The estimation and translation uncertainties in applying NOAEL to clinical dose escalation.

The systemic exposure at the no-observed-adverse-effect-level (NOAEL) estimated from animals is an important criterion commonly applied to guard the safety of participants in clinical trials of investigational drugs. However, the discrepancy in toxicity profile between species is widely recognized. The objective of the work reported here was to assess, via simulation, the level of uncertainty in the NOAEL estimated from an animal species and the effectiveness of applying its associated exposure value to minimizing the toxicity risk to human. Simulations were conducted for dose escalation of an investigational new chemical entity with hypothetical exposure-response models for the dose-limiting toxicity under a variety of conditions, in terms of between-species relative sensitivity to the toxicity and the between-subject variability in the key parameters determining the sensitivity and pharmacokinetics. Results show a high uncertainty in the NOAEL estimation. Notably, even when the animal species and humans are assumed to have the same sensitivity, which may not be realistic, limiting clinical dose to the exposure at the NOAEL that has been identified in the animals carries a high risk of either causing toxicity or under-dosing, hence undermining the therapeutic potential of the drug candidate. These findings highlight the importance of understanding the mechanism of the toxicity profile and its cross-species translatability, as well as the importance of understanding the dose requirement for achieving adequate pharmacology.

Novel investigational drugs for alopecia areata and future perspectives.

INTRODUCTION: Alopecia areata (AA) is an immune-mediated disease that causes non-scarring hair loss. While acute, solitary patches often spontaneously remit, developing secondary patches or failure of the disease to resolve within 6-12 months predicts a poor prognosis, with an increased risk of alopecia totalis or universalis. Chronic AA increases the risk of depression and suicidality and reduces quality of life. Treatment options for chronic or acute diffuse AA were previously limited to corticosteroids and traditional immunomodulators. Two Janus Kinase (JAK) inhibitors are now approved for the treatment of chronic AA. AREAS COVERED: The results of landmark phase 3 trials for three JAK inhibitors, baricitinib, ritlecitinib, and deuruxolitinib are discussed. Evidence for other JAK inhibitors, biologics, and phosphodiesterase-4 inhibitors are also presented. Therapies currently undergoing clinical trials are listed. EXPERT OPINION: JAK inhibitors are a safe and efficacious treatment of moderate-to-severe AA. Early intervention, regardless of severity, allows for improved treatment efficacy. It is uncertain how long patients should remain on JAK inhibitors; discontinuation often leads to relapse. A black-box warning for JAK inhibitors was extrapolated from safety data in a rheumatoid arthritis cohort; recent meta-analyses of JAK inhibitors used in dermatology cohorts do not demonstrate the same risk profile.

Investigational drugs for the treatment of acromegaly: new agents to transform therapy.

INTRODUCTION: Disease control is essential to decrease morbidity burden and mortality in acromegaly patients. In the last decades, the availability of new drugs increased the rate of disease control. However, up to 55% of patients remain uncontrolled despite available treatment strategies in real-world data. The reasons for this finding may include poor adherence, inadequate tolerability, therapeutic inertia, and high costs. Since acromegaly is a chronic disease and medical therapy is usually life-long, patient's adherence to treatment is fundamental in both achieving and maintaining disease control. Less invasive routes of administration could improve adherence and concur to increase disease control rate. AREAS COVERED: The aim of current review is to provide a detailed update about investigational drugs for acromegaly treatment currently under investigation as paltusotine, ONO-5788, AP102, GT-02037, ISIS 766720, CAM2024, Lanreotide PRF, DP1038, MTD201, solid dose injection of octreotide. EXPERT OPINION: Medical therapy of acromegaly is an evolving field. Current studies are addressing patient's need for both new molecules and less invasive routes of administration for already existing drugs. It cannot be ruled out that drugs currently used for other diseases such as cancer could be considered in the future for the treatment of acromegaly.

Immunogenicity and Safety of Investigational MenABCWY Vaccine and of 4CMenB and MenACWY Vaccines Administered Concomitantly or Alone: a Phase 2 Randomized Study of Adolescents and Young Adults.

