Once-weekly Dosing Research Articles

Pharmacodynamics of a Long-Acting Echinocandin, CD101, in a Neutropenic Invasive-Candidiasis Murine Model Using an Extended-Interval Dosing Design.

Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans, making it possible to design once-weekly dosing strategies. The present study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select Candida albicans (n = 4), C. glabrata (n = 3), and C. parapsilosis (n = 3) strains. The CD101 MIC ranged from 0.03 to 1 mg/liter. Plasma pharmacokinetic measurements were performed using uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 to 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days, at which time the organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC index) correlated well with efficacy (R2, 0.74 to 0.93). The median stasis 24-h free-drug AUC/MIC targets were as follows: for C. albicans, 2.92; for C. glabrata, 0.07; and for C. parapsilosis, 2.61. The PK/PD targets for 1-log10 kill endpoint were 2- to 4-fold higher. Interestingly, the aforementioned PK/PD targets of CD101 were numerically lower for all three species than those of other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent in vivo pharmacodynamic activity.

Effect of dosing frequency of teriparatide (PTH 1-34) on bone formation in rats: comparison of bone metabolism marker levels

Teriparatide, a drug used in the treatment of osteoporosis, was administered to rats subcutaneously for the duration of 3 months, at a frequency of either once weekly or once daily to demonstrate the varying levels of anabolic action the drug can have on bone depending on the dosing frequency. The levels of biomarkers in the blood were compared and found to vary in osteocalcin (OC), a biomarker of bone formation, and cross-linked N-telopeptide of type 1 collagen (NTx), a biomarker of bone resorption, according to the dosing frequency. In the once-weekly regimen, teriparatide did not affect NTx levels at any of the doses studied, while OC levels increased with dose, peaking at 72 hr, then returning to normal before the next injection (after 1 week). Bone mineral density (BMD) levels increased moderately with no difference between doses. This was thought to result from the steady state achieved following increases in bone formation and bone absorption. In the once-daily dosing regimen, meanwhile, NTx levels increased with dose, and OC levels were markedly higher when compared to those with the once-weekly dosing. BMD levels were higher than those with the once-weekly dosing, but with no difference between doses. This was considered a result of unlimited, excessive increases in bone formation due to daily administration of the drug. These results suggest that teriparatide promotes normal bone metabolism ("stationary mini-modeling") when administered once weekly, and has an anabolic action with high metabolic turnover ("high-turnover remodeling") when administered once daily.

