Investigational new drugs for the treatment of chronic renal failure: an overview of the literature.

INTRODUCTION: Chronic kidney disease (CKD) is widespread throughout the world, with a high social and health impact. It is considered a 'silent killer' for its sudden onset without symptoms in the early stages of the disease. The main goal of nephrologists is to slow the progression of kidney disease and treat the associated symptoms with a range of new medications. AREAS COVERED: The aim of this systematic review is to analyze the new investigational drugs for the treatment of chronic renal failure. Data were obtained from the available scientific literature and from the ClinicalTrials.gov website. EXPERT OPINION: Among the drugs currently being researched, SGLT2 inhibitors appear to be the most promising drugs for the treatment of CKD, has they have slower progression of CKD and protection of cardiorenal function. An important role in the future of CKD treatment is played by autologous cell-therapy, which appears to be a new frontier in the treatment of CKD. Other therapeutic strategies are currently being investigated and have been shown to slow the progression of CKD. However, further studies are needed to determine whether these approaches may offer benefits in slowing the progression of CKD in the near future.

Investigational drugs for the treatment of dysmenorrhea.

INTRODUCTION: Dysmenorrhea is the most common cause of gynecological pain among women that has considerable impact on quality of life and psychosocial wellbeing. Non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal therapies are most commonly used to treat dysmenorrhea. However, given these drugs are often associated with bothersome side effects and are less effective when there is an underlying cause contributing to dysmenorrhea (e.g. endometriosis), a patient-centered approach to managing dysmenorrhea is important. Various new drugs are currently being investigated for the treatment of primary and secondary dysmenorrhea. AREAS COVERED: This review provides an updated overview on new therapeutic targets and investigational drugs for the treatment of primary and secondary dysmenorrhea. The authors describe the clinical development and implications of these drugs. EXPERT OPINION: Among the investigative drugs discussed in this review, anti-inflammatories show the most promising results for the treatment of dysmenorrhea. However, given some trials have considerable methodological limitations, many drugs cannot be currently recommended. Research focused on understanding the mechanisms involved in menstruation and its associated symptoms will be important to identify new therapeutic targets for dysmenorrhea. Further robust clinical trials are required to better understand the efficacy and safety of investigational drugs for treating primary and secondary dysmenorrhea.

Aggregate IND Safety Reporting for Smaller Companies and Programs.

The United States (US) Food and Drug Administration (FDA) Investigational New Drug (IND) Final Rule (US FDA, Final rule: Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 2010) applies to all human drugs and biological products being studied under an IND. The Final Rule specifies that a sponsor must file an IND safety report for any Suspected Unexpected Serious Adverse Reaction (SUSAR) of a medicinal product being investigated. To make a proper SUSAR classification, sponsors need to go beyond conventional Data Monitoring Committees (DMCs) with an interdisciplinary effort, using all relevant data (including data outside clinical trials), to make judgments on the possibility of serious adverse events being caused by the study drug-rather than the underlying condition of the patient or a concomitant therapy. Ball et al. (Ball et al. in Ther Innov Regul Sci 55:705-716, 2021) have reported on how the Final Rule has been implemented by large pharmaceutical companies. This paper explores the experiences of small sponsor companies regarding the Final Rule, to understand the current challenges that they have been facing to meet aggregate IND safety reporting requirements.

The Importance of Assessing Drug Exposure and Medication Adherence in Evaluating Investigational Medications: Ensuring Validity and Reliability of Clinical Trial Results.

The objective of this current opinion paper is to draw global attention to medication adherence, emphasizing its crucial role in drug trials. Frequently, trialists lean on traditional approaches to assess medication adherence, which, while comfortable, may only reveal what trialists desire rather than offering the essential insights needed for informed decision making in drug development. Understanding drug exposure and medication adherence is paramount when evaluating the effectiveness and safety of investigational medications. Without a comprehensive understanding of how patients adhere to their prescribed treatment regimens, the integrity and dependability of clinical trial results can be compromised. This paper emphasizes the need for measures that accurately and reliably assess medication intake behaviors, enabling the differentiation between minor dosing errors and significant deviations that may impact the drug's efficacy and safety. Accurate knowledge of drug exposure empowers researchers to make informed decisions, identify potential confounding factors, and appropriately interpret study outcomes, ultimately ensuring the validity and reliability of the research findings. By prioritizing drug exposure assessment and medication adherence measurement, clinical trials can enhance their scientific rigor, contribute to more accurate evaluations of investigational medications, and ultimately speed up the development process.

