer but not in healthy cells. IT848 significantly improved survival in an immunocompetent mouse model of multiple myeloma when combined with PD-1 inhibition, and correlative immune studies revealed that this clinical benefit was associated with suppression of regulatory T cell infiltration of the tumor microenvironment. We optimized the safety profile as well as the efficacy of IT848 by adapting HA-coated gold nanoparticles as an integrative platform for CD44-targeted delivery of IT848. Among a plethora of functionalized nanomaterials used for drug delivery, gold nanoparticles/nanoframeworks (AuNF) demonstrate excellent efficacy as drug carriers, photothermal or contrast agents, and radiosensitizers. Furthermore, easy synthesis and apt control over particle size, shape, porosity, and surface chemistry, together with their excellent biocompatibility make these particles ideal vehicles for small molecules such as IT848. HA-functionalized and IT848-loaded AuNFs were synthesized via a simple, reproducible, and inexpensive liposome-assisted technique that can easily be scaled up, a critical feature for clinical relevance. AuNFs were loaded with IT848 and surface functionalized with HA to formulate nanotherapeutics that were able to efficiently deliver the payload with high specificity to myeloma and lymphoma cell lines in vitro. In vivo studies characterized biodistribution, pharmacokinetics and safety of HA-AuNFs, and we demonstrated significantly superior specificity and efficacy of HA-AuNF formulated IT848 versus free IT848 in lymphoma mouse models (Figure 1). Our results indicate that active targeted delivery of IT848 using AuNFs via HA-CD44 ligand-receptor mediated endocytosis is a promising strategy to augment IT848 uptake by CD44-overexpressing tumor cells, mitigate rapid clearance of nanoparticles from the body and yield a highly desirable and sustained (as compared to free IT848) anti-tumor therapeutic effect. Our HA-AuNF-based drug delivery approach offers infrequent (weekly) low dose administration and robust efficacy with minimal toxicity risk. In fact, i.v. administration of IT848-loaded HA-AuNFs once or twice a week was not associated with any signs of toxicity, while traditional intraperitoneal administration of free IT848 twice a week over a 2-week period typically leads to ascites development in up to 50% of the recipients. Collectively, both our in vitro and in vivo results affirm that our AuNF system facilitates targeted drug delivery, improving the drug safety profile, and enhancing the efficacy of our novel NF-kB inhibitor molecule with minimal dosing. Our data therefore provide a strong preclinical rationale for the clinical development of HA-AuNF formulated IT848 as a therapeutic modality for the treatment of hematological malignancies. Additional studies are needed to develop curative treatment regimens based on synergistic, highly active, and well-tolerated combinatorial approaches with other targeted agents such as immune checkpoint inhibitors, hypomethylating agents, or CAR-T cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Small interfering RNA: Discovery, pharmacology and clinical development-An introductory review.

Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability toallow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.

Expansion of the osteocytic lacunar-canalicular system involved in pharmacological action of PTH revealed by AI-driven fluorescence morphometry in female rabbits

Osteoporosis is an age-related disorder that is characterized by reduced bone mass. Its prevention and treatment are important healthcare issues for maintaining social activity in aged societies. Although bone fractures mostly occur at sites of weakened cortical bone, pathophysiological and pharmacological evaluations of bone mass have tended to be predominantly assessed in trabecular bone. To statistically characterize cortical bone remodeling, we originally established multimode fluorescence imaging and artificial intelligence (AI)-driven morphometric analyses in six-month-old female rabbits with well-defined cortical remodeling, similar to that in humans. We evaluated three distinct administration frequencies of teriparatide [TPTD; human parathyroid hormone, hPTH (1–34)]: once (1/w), twice (2/w), and seven times (7/w) a week, with the same total dose (140 μg/kg/week). Our analyses revealed significant expansions of the osteocytic lacunar-canalicular system and Haversian canals accompanied by the development of cortical porosity and endosteal naïve bone formation induced by a frequent administration regimen (7/w) of TPTD; however, once-weekly (1/w) and twice-weekly (2/w) administration of TPTD showed little effect. These findings demonstrate a clear contrast between the effects of frequent and infrequent administration of TPTD on cortical bone metabolism and suggest that osteocytic bone remodeling is involved in the pharmacological action of PTH.