Activity of CD19/CD3 Bispecific Antibodies in Chronic Lymphocytic Leukemia

▪Kinase inhibitors such as ibrutinib have advanced treatment of chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments capable of deepening response or overcoming resistance to kinase inhibitors. CD19/CD3 bispecific antibodies (bsAbs) recruit endogenous T cells to form cytolytic synapses with CD19+ tumor cells. Blinatumomab, a CD19/CD3 bsAb designed in the 54 kDa BiTE format, is FDA approved for the treatment of some forms of acute lymphoblastic leukemia, and has potential for use in other B-cell malignancies. However, due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy. We have developed a novel CD19/CD3 bsAb in the 100 kDa single chain-Fv Fc format (19/3-scFv-Fc). With a half-life of approximately 7 days, 19/3-scFv-Fc may be suitable for weekly dosing, providing a significant logistical advantage. Here we investigated the potential use of 19/3-scFv-Fc for treatment of CLL.We first cultured peripheral blood mononuclear cells (PBMCs) from treatment-naïve CLL patients with bsAbs and measured CLL cell death by flow cytometry. After 12 days of exposure, median specific-killing compared to the non-targeting control HER2/CD3-scFv-Fc was 91.2% for blinatumomab (P= 0.0009) and 92.1% for 19/3-scFv-Fc (P= 0.003)(n = 12). Both CD19/CD3 bsAbs induced over 25-fold expansion of autologous CD8 and CD4 T cells, as demonstrated by increase in absolute cell counts and by CFSE proliferation assays. Activation markers CD69 and CD25, as well as granzyme B, were also increased in both CD8 and CD4 T cell subsets cultured with blinatumomab or 19/3-scFv-Fc.As blinatumomab and 19/3-scFv-Fc demonstrated comparable activity against CLL ex vivo, we next evaluated efficacy of bsAbs in vivo using the NOD/SCID/IL2Rγnull (NSG) patient-derived xenograft model. Fifty million CLL PBMCs were injected per mouse, with 2-5 mice tested per treatment group and patient combination. bsAbs were then given once-weekly, with blinatumomab dosed at 0.25 mg/kg and 19/3-scFv-Fc at 0.5 mg/kg to achieve equal molar concentrations. Treatment with 19/3-scFv-Fc resulted in elimination of over 98% of CLL cells in the blood (P < 0.0001) and spleen (P= 0.0026) compared to treatment with HER2/CD3-scFv-Fc (n = 4). Blinatumomab failed to induce any response, either with once-weekly dosing or daily dosing for 8 days.Ibrutinib has been shown to improve T cell dysfunction characteristic of CLL, suggesting immunotherapy may work well with concurrent ibrutinib treatment. Culture of CLL PBMCs from ibrutinib-treated patients (n = 10, 12 ± 1 months on ibrutinib) with 19/3-scFv-Fc induced T cell activation and increased granzyme B expression comparable to that seen in cells obtained from treatment-naïve patients. However, treatment with 19/3-scFv-Fc drove significantly more killing of ibrutinib-treated CLL cells compared to treatment-naïve CLL cells after 3 days of exposure (43.7% versus 2.23% median specific-killing, P= 0.004). By day 7, 95.3% of ibrutinib-treated and 45.3% of treatment-naïve CLL cells were eliminated (P= 0.02).Resistance to ibrutinib has been commonly linked to mutations in BTK and/or PLCG2 and is associated with early mortality. We assessed activity of 19/3-scFv-Fc in 3 patients with acquired ibrutinib resistance, manifest 34 to 44 months from the start of ibrutinib. Multiple BTK and/or PLCG2 mutations were present in all 3 patients, with cancer cell fractions of the most abundant mutation in each patient ranging from 8-32%. 19/3-scFv-Fc treatment in culture resulted in >90% specific-killing of CLL cells from all 3 ibrutinib-resistant patients (range 91.50 - 97.83%, P= 0.0066). After engraftment of ibrutinib-resistant cells in NSG mice, 1 dose of 19/3-scFv-Fc eliminated >90% of circulating CLL cells, while HER2/CD3-scFv-Fc had no anti-leukemic activity (P < 0.0001), indicating that 19/3-scFv-Fc can effectively target mutant CLL clones resistant to ibrutinib. Taken together, these data support the investigation of 19/3-scFv-Fc as a promising immunotherapy for CLL, either in combination with ibrutinib or as rescue therapy in ibrutinib-resistant disease. DisclosuresWiestner:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding.

Sex differences in high fat diet-induced impairments to striatal Akt signaling and enhanced sensitivity to the behavioral effects of dopamine D2/D3 receptor agonist quinpirole

Eating a high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g., cocaine). Further, in male rats, eating high fat chow impairs expression of insulin signaling phosphorylated protein kinase B (pAkt), which is vital for maintaining dopamine homeostasis. Eating high fat chow enhances sensitivity of female rats to drugs that act indirectly on dopamine receptors (e.g., cocaine); however, less is known about sensitivity of females to drugs that act directly on dopamine receptors (e.g., quinpirole). Further, it is not known if pAkt expression is impaired in female rats eating high fat chow. Some quinpirole-induced behaviors (e.g., penile erections and yawning) are either absent or occur at very low frequency in adult female rats. It is not known if quinpirole sensitivity in adolescent rats is more comparable between sexes. The present report examined another unconditioned behavioral effect (i.e., rearing) induced by once-weekly cumulative doses of quinpirole (0.0032–0.32mg/kg) in male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), for several weeks throughout development, (spanning adolescence and early adulthood). Following behavioral assessments, pAkt expression was examined using western blot protein analysis. Eating high fat chow increased sensitivity of male rats to the quinpirole-induced yawning, as compared to male rats eating standard chow. However, other unconditioned behavioral effects of quinpirole (yawning and hypothermia) remained unchanged. Female rats yawned significantly less than male rats, and eating a high fat chow had no effect on any quinpirole-induced unconditioned behavioral effect in female rats. Eating high fat chow also reduced pAkt levels in male, but not female rats. Taken together, these data suggest that alternative behavioral and biochemical assays should be considered to measure sensitivity of female rats to the behavioral effects of dopamine receptor agonists, and further demonstrate the importance of studying drug sensitivity in both male and female subjects.