Use of suboptimal control arms in randomized clinical trials of investigational cancer drugs in China, 2016-2021: An observational study.

BACKGROUND: The use of suboptimal controls in randomized trials of new cancer drugs can produce potentially unreliable clinical efficacy results over the current standard of care and expose patients to substandard therapy. We aim to investigate the proportion of randomized trials of investigational cancer drugs that used a suboptimal control arm and the number of trial participants at risk of exposure to suboptimal treatments in China. The association between the use of a suboptimal control and concluding statistical significance on the primary endpoint was also examined. METHODS AND FINDINGS: This observational study included randomized controlled trials (RCTs) of cancer drugs that were authorized by specific Chinese institutional review boards between 2016 and 2021, supporting investigational new drug applications of these drugs in China. The proportion of trials that used a suboptimal control arm and the total number of trial participants at risk of exposure to suboptimal treatments were calculated. In a randomized trial for a specific condition, a comparator was deemed suboptimal if it was not recommended by clinical guidelines published in priori or if there existed a regimen with a higher level of recommendation for the indication. The final sample included 453 Phase II/III and Phase III randomized oncology trials. Overall, 60 trials (13.2%) adopted a suboptimal control arm. Among them, 58.3% (35/60) used comparators that were not recommended by a prior guideline for the indication. The cumulative number of trial participants at risk of exposure to suboptimal treatments totaled 18,610 by the end of 2021, contributing 15.1% to the total number of enrollees of all sampled RCTs in this study. After adjusting for the year of ethical approval, region of participant recruitment, line of therapy, and cancer site, second-line therapies (adjusted odds ratio [aOR] = 2.7, 95%CI [1.2, 5.9]), adjuvant therapies (aOR = 8.9, 95% CI [3.4, 23.1]), maintenance therapies (aOR = 5.2, 95% CI [1.6, 17.0]), and trials recruiting participants in China only (aOR = 4.1, 95% CI [2.1, 8.0]) were more likely to adopt a suboptimal control. For the 105 trials with publicly available results, no statistically significant difference was observed between the use of a suboptimal control and concluding positive on the primary endpoint (100.0% [12/12] versus 83.9% [78/93], p = 0.208). The main limitation of this study is its reliance on clinical guidelines that could vary across cancer types and time in assessing the quality of the control groups. CONCLUSIONS: In this study, over one-eighth of randomized trials of cancer drugs registered to apply for regulatory approval in China used a suboptimal comparator. Our results highlight the necessity to refine the design of randomized trials to generate optimal clinical evidence for new cancer therapies.

Efficacy and safety of compassionate use for rare diseases: a scoping review from 1991 to 2022.