AML-194 Second Hematological Malignancies in Survivors of Breast Cancer: An Indian Institutional Analysis

Breast cancer survivors are at increased risk of developing second hematological malignancies (SHM). As the survival rates increase in breast cancer patients, SHM have become a cause of concern. To determine the incidence of various SHM in breast cancer survivors at a large tertiary care center in India. This retrospective study was conducted at the All India Institute of Medical Sciences, New Delhi, India. Women who were diagnosed with first primary breast cancer between 2006 and 2019 at our institute and subsequently developed SHM ≥1 year after primary breast cancer diagnosis were analyzed. The incidence of various myeloid or lymphoid malignancies developing at least one year after primary breast cancer diagnosis. Between 2006 and 2019, a total of 4,900 patients were diagnosed with female breast cancer and treated with multimodality treatment, including chemotherapy, at our center. Seventy-nine percent (79%) of patients received 3 weekly sequential anthracyclines and taxane, 2% received only anthracyclines, and 19% received only taxane-based chemotherapy. Primary or secondary GCSF prophylaxis was used in 18% of cases. With a median follow-up period of 54 months (4.5 years), 21 (0.43%) patients developed SHM. The median age at diagnosis of SHM was 59 years, and the median interval between breast cancer diagnosis and SHM was 42 months. The most common SHM was acute myeloid leukemia (AML; n=12) followed by non-Hodgkin lymphoma (n=3); 2 cases of myelodysplastic syndrome, 2 cases of acute lymphocytic leukemia, and 1 case each of chronic myeloid leukemia, Hodgkin lymphoma, and multiple myeloma were observed. Of the breast cancer survivors included, 0.43% developed SHM, and AML (0.24%) is the most common. The incidence of secondary AML is probably low from the reported western literature because of not routinely using a dose-dense protocol, infrequent GCSF administration, and one-fifth of patients received non-anthracycline-based treatment protocol in a specific subgroup of breast cancer.

PCSK9 inhibitor recaticimab for hypercholesterolemia on stable statin dose: a randomized, double-blind, placebo-controlled phase 1b/2 study

BackgroundRecaticimab (SHR-1209, a humanized monoclonal antibody against PCSK9) showed robust LDL-C reduction in healthy volunteers. This study aimed to further assess the efficacy and safety of recaticimab in patients with hypercholesterolemia.MethodsIn this randomized, double-blind, placebo-controlled phase 1b/2 trial, patients receiving stable dose of atorvastatin with an LDL-C level of 2.6 mmol/L or higher were randomized in a ratio of 5:1 to subcutaneous injections of recaticimab or placebo at different doses and schedules. Patients were recruited in the order of 75 mg every 4 weeks (75Q4W), 150Q8W, 300Q12W, 150Q4W, 300Q8W, and 450Q12W. The primary endpoint was percentage change in LDL-C from the baseline to end of treatment (i.e., at week 16 for Q4W and Q8W schedule and at week 24 for Q12W schedule).ResultsA total of 91 patients were enrolled and received recaticimab and 19 received placebo. The dose of background atorvastatin in all 110 patients was 10 or 20 mg/day. The main baseline LDL-C ranged from 3.360 to 3.759 mmol/L. The least-squares mean percentage reductions in LDL-C from baseline to end of treatment relative to placebo for recaticimab groups at different doses and schedules ranged from −48.37 to −59.51%. No serious treatment-emergent adverse events (TEAEs) occurred. The most common TEAEs included upper respiratory tract infection, increased alanine aminotransferase, increased blood glucose, and increased gamma-glutamyltransferase.ConclusionRecaticimab as add-on to moderate-intensity statin therapy significantly and substantially reduced the LDL-C level with an infrequent administration schedule (even given once every 12 weeks), compared with placebo.Trial registrationClinicalTrials.gov, number NCT03944109

Abstract 1716: WTX-330, a conditionally activated IL-12 INDUKINE, releases IL-12 selectively in the tumor microenvironment to activate anti-tumor immune responses and induce regressions in mouse tumor models