Treatment of Tuberculosis Infection in Children

AbstractThe last decade has seen publication of more robust data for shorter course regimens for tuberculosis infection. These regimens are associated with higher completion rates than the traditional 6- to 9-month course of daily isoniazid (INH). These shorter regimens include 4 months of daily rifampin (RIF) and 12 once-weekly doses of INH and a long-acting rifamycin and rifapentine. In addition, a widely used regimen in the United Kingdom is 3 or 4 months of daily INH and RIF. All regimens have demonstrated efficacy in the ideal conditions of clinical studies, and all have very low rates of hepatotoxicity in children. These newer regimens likely are more effective than longer courses of INH once patient and family adherence is considered. Clinicians need to be cognizant of poor completion rates with traditional INH therapy and how the use of rifamycin-containing regimens offers more palatable options for children and their families.

Abstract 55: Generation of half-life extended anti-CD33 BiTE® antibody constructs compatible with once-weekly dosing

Abstract T cell engaging bispecific antibody constructs (BiTE®), such as blinatumomab which targets CD19-positive cells, have shown great promise for treating certain CD19-positive hematological malignancies. Blinatumomab comprises a single chain Fv (scFv) that binds CD19 and a scFv that targets the T cell CD3 protein. The molecular weight of this “canonical” BiTE® is ~ 55 kDa, making it susceptible to kidney-mediated clearance and resulting in a short serum half-life (~ 4 hours). To maintain effective serum concentrations, canonical BiTE® antibody constructs must be administered by continuous IV (cIV) infusion. While there are many advantages associated with cIV administration (e.g., safety and uniform PK profile), patient convenience could be enhanced if the BiTE® antibody construct were compatible with once-weekly administration. To achieve this, the serum half-life of the BiTE® antibody construct would need to be extended. A canonical BiTE® targeting CD33 (AMG 330) is currently being evaluated in a phase I clinical trial. Like blinatumomab, AMG 330 is dosed cIV. To extend the serum half-life of AMG 330 and enable once-weekly dosing, several approaches were evaluated including fusion of AMG 330 to human albumin and Fc-containing moieties. Each of these half-life extended (HLE) constructs was evaluated in vitro, in mouse xenograft models and in non-human primates. In vitro assays evaluated 1) binding to both human and cynomolgus CD33 and CD3 proteins, and 2) cytotoxicity using human and cynomolgus target and effector cells. In each of these assays the canonical and HLE BiTE® antibody constructs demonstrated similar activity: single-digit nM binding and single digit pM cytotoxicity. Canonical and HLE BiTE® antibody constructs were subsequently evaluated in an orthotopic mouse model in which MOLM13 cells were administered IV and activated human T cells were administered IP two days later. The Fc-based HLE BiTE® antibody constructs provided a similar survival advantage when administered Q4D or Q5D as the canonical BiTE® when administered QD. However, the albumin fusion–based HLE BiTE® was less efficacious when administered Q4D than the QD- administered canonical BiTE®. Lastly, the PK/PD relationship was evaluated for each of the constructs in non-human primates. The serum half-lives varied from 6 hours for the canonical BiTE® to 44-167 hours for the HLE BiTE® antibody constructs. Each of the HLE BiTE® antibody constructs showed on-target depletion of CD33-positive monocytes and neutrophils in the blood and depletion of CD33-positive cells in the bone marrow. These data demonstrate that half-life extended BiTE® antibody constructs can be generated that retain comparable in vitro and in vivo activity as a canonical BiTE® and achieve a serum half-life compatible with once weekly dosing. Citation Format: Tara L. Arvedson, Mercedesz Balazs, Pamela Bogner, Kurt Black, Kevin Graham, Anja Henn, Matthias Friedrich, Patrick Hoffmann, Roman Kischel, Peter Kufer, Ralf Lutterbuese, Markus Muenz, Tobias Raum, Benno Rattel, Karen Rex, Dan Rock, Oliver Thomas, Joachim Wahl, Andreas Wolf, Angela Coxon. Generation of half-life extended anti-CD33 BiTE® antibody constructs compatible with once-weekly dosing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 55. doi:10.1158/1538-7445.AM2017-55

Somapacitan expected to provide IGF-I levels suitable for once-weekly dosing in children

Somapacitan expected to provide IGF-I levels suitable for once-weekly dosing in children

Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine.

ABSTRACTIntermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

Pharmacokinetics and pharmacodynamics of a buprenorphine subcutaneous depot formulation (CAM2038) for once-weekly dosing in patients with opioid use disorder

IntroductionSublingual buprenorphine is effective for opioid dependence treatment but associated with misuse, abuse, and diversion. The present Phase I/II study evaluated a novel buprenorphine subcutaneous depot formulation for once-weekly dosing (CAM2038 q1w) in patients receiving maintenance treatment for opioid use disorder with daily sublingual buprenorphine. MethodsAfter discontinuation of buprenorphine for 48h, patients received a single CAM2038 q1w dose based on their pre-study daily sublingual maintenance dose. CAM2038 q1w doses of 7.5, 15, 22.5, and 30mg were administered in a sequential dose-escalating design. The following assessments were performed: pharmacokinetics of buprenorphine and norbuprenorphine, pharmacodynamics (evaluated using the Subjective and Clinical Opiate Withdrawal Scales), and time to intake of rescue sublingual buprenorphine medication. ResultsSingle doses of CAM2038 q1w indicated dose-proportional buprenorphine pharmacokinetics (Cmax and AUC0–7d), with time to Cmax ~20h and an apparent terminal half-life of 3–5days, supporting once-weekly dosing. On average, patients showed a rapid and extended decrease in opiate-withdrawal symptoms from baseline, with zero or very low SOWS and COWS values measured at least up to 7days after dosing of CAM2038 q1w. The median time to first use of rescue buprenorphine was 10days. No dose dependence was seen in the pharmacodynamics, attributable to the selection of CAM2038 q1w doses based on patients' pre-study maintenance doses. CAM2038 q1w was safe and generally well tolerated. ConclusionsPharmacokinetics and pharmacodynamics of a novel buprenorphine subcutaneous depot formulation for once-weekly dosing was evaluated, suggesting utility in maintenance treatment of patients with opioid use disorder.

Teriparatide Enhancement of Lumbar Fusion: Bone Enhancement Versus Cost, Convenience, and Risk of Cancer: Commentary on an article by Shigeto Ebata, MD, PhD, et al.: "Role of Weekly Teriparatide Administration in Osseous Union Enhancement within Six Months After Posterior or Transforaminal Lumbar Interbody Fusion for Osteoporosis-Associated Lumbar Degenerative Disorders. A Multicenter, Prospective Randomized Study".

