Clinical development of nitisinone for alkaptonuria (developakure) - a rare disease clinical trials design

Duchenne muscular dystrophy (DMD) is a devastating, rare disease. While clinically described in the 19th century, the genetic foundation of DMD was not discovered until more than 100 years later. This genetic understanding opened the door to the development of genetic treatments for DMD. Over the course of the last 30 years, the research that supports this development has moved into the realm of clinical trials and regulatory drug approvals. Exon skipping to therapeutically restore the frame of an out-of-frame dystrophin mutation has taken center stage in drug development for DMD. The research reviewed here focuses on the clinical development of exon skipping for the treatment of DMD. In addition to the generation of clinical treatments that are being used for patient care, this research sets the stage for future therapeutic development with a focus on increasing efficacy while providing safety and addressing the multi-systemic aspects of DMD.

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New Anti-VEGF Drugs in Ophthalmology

Current Drug Targets ◽

10.2174/1389450121666200428101738 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1194-1200

Author(s):

Claudio Campa

Keyword(s):

Clinical Trials ◽

Delivery System ◽

Clinical Development ◽

Advanced Stage ◽

Phase 3 ◽

Anti Vegf

: This review focuses on 5 new anti-VEGF drugs in the advanced stage of clinical development (i.e., phase 3): conbercept, brolucizumab, port delivery system with ranibizumab, abicipar pegol and faricimab. : Results of clinical trials and the advantages of each drug compared to the available molecules are discussed in detail.

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WEE1 Inhibitor: Clinical Development

Current Oncology Reports ◽

10.1007/s11912-021-01098-8 ◽

2021 ◽

Vol 23 (9) ◽

Author(s):

Anthony Kong ◽

Hisham Mehanna

Keyword(s):

Clinical Trials ◽

Tp53 Mutation ◽

Predictive Biomarker ◽

Concurrent Chemotherapy ◽

Clinical Development ◽

Novel Agents ◽

The Novel ◽

Grade 3 ◽

Chemotherapy Agents

Abstract Purpose of Review WEE1 inhibitor has been shown to potential chemotherapy or radiotherapy sensitivity in preclinical models, particularly in p53-mutated or deficient cancer cells although not exclusively. Here, we review the clinical development of WEE1 inhibitor in combination with chemotherapy or radiotherapy with concurrent chemotherapy as well as its combination with different novel agents. Recent Findings Although several clinical trials have shown that WEE1 inhibitor can be safely combined with different chemotherapy agents as well as radiotherapy with concurrent chemotherapy, its clinical development has been hampered by the higher rate of grade 3 toxicities when added to standard treatments. A few clinical trials had also been conducted to test WEE1 inhibitor using TP53 mutation as a predictive biomarker. However, TP53 mutation has not been shown to be the most reliable predictive biomarker and the benefit of adding WEE1 inhibitor to chemotherapy has been modest, even in TP53 biomarker-driven studies. Summary There are ongoing clinical trials testing WEE1 inhibitor with novel agents such as ATR and PAPR inhibitors as well as anti-PDL1 immunotherapy, which may better define the role of WEE1 inhibitor in the future if any of the novel treatment combination will show superior anti-tumor efficacy with a good safety profile compared to monotherapy and/or standard treatment.

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The exosome journey: from biogenesis to uptake and intracellular signalling

Cell Communication and Signaling ◽

10.1186/s12964-021-00730-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Sonam Gurung ◽

Dany Perocheau ◽

Loukia Touramanidou ◽

Julien Baruteau

Keyword(s):

Clinical Trials ◽

Plasma Membrane ◽

Scientific Community ◽

Cell Types ◽

Clinical Applications ◽

Clinical Development ◽

Intracellular Signalling ◽

Clinical Settings ◽

Health And Disease ◽

Adequate Definition

AbstractThe use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications.

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Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient

Current Clinical Pharmacology ◽

10.2174/1574884716666210316120615 ◽

2021 ◽

Vol 16 ◽

Author(s):

Erica Winter ◽

Scott Schliebner

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Drug Development ◽

Rare Disease ◽

Rare Diseases ◽

Statistical Analyses ◽

Clinical Trial Designs ◽

Novel Approaches

: Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.

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Clinical Trials and Machine Learning: Regulatory Approach Review

Reviews on Recent Clinical Trials ◽

10.2174/1574887116666210715114203 ◽

2021 ◽

Vol 16 ◽

Author(s):

Diego Alejandro Dri ◽

Maurizio Massella ◽

Donatella Gramaglia ◽

Carlotta Marianecci ◽

Sandra Petraglia

Keyword(s):

Artificial Intelligence ◽

Machine Learning ◽

Clinical Trials ◽

Patient Safety ◽

Drug Discovery ◽

Clinical Applications ◽

Clinical Development ◽

Regulatory Approach ◽

National Competent Authorities ◽

Review Current

: Machine Learning, a fast-growing technology, is an application of Artificial Intelligence that has significantly contributed to drug discovery and clinical development. In the last few years, the number of clinical applications based on Machine Learning has constantly been growing. Moreover, it is now also impacting National Competent Authorities during the assessment of most recently submitted Clinical Trials that are designed, managed, or generating data deriving from the use of Machine Learning or Artificial Intelligence technologies. We review current information available on the regulatory approach to Clinical Trials and Machine Learning. We also provide inputs for further reasoning and potential indications, including six actionable proposals for regulators to proactively drive the upcoming evolution of Clinical Trials within a strong regulatory framework, focusing on patient safety, health protection, and fostering immediate access to effective treatments.