Abstract Systemic therapy with proinflammatory immune modulators is a promising approach to treat cancer by activating innate and adaptive anti-tumor immunity. However, dose-limiting toxicities such as inflammation, cytokine release syndrome, and tissue damage rendered the strategy impractical for cytokines such as the cytotoxic T and NK cell activating interleukin 12 (IL-12). WTX-330 is a novel systemically delivered therapy with targeted intra-tumoral activation to deliver wild-type IL-12 in the tumor microenvironment identified using the Predator™ discovery platform. WTX-330 is a member of a class of inducible polypeptides (INDUKINE™ therapies) designed to be an inactive IL-12 pro-drug with a half-life extension (HLE) domain to support infrequent systemic administration. The INDUKINE™ polypeptide is kept inactive in the periphery via high affinity antibody blockade tethered to IL-12 via a tumor protease-sensitive linker. Cleavage of the same linker also removes the HLE domain producing a PK profile similar to wild-type IL-12. WTX-330 was selected as a lead molecule due to its beneficial in vitro profile. The mouse MC38 syngeneic tumor model was used to demonstrate strong anti-tumor activity of lead mouse INDUKINE™ polypeptides. Intraperitoneal (i.p.) administration of mouse WTX-330 led to complete regression of all MC38 tumors at dose levels which only moderately induced systemic IFNγ and were well tolerated by the mice. Similar efficacy was observed in CT26, B16F10, and EMT-6 syngeneic models. Importantly, wild-type IL-12, while active in mouse tumor models, was not tolerated by the mice after i.p. injection at equimolar amounts compared to the IL-12 INDUKINE™ polypeptide. Mouse WTX-330 strongly activated NK and CD8+ cell responses and induced APC and effector cell markers in MC38 tumors supporting a mechanism of action as described for wild-type IL-12. In non-human primates, WTX-330 was well tolerated at exposure levels which vastly exceeded the levels needed for efficacy in mice. In addition, plasma levels of free IL-12 after dosing with WTX-330 were very low compared to tolerated levels after treatment with wild-type IL-12. Ex vivo incubation of WTX-330 with numerous primary human tumors led to the rapid release of IL-12, while WTX-330 proved to be stable in human serum and normal tissues. Pharmacological and translational data obtained so far clearly support continued preclinical development with the goal of moving this innovative and differentiated engineered IL-12 therapy into human clinical testing. Citation Format: Philipp Steiner, Heather Brodkin, Dan Hicklin, Nesreen Ismail, Kristin Morris, Christopher Nirschl, Andres Salmeron, Cindy Seidel-Dugan, Zoe Steuert, Jenna Sullivan, William Winston. WTX-330, a conditionally activated IL-12 INDUKINE, releases IL-12 selectively in the tumor microenvironment to activate anti-tumor immune responses and induce regressions in mouse tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1716.

Pharmacokinetics and Drug-Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine.

Combined antiretroviral treatments have significantly improved the morbidity and mortality related to HIV infection, thus transforming HIV infection into a chronic disease; however, the efficacy of antiretroviral treatments is highly dependent on the ability of infected individuals to adhere to life-long drug combination therapies. A major milestone in HIV treatment is the marketing of the long-acting intramuscular antiretroviral drugs cabotegravir and rilpivirine, allowing for infrequent drug administration, with the potential to improve adherence to therapy and treatment satisfaction. Intramuscular administration of cabotegravir and rilpivirine leads to differences in pharmacokinetics and drug–drug interaction (DDI) profiles compared with oral administration. A notable difference is the long elimination half-life with intramuscular administration, which reaches 5.6–11.5 weeks for cabotegravir and 13–28 weeks for rilpivirine, compared with 41 and 45 h, respectively, with their oral administration. Cabotegravir and rilpivirine have a low potential to cause DDIs, however these drugs can be victims of DDIs. Cabotegravir is mainly metabolized by UGT1A1, and rilpivirine is mainly metabolized by CYP3A4, therefore these agents are susceptible to DDIs with inhibitors, and particularly inducers of drug-metabolizing enzymes. Intramuscular administration of cabotegravir and rilpivirine has the advantage of eliminating DDIs occurring at the gastrointestinal level, however interactions can still occur at the hepatic level. This review provides insight on the intramuscular administration of drugs and summarizes the pharmacology of long-acting cabotegravir and rilpivirine. Particular emphasis is placed on DDI profiles after oral and intramuscular administration of these antiretroviral drugs.