Commentary The article by Ebata et al. contains several interesting and important points. However, the encouraging aspects of the study must be tempered by its short follow-up duration as well as the cost and potential for serious side-effects with the use of teriparatide. Those of us who perform spinal fusion surgery are interested in options that will stimulate healing, optimize the percentage of solid fusions, and improve patient outcomes. We are particularly looking for enhancements for challenging clinical situations, such as osteoporosis, where the quality of osseous fusion, the subsidence of implants, and screw pullout have been concerns. Teriparatide holds appeal as an intervention to address these issues, as teriparatide has been generally shown to improve bone mineral density and reduce fracture rates when compared with bisphosphonates in postmenopausal osteoporosis1,2. It is also germane that bisphosphonates have been shown to improve bone formation in osteoporotic patients who undergo posterior lumbar interbody fusion (PLIF)3. Thus, a logical research question is whether teriparatide would further enhance fusion following PLIF or TLIF (transforaminal lumbar interbody fusion)? While the short-term follow-up of 6 months in the present study limits the conclusions that can be drawn, it is encouraging that enhanced bone formation was seen within this short time frame. Fusion enhancement then leads us to look at whether teriparatide is likely to be generally applicable in day-to-day patient care. The limitations in the clinical scenario tend to be cost, convenience, and side-effects and/or complications. Teriparatide is clearly more expensive than other medications for osteoporosis. The estimated cost of daily subcutaneous injection is approximately $560 (USD) per month4 compared with $10 to $20 for the use of bisphosphonates5. One of the interesting aspects of the study by Ebata et al. is the efficacy of treatment involving the administration of a weekly dose of teriparatide compared with a daily regimen, as was studied by other authors investigating treatment following lumbar posterolateral fusion6. Weekly dosing would clearly be substantially cheaper than daily. In terms of patient convenience, a weekly dosing regimen would also have important implications, as the route of administration, subcutaneous injection, is somewhat invasive. Considering side-effects and/or complications, the potential inducement of cancer, particularly osteosarcoma, has been the primary concern with teriparatide. This has translated to a recommendation that teriparatide be used for a maximum 2-year time frame7,8. Osteosarcoma has been observed in small-animal studies involving rats at doses 3 to 60 times the standard prescription for humans7,8. However, the post-market surveillance funded by Eli Lilly but overseen by the U.S. Food and Drug Administration has not identified any cases of osteosarcoma7,8. To substantiate the encouraging early enhancement of healing, longer-term follow-up is needed. A treatment effect seen with a once-weekly dose (as opposed to the traditional daily dosing) suggests that additional investigation is necessary to further define the dose-response curve for teriparatide. Surgeons should be aware of the concern regarding the inducement of osteosarcoma with teriparatide treatment, even though this appears to be a relatively low risk. Similarly, the relatively high cost and the inconvenience of teriparatide administration by subcutaneous injection remain issues to be considered when evaluating treatment options.

Abstract P4-21-03: A randomized phase II study of Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer

Abstract As for the HER2-positive breast cancer, there are many cases to be effective for neoadjuvant chemotherapy in comparison with other intrinsic subtypes. However, pCR is not provided by neoadjuvant chemotherapy in all cases. [Aim] This study evaluated the effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumor expression after initial therapy, relative to that of standard chemotherapy in patients with HER2-positive breast cancer. [patients and methods] Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumor biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab was continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Early Ki-67 responders continued to received paclitaxel plus trastuzumab for a total of 12 doses, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide every 3 weeks for three cycles with once-weekly trastuzumab for a total of 12 doses. The primary endpoint was the pathological complete response (pCR) rate. [Results] When 237 patients were enrolled, an interim analysis was conducted in 200 patients. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm (23.6%; 95% CI, 12.4 to 34.9) was inferior to that in the control arm (44.1%; 31.4 to 56.7; p=0.025). A strong correlation was not found between the Ki-67 reduction rate and the clinical response rate (Spearman's correlation coefficient 0.22). pCR rate among Ki-67 early non-responders and responders TotalpCR nn%95%CIKi-67 early non responderControl arm59264431.4-56.7 Ki-67 response guided arm55132312.4-34.9Ki-67 early responderControl arm21104726.3-69.0 Ki-67 response guided arm2084018.5-61.5 Conclusions: The pCR rate in the Ki-67 arm was inferior to that in the control arm. A therapeutic strategy that switches chemotherapy, based on Ki-67 tumor expression after initial therapy, was not effective. The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer. Citation Format: Takahashi M, Nishiyama Y, Hara F, Naito Y, Baba M, Sasaki M, Sato M, Watanabe K, Uemura Y, Yamaguchi T, Mukai H. A randomized phase II study of Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-03.

Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study

BackgroundInfants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age.ResultsNine patients were enrolled; median age at baseline was 3.0 months (range 1.1–5.8 months). Sixty-seven percent (exact 95% CI 30%–93%) of sebelipase alfa–treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%–16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious.ConclusionSebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiencyTrial registrationClinicaltrials.gov NCT01371825. Registered 9 June 2011.