BACKGROUND: Compassionate use is a system that provides patients with expedited access to drugs which has not yet been approved, but currently in clinical trials. The investigational drugs have been authorized for compassionate use in cases involving patients suffered from life-threatening diseases and with no alternative treatments. For instance, patients afflicted with highly heterogeneous rare diseases are eligible for treatment assistance through the compassionate use program. This study aims to investigate the characteristics of compassionate use in the context of rare diseases, evaluate the efficacy and safety of compassionate use for rare diseases, and analyze the marketing approval of investigational drugs. METHODS: The case reports/case series of compassionate use were collected by conducting searches on Embase, PubMed, Web of Science, CNKI and SinoMed, spanning from January 1991 to December 2022. Subsequently, two independent reviewers evaluated these reports. Case reports/case series that met the inclusion criteria and exclusion criteria were enrolled. Information extracted from these reports and series included patients' basic information, the investigational drug's name, its indication, adverse events, treatment outcomes, and other relevant data. RESULTS: A total of forty-six studies were included, encompassing 2079 patients with an average age of 38.1 years. Thirty-nine different drugs were involved in 46 studies. Furthermore, neoplasms emerged as the most common therapeutic area for compassionate use in rare disease management (23/46, 50.0%). Regarding the treatment efficacy, four studies reported successful disease resolution, while 35 studies observed symptom improvement among patients. Conversely, four studies documented no significant effects on patients' diseases. Moreover, one study reported worsened results following compassionate use, while the efficacy was not described in 2 studies. Adverse events were reported in 31 studies (67.4%) because of the compassionate use, while no adverse events occurred in 13 studies (28.3%). In other 2 studies, there was no description about whether treatment-emergent adverse events (TEAEs) were happened. 136 patients (6.5%) had Grade 5 adverse events (death), of which 19 deaths (0.9%) were considered to be related to compassionate use. Furthermore, the investigational drugs in 33 studies (33/46, 71.7%) received new drug approval at the end of January 31, 2023.The time lag from the start of the compassionate use to the formal approval of the investigational drug was 790.5 (IQR 359-2199.3) days. We found that in 11 studies, encompassing 9 different drugs, some compassionate use indications had not received regulatory authorities at the end of January 31, 2023. CONCLUSION: The current status of compassionate use for rare diseases was clarified systematically in this study. Compassionate use of investigational drug is a significant treatment option for rare disease. In general, compassionate use appears to demonstrate favorable efficacy in the context of rare diseases, with a significant proportion of compassionate use drugs subsequently receiving marketing approval. However, the safety of drugs for compassionate use cannot be fully evaluated due to the safety data were not covered in some enrolled studies. Therefore, the establishment of an adverse event reporting system specific to compassionate use is warranted.

Investigational drugs inhibiting complement for the treatment of geographic atrophy.

INTRODUCTION: Geographic atrophy (GA) is a progressive form of age-related macular degeneration (AMD) that leads to severe visual impairment and central vision loss. Traditional treatment options for GA are limited, highlighting the need for new therapeutic approaches. In recent years, targeting the complement system has emerged as a promising strategy for the treatment of GA. AREAS COVERED: This expert opinion article reviews the investigational drugs inhibiting the complement cascade for the treatment of GA. Specifically, it focuses on the recent FDA approved pegcetacoplan, a C3 complement inhibitor, and avacincaptad pegol, a C5 complement inhibitor, highlighting their potential efficacy and safety profiles based on clinical trial data. EXPERT OPINION: FDA approval of intravitreal pegcetacoplan and avacincaptad pegol marks significant progress in the landscape of GA treatment. However, variable results from trials underscore the complex nature of GA and the importance of patient selection. Complement inhibition holds promise, but ongoing research is vital to refine treatment strategies and offer improved outcomes for GA patients.

The ARTS (Avoiding Risks of Thrombosis and Bleeding in Surgery) Trial: Lessons Learnt in Setting Up an International Multicentre Clinical Trial of an Investigational Medicinal Product in the UK.

We describe our experience in setting up the UK arm of the ARTS trial and highlight regulatory and funding challenges in relation to an international multicentre setting for an investigational medicinal product.

The holistic approach to psoriasis patients with comorbidities: the role of investigational drugs.

INTRODUCTION: Psoriasis is a high-burden syndrome characterized by cutaneous and extracutaneous manifestations that profoundly reduce patients' quality of life. The presence of concomitant comorbidities often represents a limit to the most appropriate psoriasis treatment that will be overcome by the development of drugs effective for diseases with common pathogenetic pathways. AREAS COVERED: The current review summarizes the latest findings on investigational drugs for psoriasis and their role on potentially concomitant diseases that share similar pathogenetic pathways. EXPERT OPINION: The development of novel drugs that target key-molecules in the pathogenesis of several diseases, including psoriasis, will impact on the reduction of polypharmacy and drug interaction with increased patients' compliance to treatment, wellbeing, and quality of life. Certainly, the efficacy and safety profile of each novel agent must be defined and evaluated in real-life since the performance may vary according to comorbidities and their severity. Anyway, future is now, and research must continue in this direction.

Investigational new drugs for the treatment of Dravet syndrome: an update.