This phase 2, randomized, open-label study assessed the immunogenicity and safety of an investigational meningococcal ABCWY vaccine (MenABCWY) that contains components of licensed vaccines against meningococcal serogroup B (4CMenB) and serogroups ACWY (MenACWY). A total of 500 healthy 10- to 25-year-old participants were randomly assigned to one of five study groups in a 1:1:1:1:1 ratio. Four groups received two doses 2 months apart of MenABCWY and 4CMenB plus MenACWY administered concomitantly in the same arm (4CMenB+ACWY/S group) or different arms (4CMenB+ACWY/D group) or 4CMenB administered alone. A fifth group received a single MenACWY dose. Immunogenicity was determined by serum bactericidal assay using human complement (hSBA). The study was powered to assess immunological interference against pooled serogroup B test strains. One month after the second vaccine dose, hSBA geometric mean titers (GMTs) (with 80% confidence intervals [CI]) against pooled serogroup B strains were 31.84 (80% CI, 28.18 to 35.98), 38.48 (80% CI, 34.23 to 43.26), 40.08 (80% CI, 35.44 to 45.33), and 42.38 (80% CI, 37.31 to 48.13) in the MenABCWY, 4CMenB+ACWY/S, 4CMenB+ACWY/D, and 4CMenB groups, respectively. Immune responses (GMTs and 80% CIs) were lower for PorA and NHBA serogroup B test strains in the MenABCWY group compared to the 4CMenB+ACWY/D group and 4CMenB group. Evaluation of solicited and unsolicited adverse events (AEs) identified no safety concerns for the MenABCWY vaccine. One serious AE (syncope in the 4CMenB group) was considered related to vaccination. In conclusion, there is no evidence of substantial immunological interference between 4CMenB and MenACWY vaccine components against serogroup B. The safety and tolerability profile of the investigational MenABCWY vaccine was acceptable. (This study has been registered at ClinicalTrials.gov under registration no. NCT03587207.) IMPORTANCE The bacterial species Neisseria meningitidis is a major cause of meningitis, with six meningococcal groups (serogroups) causing most cases. A licensed vaccine, MenACWY (Menveo), targets four of these meningococcal serogroups, and another vaccine, 4CMenB (Bexsero), targets serogroup B. A combined vaccine (MenABCWY) that targets all five serogroups is under development to simplify the vaccination schedule. In a previous study, the immune response to serogroup B was found to be overall higher in individuals who received 4CMenB than in those who received an investigational MenABCWY vaccine. We investigated this further by giving healthy adolescents and young adults the MenABCWY vaccine, 4CMenB plus MenACWY vaccine in the same or different arms, 4CMenB vaccine alone, or MenACWY vaccine alone. Immunogenicity results for serogroup B across study groups suggest no major interference between the MenB and MenACWY vaccine components. This supports further development of the combined MenABCWY vaccine.

Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): insights into promising agents.

INTRODUCTION: Despite huge and increasing developments in the treatment of inflammatory bowel disease (IBD), a significant percentage of patients with Crohn's disease (CD) and ulcerative colitis (UC) is still in need of an effective and safe therapeutic option. Tackling the trafficking of leukocytes specifically within or directed to the inflamed gut appears to be a particularly promising strategy, and several new anti-integrin agents are currently under investigation in clinical trials. AREAS COVERED: This review summarizes efficacy and safety data from phase 1, 2 and 3 clinical trials on investigational drugs, including monoclonal antibodies (etrolizumab, abrilumab, ontamalimab) and oral small molecules (AJM300, PTG-100). It also discusses the future perspectives for the treatment of IBD patients with this class of agents. EXPERT OPINION: The pipeline of anti-integrin agents is well assorted, and it is reasonable to expect that some will be introduced in the market soon. Among the most exciting features of this class are the gut selectivity, the convenient subcutaneous and oral administrations and the reassuring safety profiles. Most of the new anti-integrins seem to improve outcomes in UC but not in CD, however these data are far from definitive and several pivotal trials are still under way.

Lenvatinib: an investigational agent for the treatment of differentiated thyroid cancer.

INTRODUCTION: Differentiated thyroid cancer (DTC; >90% of all TCs) derives from follicular cells. Surgery is the main therapeutic strategy, and radioiodine (RAI) is administered after thyroidectomy. When DTC progresses, it does not respond to RAI and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone treatment, and other therapies (i.e. surgery, external beam radiation therapy and chemotherapy) do not lead to a better survival. Thanks to the understanding of the molecular pathways involved in TC progression, important advances have been done. Lenvatinib is a multitargeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT signaling networks implicated in tumor angiogenesis, approved in locally recurrent or metastatic, progressive, RAI-refractory DTC. Unmet needs regarding the patient clinical therapy responsiveness in aggressive RAI-refractory DTC still remain. AREAS COVERED: We provide an overview from the literature of in vitro, in vivo and real-life studies regarding lenvatinib as an investigational agent for the treatment of aggressive TC. EXPERT OPINION: According to the SELECT trial, the treatment should be initiated with a dosage of 24 mg/day, subsequently decreasing it in relation to the side effects. The decision making process in patients with aggressive RAI-refractory DTC should be personalized and the potential toxicity should be properly managed.