Abstract PS13-11: Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): Management of gastrointestinal adverse events (GI AE). Study KX-ORAX-001

Abstract Background: There is a need for more effective and less toxic treatments for patients with mBC. Patients may prefer oral vs IV cytotoxic therapies to avoid frequent hospital visits. In addition, oral therapies allow frequent or metronomic dosing regimens which may alter the toxicity or activity profile of agents vs infrequent IV administration. oPac+E is oral paclitaxel combination with Encequidar, a specific, minimally absorbed, oral p-glycoprotein inhibitor that facilitates the absorption of oral paclitaxel. mBC patients who received oPac+E had significantly greater confirmed tumor response and longer survival with lower rates and severity of neuropathy but increased GI AE compared to IV paclitaxel (IVPac) (Study KX-ORAX-001 presented at SABCS, 2019, Abstract # GS6-01). Methods: Study KX-ORAX-001 was a phase III, randomized, study in women with mBC for whom treatment with IVPac was recommended. Patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: All IVPac patients received high-dose dexamethasone and antihistamine premedication, which have significant anti-emetic activity and may have received additional anti-emetic agents as needed. The protocol did not allow any prophylaxis for GI AE for oPac+E patients nor were they to receive predose corticosteroids, nor antihistamines. The protocol was amended after approximately 30% of patients were enrolled to allow prophylactic anti-emetic medications for patients randomized to oPac+E. Patients were also given loperamide to take at home and were instructed to initiate loperamide with the onset of diarrhea. The rates of Grade ≥2, vomiting and diarrhea for patients treated with IVPac, the patients treated with oPac+E prior to after the amendment are summarized in the table below. Prophylactic anti-emetic therapy and early use of loperamide markedly decreased the incidence of ≥Grade 2 vomiting and diarrhea although there was a greater incidence than IVPac. The most frequently prescribed anti-emetic agents for oPac+E treated patients were ondansetron (54%), metoclopramide (21%), domperidone (4%) and aprepitant (3%). For patients randomized to IVPac, the most frequently prescribed agents were ondanesteron (59%), granisetron (24%), palenosetron (7%) and aprepitant (2%). Oral administration of the oral NK1 inhibitor aprepitant appeared to be associated with increased incidence of oral paclitaxel systemic toxicity, potentially due to inhibition of metabolism of oPac by cytochrome P450 3A4. Conclusions: oPac+E was associated with greater efficacy in the treatment of mBC and lower rates and severity of peripheral neuropathy, but increased GI AE compared to IVPac 175mg/m2. GI AE in oPac+E treated patients can be managed by prophylactic use of anti-emetics, primarily 5-HT3 inhibitors and early intervention with the anti-diarrhea agent loperamide. The use of the oral NK1 inhibitor aprepitant in combination with oPac+E is not recommended.(NTC02594371) IVPacoPac+E Pre-AmendmentoPac+E Post AmendmentGrade 2Grade 3Grade 4Grade 2Grade 3Grade 4Grade 2Grade 3Grade 4Vomiting4%1%0%24%7%0%7%4%0%Diarrhea7%1%0%27%9%0%16%3%0.5% Citation Format: H S Rugo, G Umanzor, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): Management of gastrointestinal adverse events (GI AE). Study KX-ORAX-001 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-11.

Personalized medicine in lipid-modifying therapy.

The choice of lipid-modifying treatment is largely based on the absolute level of cardiovascular risk and baseline lipid profile. Statins are the first-line treatment for most patients requiring reduction of low-density-lipoprotein cholesterol (LDL-C) and ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors can be added to reach LDL-C targets. Statins have some adverse effects that are somewhat predictable based on phenotypic and genetic factors. Fibrates or omega-3 fatty acids can be added if triglyceride levels remain elevated. The RNA-targeted therapeutics in development offer the possibility of selective liver targeting for specific lipoproteins such as lipoprotein(a) and long-term reduction of LDL-C with infrequent administration of a small-interfering RNA may help to overcome the problem of adherence to therapy.

Preparing for sperm-targeted contraception: College students' perceptions and intentions related to non-hormonal intravas injectable gel.

The objective of the study was to evaluate college students' perceptions and behavioral intentions related to a new long-acting reversible contraceptive (LARC) for people with penises: non-hormonal intravas injectable gel (NH-IVIG). Data collection utilized predictive constructs from the theory of planned behavior. An online questionnaire surveyed undergraduates (ages 18-24years) at a Midwestern, liberal arts college (N=460). Of potential NH-IVIG users, 28.6% of males and 51.4% of females reported being overall likely to use or encourage its usage. The top three hypothetical NH-IVIG promoters were low cost, reversibility, and infrequent administration. High cost, new product uncertainties, plus administration via injection for the males, were the most frequently cited NH-IVIG deterrents. A majority of potential users indicated intentions to use protective barriers or other contraceptives simultaneously with NH-IVIG; females were more likely overall. Most respondents (males, 90.4%; females, 98.5%) agreed all sexual partners should be equally responsible for contraception. Over half trusted both males and females to use contraception, but females were significantly more trusted and trusting. Understanding factors influencing NH-IVIG usage can direct initiatives for sperm-targeted LARCs to mitigate risk behaviors and optimize public health promotion.