Evaluation of Cisplatin Induced Toxicity in Head and Neck Cancer and Cervical Cancer During Concurrent Chemoradiotherapy. Experience of National Institute of Oncology in Morocco

Background: Cisplatin is widely used as radio sensitizer in head and neck cancer (HNC) and cervical cancer. We conducted this prospective study to evaluate cisplatin induced toxicity as once-weekly regimen in HNC and cervical cancer during concurrent chemoradiotherapy (CCRT) to optimize its administration. Patients and methods: From 01 January 2015 to 11 May 2015, a data of all eligible patients treated by chemoradiation regimens containing a low dose of cisplatin were collected at the Department of radiotherapy in National Institute of Oncology in Morocco. Cisplatin was used weekly at 40 mg/m2 with adequate hydration and premedication in all patients. A complete blood count and renal function tests were done prior to each cycle of chemotherapy to evaluate toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). Results: A total of 96 patients were eligible for the analysis. Mean age, PS, initial weight, enteral nutrition, cisplatin mean dose, use of oral Ondansetron and baseline serum tests did not differ significantly among the types of malignancy. However, weight loss was significantly noted among HNC group compared to cervical cancer patients with 6.06 ± 2.92 kg and 0.02 ± 0.13 kg respectively. Toxicity was observed only in 16 (20%) patients after the 4th week of treatment especially among HNC group. The neutropenia and thrombocytopenia were significantly greater for patients of HNC. However, we did not observe any renal toxicity, thrombocytopenia and ≥ grade 3 neutropenia toxicity in cervical cancer group. In multivariated analysis, only a subtype of HNC (OR, 1233; 95% CI, 16-95 103; P=0.001) and grade 2 emetogenicity (OR, 34.8; 95% CI, 2.1-583; P=0.014) were significantly associated with an increased risk for cisplatin toxicity. Whereas, less than 4 weekly cisplatin treatment (OR, 0.4; 95% CI, 0.1-0.9; P=0.046) was associated with a significantly reduced risk. Conclusion: Our data have revealed that individuals with HNC were at a significantly higher risk for cisplatininduced toxicity during CCRT and suggest that the once-weekly smaller dose of cisplatin regimen and conventional prophylactic procedures of administration might be effective for protection against the renal toxicity of cisplatin.

Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy.

Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer’s disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies. Prior studies demonstrated that the brain-penetrant MT-stabilizing drug, epothilone D, had salutary effects in transgenic (Tg) mouse models of tauopathy, improving MT density and axonal transport, while reducing axonal dystrophy. Moreover, epothilone D enhanced cognitive performance and decreased hippocampal neuron loss, with evidence of reduced tau pathology. To date, epothilone D has been the only non-peptide small molecule MT-stabilizing agent to be evaluated in Tg tau mice. Herein, we demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, dictyostatin, in the PS19 tau Tg mouse model. Although dictyostatin was poorly tolerated at once-weekly doses of 1 mg/kg or 0.3 mg/kg, likely due to gastrointestinal (GI) complications, a dictyostatin dose of 0.1 mg/kg was better tolerated, such that the majority of 6-month old PS19 mice, which harbor a moderate level of brain tau pathology, completed a 3-month dosing study without evidence of significant body weight loss. Importantly, as previously observed with epothilone D, the dictyostatin-treated PS19 mice displayed improved MT density and reduced axonal dystrophy, with a reduction of tau pathology and a trend toward increased hippocampal neuron survival relative to vehicle-treated PS19 mice. Thus, despite evidence of dose-limiting peripheral side effects, the observed positive brain outcomes in dictyostatin-treated aged PS19 mice reinforces the concept that MT-stabilizing compounds have significant potential for the treatment of tauopathies.

Characterization of In Vitro Resistance Development to the Novel Echinocandin CD101 in Candida Species.

CD101 is a novel echinocandin with a long half-life undergoing clinical development for treatment of candidemia/invasive candidiasis and vulvovaginal candidiasis. The potential for and mechanisms underlying the development of resistance to CD101 in Candida species were investigated by using spontaneous resistance and serial passage selection methodologies. Four Candida spp. (C. albicans, C. glabrata, C. parapsilosis, and C. krusei) were chosen for resistance characterization with CD101, anidulafungin, and caspofungin. The frequency of spontaneous, single-step mutations conferring reduced susceptibility to CD101 at 1× the agar growth inhibition concentration was low across all species, with median frequencies ranging from 1.35 × 10−8 to 3.86 × 10−9, similar to ranges generated for anidulafungin and caspofungin. Serial passage of Candida spp. on agar plates containing drug gradients demonstrated a low potential for resistance development, with passage 20 CD101-selected strains possessing increases in MICs equivalent to or lower than those for the majority of strains generated under selection with anidulafungin and caspofungin. A total of 12 fks “hot spot” mutations were identified, typically in strains with the highest MIC shifts. Cross-resistance was broadly observed among the 3 echinocandins evaluated, with no CD101-selected mutants (with or without fks hot spot mutations) exhibiting reduced susceptibility to CD101 but not also to anidulafungin and/or caspofungin. Consistent with currently approved echinocandins, CD101 demonstrates a low potential for resistance development, which could be further enhanced in vivo by the high maximum concentration of drug in serum (Cmax)/area under the concentration-time curve (AUC) plasma drug exposure achieved with once-weekly dosing of CD101.