INTRODUCTION: While there are already approved anticonvulsants for treatment of children with Dravet syndrome, disease modifying therapy is at its beginning. AREAS COVERED: This narrative review is updating the latest information about efficacy and safety of both anticonvulsant and disease modifying investigational drugs for Dravet syndrome. Relevant publications were searched for in MEDLINE, GOOGLE SCHOLAR, SCINDEKS, and CLINICALTRIALS.GOV databases, from the dates of their foundation till January 2023. EXPERT OPINION: The main advancements were made in the treatment of Dravet syndrome with confirmed haploinsufficiency of SCN1A gene. The application of antisense oligonucleotides has so far proven to be the most successful within disease-modifying therapy, but it also requires further refinement of the methodology of application and delivery to target cells, as well as additional testing of the effectiveness of antisense oligonucleotides outside of TANGO technology. Also, the full potential of gene therapy has yet to be explored, given that high capacity adenoviral vectors that can incorporate the SCN1A gene have recently been prepared.

Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute.

Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e., demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g., supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g., the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).

Toxicologic Pathology Forum: Opinion on Approaches for Reporting Toxic and Adverse Dose Levels in Nonclinical Toxicology Studies Supporting the Development of Anticancer Pharmaceuticals.

The advancement of an investigational new drug in humans is a significant developmental milestone. In first-in-human (FIH)-enabling toxicology studies, the highest dose without a test article-related adverse effect (no-observed-adverse-effect-level [NOAEL]) serves as the basis for deriving a safe FIH starting dose. For anticancer pharmaceuticals, the FIH dose may be calculated using the highest non-severely toxic dose (HNSTD) in nonrodent models or the dose severely toxic to 10% (STD10) in rodents. Given the practice of reporting the NOAEL, but the lack of regulatory requirements to do so for anticancer pharmaceuticals, we conducted an informal survey of 20 companies to answer the question "How is our industry reporting toxic/adverse dose levels in FIH-enabling toxicology studies for anticancer indications?" The data indicated 4 reporting approaches, each providing a path to regulatory acceptance. Within the integrated toxicology study report, 45% of respondents report the HNSTD/STD10, 25% report the NOAEL, 20% report both the HNSTD/STD10 and NOAEL, and 10% do not define either, reserving definitions for regulatory submissions. One reporting approach may be preferred over another for reasons including consistency across indications, repurposing pharmaceuticals, regulatory feedback, or simplicity. The reporting approach should be defined in advance of study initiation, and the pathologist should provide context to support the chosen approach.

Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials.

Ocular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33-76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug's maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered).

Seladelpar: an investigational drug for the treatment of early-stage primary biliary cholangitis (PBC).

INTRODUCTION: Generic fibrates are used off-label as add-in therapy for the management of primary biliary cholangitis (PBC) but with unproven long-term liver-related survival benefits. The recently developed fibrate, seladelpar, has shown promising results in clinical trials, but these outcomes have been previously marred by safety concerns. AREAS COVERED: We summarize existing treatment options in PBC and evaluate current trial data for seladelpar in relation to liver biochemistry, symptomology, and safety. EXPERT OPINION: Seladelpar leads to marked improvement in liver biochemistry and may improve symptoms. Safety concerns around liver toxicity appear to have been addressed. With likely increasing evidence compared to existing off-label fibrates, seladelpar has the potential as an attractive future second-line agent in PBC.

Investigational drugs for the treatment of kidney transplant rejection.

INTRODUCTION: Kidney transplant rejection remains an important clinical problem despite the development of effective immunosuppressive therapy. Two major types of rejection are recognized, T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), which have a different pathophysiology and are treated differently. Unfortunately, long-term outcomes of both TCMR and ABMR remain unsatisfactory despite current therapy. Hence, alternative therapeutic drugs are urgently needed. AREAS COVERED: This review covers novel and investigational drugs for the pharmacological treatment of kidney transplant rejection. Potential therapeutic strategies and future directions are discussed. EXPERT OPINION: The development of alternative pharmacologic treatment of rejection has focused mostly on ABMR, since this is the leading cause of kidney allograft loss and currently lacks an effective, evidence-based therapy. At present, there is insufficient high-quality evidence for any of the covered investigational drugs to support their use in ABMR. However, with the emergence of targeted therapies, the potential arises for individualized treatment strategies. In order to generate more high-quality evidence for such strategies and overcome the obstacles of classic randomized controlled trials, we advocate the implementation of adaptive trial designs and surrogate clinical endpoints. We believe such adaptive trial designs could help to understand the risks and benefits of promising drugs such as tocilizumab, clazakizumab, belimumab, and imlifidase.