Effects of the publication of Clinical Guidelines for the Management of Chemotherapy-Induced Peripheral Neuropathy on the Administration Preferences of Oncology Specialists: Japanese Association of Supportive Care in Cancer.

We conducted a questionnaire survey of oncology specialists to investigate the frequency of administration of different drugs for the management of chemotherapy-induced peripheral neuropathy in Japan in 2015. Our group published Clinical Guidelines for the Management of Chemotherapy-Induced Peripheral Neuropathy in 2017 (CIPN-GL2017). In these guidelines, we recommended duloxetine only. To verify the effect of the publication of the CIPN-GL2017, we conducted a questionnaire survey in 2019. In 2015 and again in 2019, we investigated the use of vitamin B12, antiepileptic agents, duloxetine, antidepressants other than duloxetine, non-steroidal anti-inflammatory drugs, opioids and the Kampo compound (goshajinkigan) in a questionnaire employing a three-point scale wherein A implies routine or prophylactic administration, B implies occasional administration and C implies infrequent administration. We sent the questionnaires via email to 971 diplomates of the Subspecialty Board of Japanese Society of Medical Oncology in 2015 and 1239 diplomates in 2019. The administration ratio (A+B) of duloxetine for numbness and pain was 46.8 and 31.7%, respectively, in 2015 and 68.9% (P<0.01) and 73.1% (P<0.01) in 2019. In response to the question regarding awareness of the CIPN-GL2017, 53.2% of respondents to the 2019 questionnaire were aware of the CIPN-GL2017. Among the respondents with an awareness of the CIPN-GL2017, the prescription rate of duloxetine (78.3%) for pain was significantly higher than that among respondents without any awareness (67.4%). It is possible that the publication of CIPN-GL2017 influenced administration preferences of oncology specialists.

Investigational RNAi Therapeutic Targeting C5 Is Efficacious in Pre-clinical Models of Myasthenia Gravis

Complement-mediated damage to the neuromuscular junction (NMJ) is a key mechanism of pathology in myasthenia gravis (MG), and therapeutics inhibiting complement have shown evidence of efficacy in the treatment of MG. In this study, we describe the development of a subcutaneously administered N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the C5 component of complement that silences C5 expression in the liver (ALN-CC5). Treatment of wild-type rodents with ALN-CC5 resulted in robust and durable suppression of liver C5 expression. Dose-dependent serum C5 suppression was observed in non-human primates, with a lowering of serum C5 of up to 97.5% and the concomitant inhibition of serum complement activity. C5 silencing was efficacious in ameliorating disease symptoms in two standard rat models of MG, demonstrating the key role of circulating C5 in pathology at the NMJ. Improvement in disease activity scores and NMJ pathology was observed at intermediate levels of complement activity inhibition, suggesting that complete ablation of complement activity may not be required for efficacy in MG. The pre-clinical studies of ALN-CC5 and efficacy of C5 silencing in rat models of MG support further clinical development of ALN-CC5 as a potential therapeutic for the treatment of MG and other complement-mediated disorders.

Injectable long-acting human immunodeficiency virus antiretroviral prodrugs with improved pharmacokinetic profiles

While highly active antiretroviral therapy (HAART) has significantly reduced mortality rates in patients with human immunodeficiency virus type 1 (HIV-1), its efficacy may be impeded by emergence of drug resistance caused by lack of patient adherence. A therapeutic strategy that requires infrequent drug administration as a result of sustained release of antiretroviral drugs would put less burden on the patient. Long-acting antiretroviral prodrugs for HIV therapy were synthesized through modification of the active drugs, emtricitabine (FTC) and elvitegravir (EVG), with docosahexaenoic acid (DHA) in one-step, one-pot, high-yielding reactions. The in vitro drug release profiles of these synthetic conjugates demonstrated sustained and controlled release of the active drug over a period of 3–4 weeks attributable to the hydrolysis of the chemical linker in conjunction with the hydrophilicity of the parent drug. Both conjugates exhibited superior antiviral activities in tissue culture models of HIV replication as compared to those of the free drugs, strengthening their role as potent prodrugs for HIV therapy. Pharmacokinetic analysis in CD1 mice further confirmed the long-acting aspect of these conjugates with released drug concentrations in plasma detected at their respective IC90/IC95 values over a period of 2 weeks and discernable amounts of active drug even at 6 weeks. Our findings suggest that the injectable small molecule conjugates could be used as long-acting controlled release of FTC and EVG in attempts to mitigate adherence-related HIV resistance.