Soy Phosphatidylinositol–Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain–Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs

Soy phosphatidylinositol (PI)–containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain–deleted factor VIII (BDD FVIII) in hemophilia A (HA) mice. We hypothesize that PI-associated BDD FVIII is more potent than the free protein and, using mathematical modeling, have projected that PI-associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI-associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. Two HA dogs were administered a 50-U/kg intravenous dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses such as whole blood clotting time and thromboelastography were conducted on recovered plasma and whole blood samples. PI association decreased clearance (∼25%) and increased plasma exposure (∼1.4-fold) of rcFVIII. PI-rcFVIII–treated animals had prolonged improvements in whole blood clotting time and thromboelastography parameters compared to free rcFVIII–treated animals. Because rcFVIII is a BDD form of FVIII, these studies provide proof of principle that observations with human BDD FVIII in mice translate to higher animal species. In addition, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients.

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma

AbstractCarfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m2 [cycle 1, days 1-2]; 27 mg/m2 thereafter). This multicenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IV infusion) on days 1, 8, and 15 of 28-day cycles. The phase 1 portion used a 3 + 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at the MTD. Patients received dexamethasone (40 mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 9+. A total of 116 patients were enrolled. The MTD was 70 mg/m2, and 104 patients (phase 1/2) received carfilzomib 70 mg/m2. At 70 mg/m2, the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m2, the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m2 was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials.gov as #NCT01677858.

Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism.

Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4- and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation ≈ 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once‐weekly DPP‐4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single‐dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP‐4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once‐weekly doses over the dose range studied. Omarigliptin resulted in ∼2‐fold increases in weighted average postprandial active GLP‐1. Omarigliptin acts by stabilizing active GLP‐1, which is consistent with its mechanism of action as a DPP‐4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once‐weekly dosing. A model‐based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.

In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator

Desferrioxamine (DFO) is currently in clinical use to remove iron from transfusion-dependent patients with β-thalassemia major, sickle-cell anemia and the myelodysplastic syndromes. However, its short half-life, burdensome, subcutaneous mode of administration and propensity to cause neurotoxicity at high doses greatly hinder its use. Thus, developing an optimized version of DFO with extended half-life, and reduced toxicity is a major goal. Using high molecular weight (MW), non-toxic, hyperbranched polyglycerol with high functionality, we demonstrate that the efficacy of DFO can be tuned with considerable reduction in toxicity. Using zebrafish embryos and mice, we tested toxicity, iron removal efficacy with low dosing and the biodistribution of ultra-long circulating DFO (ULC-DFO) conjugates. There was no significant difference in the mortality and development of zebrafish embryos upon exposure to ULC-DFO. Similarly, body weights and serum lactate dehydrogenase levels in mice treated with ULC-DFO remained within the normal range throughout the tolerance study. Moreover, ULC-DFO is significantly more effective than low MW DFO in promoting iron removal both from organs and via urine in iron overloaded mice despite using a moderate, once-weekly dosing schedule. This is probably due to the extended circulation half-life of ULC-DFO. The MW of ULC-DFO influences the accumulation and biodistribution, with highest MW (637KDa) associated with up to 12% accumulation in the liver. In contrast, ULC-DFO with MWs of 75KDa and lower were associated with relatively low organ accumulation, indicating that biodistribution of ULC-DFO can be tuned. Since ULC-DFO has improved iron removal properties, longer plasma retention time and possesses excellent biocompatibility, it represents a polymer conjugate with high clinical utility in comparison to DFO for the treatment of transfusion dependent iron overload. More importantly, ULC-DFO is anticipated to reduce the requirement for prolonged subcutaneous infusion of DFO.