Immune checkpoint inhibitors for the treatment of myeloma: novel investigational options.

INTRODUCTION: Multiple myeloma (MM) is still considered incurable and the outcome of patients with triple-class refractory remains very poor. Immunotherapy is considered as a standard of care for the treatment of MM. Among immunotherapeutic approaches, the PD-1/PD-L1 axis is an attractive target because PD-L1 is highly expressed in most myeloma plasma cells. While many types of cancer benefit from checkpoint inhibitor treatment, their relevance in multiple myeloma needs to be defined. AREAS COVERED: The authors evaluate the published data regarding the mechanism of action, safety profile, and clinical efficacy of the immune checkpoint inhibitors (ICI) for the treatment of multiple myeloma. EXPERT OPINION: The use of ICI monotherapy does not offer any clinical benefit in myeloma patients. In combination with immunomodulatory drugs (IMID), ICI failed to demonstrate clinical benefit and were associated with increased toxicity. Given the toxicities of these treatments, predictive markers would be useful to select patients who would benefit most. Clinical studies are necessary to evaluate the safety and efficacy of checkpoint inhibitors in combination with other standards of care such as proteasome inhibitors and monoclonal antibodies. The combination of anti-PD-1 with T-cell engager (TCE) or CAR-T cells seems theoretically attractive and should be explored in clinical trials.

The Randomized AMBORA Trial: Impact of Pharmacological/Pharmaceutical Care on Medication Safety and Patient-Reported Outcomes During Treatment With New Oral Anticancer Agents.

PURPOSE: Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking. METHODS: Patients were eligible for the randomized, multicenter AMBORA study, if they were newly started on any of the oral anticancer drugs approved in 2001 or later without restriction to certain tumor entities. Patients were randomly assigned to receive either standard of care (control group) or an additional, intensified clinical pharmacological/pharmaceutical care, which included medication management and structured patient counseling, over a period of 12 weeks (intervention group). Primary end points were the number of antitumor drug-related problems (ie, side effects and unresolved medication errors) and patient treatment satisfaction with the oral anticancer therapy after 12 weeks measured with the Treatment Satisfaction Questionnaire for Medication, category convenience. RESULTS: Two hundred two patients were included. Antitumor drug-related problems were significantly lower in the intervention compared with the control group (3.85 v 5.81 [mean], P < .001). Patient treatment satisfaction was higher in the intervention group (Treatment Satisfaction Questionnaire for Medication, convenience; 91.6 v 74.4 [mean], P < .001). The hazard ratio for the combined end point of severe side effects (Common Terminology Criteria for Adverse Events ≥ 3), treatment discontinuation, unscheduled hospital admission, and death was 0.48 (95% CI, 0.32 to 0.71, P < .001) in favor of the intervention group. CONCLUSION: Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. An intensified clinical pharmacological/pharmaceutical care has considerable, positive effects on the number of medication errors, patient treatment perception, and severe side effects.

Ivosidenib: an investigational drug for the treatment of biliary tract cancers.

Introduction: Biliary tract cancers (BTCs) [including cholangiocarcinoma and gallbladder cancer] are rare cancers associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line; and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable therapeutic targets including isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; it is currently approved for the treatment of acute myeloid leukemia and has been studied in patients with advanced cholangiocarcinoma.Areas covered: This article introduces current treatments for BTC and sheds light on the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of ivosidenib in advanced cholangiocarcinoma. The authors conclude with insights on the changing treatment paradigm created by emerging drugs and precision approaches.Expert opinion: Ivosidenib is well tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25-0.54; one-sided p < 0.0001); it has also demonstrated a trend toward increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potential therapeutic targets and improve the prognosis of patients with these cancers.

Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a target for cancer therapy as it is overexpressed in a wide variety of cancers. Therapeutic antibodies that bind EGFR are being evaluated in clinical trials as imaging agents for positron emission tomography and image-guided surgery. However, some of these antibodies have safety concerns such as infusion reactions, limiting their use in imaging applications. Nimotuzumab is a therapeutic monoclonal antibody that is specific for EGFR and has been used as a therapy in a number of countries. METHODS: Formulation of IRDye800CW-nimotuzumab for a clinical trial application was prepared. The physical, chemical, and pharmaceutical properties were tested to develop the specifications to determine stability of the product. The acute and delayed toxicities were tested and IRDye800CW-nimotuzumab was determined to be non-toxic. Non-compartmental pharmacokinetics analysis was used to determine the half-life of IRDye800CW-nimotuzumab. RESULTS: IRDye800CW-nimotuzumab was determined to be non-toxic from the acute and delayed toxicity study. The half-life of IRDye800CW-nimotuzumab was determined to be 38 ± 1.5 h. A bi-exponential analysis was also used which gave a t1/2 alpha of 1.5 h and t1/2 beta of 40.8 h. CONCLUSIONS: Here, we show preclinical studies demonstrating that nimotuzumab conjugated to IRDye800CW is safe and does not exhibit toxicities commonly associated with EGFR targeting antibodies.

Investigational PARP inhibitors for the treatment of biliary tract cancer: spotlight on preclinical and clinical studies.

Introduction: Alterations in DNA damage repair (DDR) genes are observed in up to 60% of biliary tract cancer (BTC) patients. Patients with advanced/metastatic BTC have few therapeutic options, so there is a demand for the development of new and innovative treatment approaches. The use of poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors (PARPis), either as a monotherapy or in combination, is being extensively studied in clinical trials.Areas Covered: This review examines the targeting of the DDR pathway with PARPis as a potential novel treatment option for the management of BTCs. The rationale behind the use of PARPis and current clinical experience is discussed. Moreover, further insights into potential future directions concerning the applicability of PARPis in the treatment of BTCs are proposed.Expert Opinion: Prospective clinical data with PARPis in the treatment of BTCs are limited. The potential combination of PARPis and IDH1 inhibitors or immune checkpoint inhibitors in clinical trials is interesting because of the potential synergistic preclinical data. There are other possible combinations including those drugs that target the angiogenesis or STAT3 pathways. An enhanced understanding of acquired resistance to PARPis is necessary to progress the use of these agents in clinical trials.

Investigational neuroprotective compounds in clinical trials for retinal disease.

INTRODUCTION: Retinal neurodegeneration causes irreversible vision loss, impairing quality of life. By targeting neurotoxic conditions, such as oxidative stress and ischemia, neuroprotectants can slow or stop sight loss resulting from eye disease. Despite limimted clinical use of neuroprotectants, there are several promising compounds in early clinical trials (pre-phase III) which may fulfil new therapeutic roles. Search terms relating to neuroprotection and eye disease were used on ClinicalTrials.gov to identify neuroprotective candidates. AREAS COVERED: Research supporting neuroprotection in eye diseases is focused on, ranging from preclinical to phase II, according to the ClinicalTrials.gov database. The compounds discussed are explored in terms of future clinical applications. EXPERT OPINION: The major challenge in neuroprotection research is translation from basic research to the clinic. A number of potential neuroprotectants have progressed to ophthalmology clinical trials in recent years, with defined mechanisms of action - saffron and CoQ10 - targeting mitochondria, and both CNTF and NGF showing anti-apoptotic effects. Enhancements in trial design and patient cohorts in proof-of-concept trials with enriched patient populations and surrogate endpoints should accelerate drug development. A further important consideration is optimising drug delivery to improve individualised management and patient compliance. Progress in these areas means that neuroprotective strategies have a much improved chance of translational success.

Emerging topical drugs for the treatment of rosacea.

Introduction: Rosacea is a common, chronic and relapsing inflammatory skin disease of the centrofacial area. Despite advancing knowledge on its pathogenesis, diagnosis, and treatment, some major unknowns still remain, including systematic evidence-based guidelines useful both for clinical assessment and therapeutic management. Topical treatment is regarded as a first-line option for mild to moderate rosacea and includes traditional and new FDA-approved prescription drugs, as well as off-label alternative topical agents.Areas covered: Since improved awareness of rosacea pathogenetic mechanisms has led to the development of new potential therapeutic agents, a search was performed on the ClinicalTrial.gov registry. The results identified several investigational topical drugs able to target one or more of the pathogenetic factors of rosacea.Expert opinion: The main unmet needs in the topical treatment of rosacea remain the management of vasomotor flushes and telangiectasias, as well as of troublesome symptoms such as burning and/or stinging. No single agent effective on all rosacea phenotypes is available so far, and preventive treatments capable of halting disease progression have not been identified yet. Finally, data on long-term efficacy and tolerability are still incomplete, especially for drugs more recently introduced in the market.

A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy.

Introduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a KD of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.