A Review of Monoclonal Antibody Therapies and Other Preventative Treatments in Migraine.

Monoclonal antibodies targeting the calcitonin gene-related peptide pathway represent a new class of mechanism-specific, migraine-targeted therapies available for migraine prevention. To date, four monoclonal antibodies have demonstrated efficacy in phase II and III trials, significantly reducing migraine days per month versus placebo with rapid onset of action. While their efficacy may be considered similar to existing preventive options, their true value may lie in an improved tolerability profile, with high specificity and selectivity for the calcitonin gene-related peptide receptor or ligand reducing the potential for off-target binding and toxicity. The infrequent parenteral administration of these therapeutic proteins, and lack of requirement for dose titration, has potential to simplify treatment selection and use for clinicians and patients. However, the treatments have not yet been tested in real-world settings in patients with the range of comorbid conditions encountered in routine clinical practice, and longer-term data on safety, efficacy, and treatment persistence are required. If data from real-world settings can confirm the initial clinical trial findings, it is hoped that antibodies antagonizing the calcitonin gene-related peptide pathway will be able to improve quality of life for patients with episodic and chronic migraine, and help relieve the huge patient and societal burden of migraine. Novel treatments designed to target the specific pathophysiology of migraine could have an important place in future migraine management.

When to switch to an oral treatment and/or to discharge a patient with skin and soft tissue infections.

Skin and soft tissue infections prevalence is increasing and represent a frequent cause of hospital admission. New guidelines have become available in order to better define these infections and their response to antimicrobial treatment. Gram-positive bacteria, in particular Staphylococcus aureus, remain the most frequently isolated pathogens in skin and soft tissue infections. To treat complicated forms and infections caused by drug-resistant bacteria, hospital admission and administration of intravenous antibiotics are often required, impacting on healthcare costs and patients' morbidity. New therapeutic options offer efficacy against drug-resistant Gram-positive bacteria as well as potential to favor early patients' discharge, including the possibility for intravenous to oral switch and infrequent drug administration because of prolonged drug half-life. Although data from real-world studies on new antimicrobials is awaited, clinicians need clear direction on how to optimize the treatment of skin and soft tissue infections in order to avoid prolonged hospitalizations and extra costs. Early assessment of patient's clinical conditions and response to treatment appear useful in order to facilitate patients' discharge. We have reported the evidence for early intravenous to oral switch and early hospital discharge for patients with skin and soft tissue infections. New therapeutic options that represent promising tools in promoting an optimized management of these infections have also been reviewed.

The role of dalbavancin in skin and soft tissue infections

The increase of skin and soft tissue infections (SSTIs) represents a major concern both in community and in the hospital setting. Staphylococcus aureus is the most frequently isolated pathogen, and the rise in infections due to methicillin-resistant Staphylococcus aureus (MRSA) has been associated with inadequate antibiotic treatment and increased morbidity. A number of new antimicrobials with activity against drug-resistant Gram-positive pathogens, including MRSA, have been recently approved for the treatment of SSTIs. New lipoglycopeptides, in particular dalbavancin, are long-acting antibiotics with potential for infrequent administration, offering the possibility for outpatient treatment and early hospital discharge. Dalbavancin is a new lipoglycopeptide showing high activity against Gram-positive bacteria, including drug-resistant strains. Dalbavancin presents a distinctive pharmacokinetic profile with a terminal prolonged half-life of approximately 14 days. This characteristic allows once-weekly dosing interval, avoiding the need for daily dosing and offering an advantage over other compounds for potential use in the outpatient setting or to promote early hospital discharge. Dalbavancin has a favorable adverse effect profile and appears to be a promising new alternative for treatment of SSTIs. We have reviewed the pharmacokinetic properties of dalbavancin and the clinical evidence for its use in complicated SSTIs and other potential applications.