Emerging therapies for juvenile arthritis: agents in early clinical trials.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatic condition in childhood. The management of JIA has been revolutionized thanks to the development of new powerful drugs and the possibility to conduct controlled clinical trials with support from legislative initiatives and availability of international collaborative networks. Trials are still needed in children because we now have new drugs related to specific JIA category. AREAS COVERED: The review is centered on the latest achievements in the field, focusing on new investigational drugs which are currently or have been recently tested for JIA treatment, encompassing agents in early phase of clinical development. EXPERT OPINION: Despite the tremendous improvement witnessed in the field of JIA treatment in the past 20 years, there are still many unmet needs to be prioritized. Studies on disease pathogenesis will hopefully help in the identification of new treatment targets for individual JIA categories, that could possibly favor a stricter disease control and contribute to solve the issue of refractory JIA. Novel strategies aimed at the prevention of the risk of long-term joint damage are also desirable, as well as the discovery of predictive biomarkers for treatment efficacy and safety in the individual patient.

The 'false hope' argument in discussions on expanded access to investigational drugs: a critical assessment.

When seriously ill patients reach the end of the standard treatment trajectory for their condition, they may qualify for the use of unapproved, investigational drugs regulated via expanded access programs. In medical-ethical discourse, it is often argued that expanded access to investigational drugs raises 'false hope' among patients and is therefore undesirable. We set out to investigate what is meant by the false hope argument in this discourse. In this paper, we identify and analyze five versions of the false hope argument which we call: (1) the limited chance at benefit argument, (2) the side effects outweighing benefits argument, (3) the opportunity costs argument, (4) the impossibility of making informed decisions argument, and (5) the difficulty of gaining access argument. We argue that the majority of these five versions do not provide normative ground for disqualifying patients' hopes as false. Only when hope is rooted in a mistaken belief, for example, about the likelihood of benefits or chances on medical risks, or when hope is directed at something that cannot possibly be obtained, should it be considered false. If patients are adequately informed about their odds of obtaining medical benefit, however small, and about the risks associated with an investigational treatment, it is unjustified to consider patients' hopes to be false, and hence, to deny them access to investigational drug based on that argument.

Investigational drugs for the treatment of olfactory dysfunction.

INTRODUCTION: Olfactory dysfunction could be the sign of acquired or degenerative diseases. The loss of the sense can be caused by a damage in the nasal structure (olfactory epithelium) or a neuro inflammation/degeneration in the superior olfactory pathway. The understanding of the origin of the smell alteration would be desirable for appropriate management of the problem. Unfortunately, clinical investigations do not always allow to define the exact cause. AREAS COVERED: This review discusses the treatments available and their mechanism of action based on the administration methods; in fact, just looking at the results obtained by the researcher using topic versus systemic treatment, might be possible to speculate about the peripheral or central origin of the olfactory disorder. EXPERT OPINION: Because COVID-19 causes olfactory loss and several treatments (topical and systemic) have been tested in this disease, we have decided to use this model of acquired olfactory loss to discuss the different therapeutical option. The authors believe these treatments might be an option also for treating olfactory disease related to neurodegeneration.

Current emerging and investigational drugs for the treatment of chronic hand eczema.

INTRODUCTION: Chronic hand eczema (CHE) is a highly prevalent, burdensome condition associated with functional impairment. Currently, topical therapeutics are the mainstay of CHE management. However, many cases are refractory to existing topical therapeutics, and the few existing systemic options are often limited in efficacy and by their side effect profiles. AREAS COVERED: Following a brief overview of CHE pathogenesis and existing treatments, this review will outline the mechanisms and available data on emerging and investigational drugs currently being studied in clinical trials for the treatment of CHE. EXPERT OPINION: Immunomodulatory drugs such as topical and systemic JAK inhibitors and Th2-targeting antibodies such as dupilumab are currently under investigation for CHE treatment, with early promise. Management of CHE will likely move toward more targeted treatments through clinical trials and away from broad immunosuppressants such as cyclosporine and methotrexate, which have previously been investigated for CHE and have more side effects. In coming years, CHE patients may benefit from a wider range of both topical and systemic therapeutics that target immune pathways relevant to the various CHE subtypes.