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Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design

US Neurology ◽

10.17925/usn.2018.14.1.47 ◽

2018 ◽

Vol 14 (1) ◽

pp. 47 ◽

Cited By ~ 5

Author(s):

Said R Beydoun ◽

Jeffrey Rosenfeld

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Trial Design ◽

Development Program ◽

Clinical Trial Design ◽

Clinical Development ◽

Disease Heterogeneity ◽

Clinical Development Program ◽

Lateral Sclerosis

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

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Macrophage checkpoint blockade: results from initial clinical trials, binding analyses, and CD47-SIRPα structure–function

Antibody Therapeutics ◽

10.1093/abt/tbaa006 ◽

2020 ◽

Vol 3 (2) ◽

pp. 80-94 ◽

Cited By ~ 3

Author(s):

AbdelAziz R Jalil ◽

Jason C Andrechak ◽

Dennis E Discher

Keyword(s):

Clinical Trials ◽

Regulatory Protein ◽

Clinical Results ◽

Structural Features ◽

Clinical Development ◽

Combination Therapies ◽

Syngeneic Mouse ◽

Solid Malignancies ◽

Anti Cancer ◽

Tumor Types

Abstract The macrophage checkpoint is an anti-phagocytic interaction between signal regulatory protein alpha (SIRPα) on a macrophage and CD47 on all types of cells – ranging from blood cells to cancer cells. This interaction has emerged over the last decade as a potential co-target in cancer when combined with other anti-cancer agents, with antibodies against CD47 and SIRPα currently in preclinical and clinical development for a variety of hematological and solid malignancies. Monotherapy with CD47 blockade is ineffective in human clinical trials against many tumor types tested to date, except for rare cutaneous and peripheral lymphomas. In contrast, pre-clinical results show efficacy in multiple syngeneic mouse models of cancer, suggesting that many of these tumor models are more immunogenic and likely artificial compared to human tumors. However, combination therapies in humans of anti-CD47 with agents such as the anti-tumor antibody rituximab do show efficacy against liquid tumors (lymphoma) and are promising. Here, we review such trials as well as key interaction and structural features of CD47-SIRPα.

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Tackling rare diseases: Clinical trials on chips

Experimental Biology and Medicine ◽

10.1177/1535370220924743 ◽

2020 ◽

Vol 245 (13) ◽

pp. 1155-1162 ◽

Cited By ~ 2

Author(s):

Sandra H Blumenrath ◽

Bo Y Lee ◽

Lucie Low ◽

Ranjini Prithviraj ◽

Danilo Tagle

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Data Collection ◽

Rare Disease ◽

Study Design ◽

Rare Diseases ◽

Working Group ◽

Design Data ◽

Chip Technology ◽

Microphysiological Systems

Technological advances with organs-on-chips and induced pluripotent stem cells promise to overcome hurdles associated with developing medical products, especially for rare diseases. Organs-on-chips—bioengineered “microphysiological systems” that mimic human tissue and organ functionality—may overcome clinical trial challenges with real-world patients by offering ways to conduct “clinical trials-on-chips” (CToCs) to inform the design and implementation of rare disease clinical studies in ways not possible with other culture systems. If applied properly, CToCs can substantially impact clinical trial design with regard to anticipated key outcomes, assessment of clinical benefit and risk, safety and tolerability profiles, population stratification, value and efficiency, and scalability. To discuss how tissue chips are best used to move the development of rare disease therapies forward, a working group of experts from industry, academia, and FDA as well as patient representatives addressed questions related to disease setting, test agents for microphysiological systems, study design and feasibility, data collection and use, the benefits and risks associated with this approach, and how to engage stakeholders. While rare diseases with no current therapies were considered the ultimate target, participants cautioned against stepping onto too many unknown territories when using rare disease as initial test beds. Among the disease categories considered ideal for initial CToC tests were well-defined diseases with known clinical outcomes; diseases where tissues on chips can serve as an alternative to risky first-in-human studies, such as in pediatric oncology; and diseases that lend itself to immuno-engineering or genome editing. Participants also considered important challenges, such as hosting the chip technology in-house, the high variability of cell batches and the resulting regulatory concerns, as well as the financial risk associated with the new technology. To make progress in this area and increase confidence with the use of tissue chips, the re-purposing of approved drugs ought to be the very first step. Impact statement Designing and conducting clinical trials are extremely difficult in rare diseases. Adapting tissue chips for rare disease therapy development is pivotal in assuring that treatments are available, especially for severe diseases that are difficult to treat. Thus far, the NCATS-led National Institutes of Health (NIH) Tissue Chip program has focused on deploying the technology towards in vitro tools for safety and efficacy assessments of therapeutics. However, exploring the feasibility and best possible approach to expanding this focus towards the development phase of therapeutics is critical to moving the field of CToCs forward and increasing confidence with the use of tissue chips. The working group of stakeholders and experts convened by NCATS and the Drug Information Association (DIA) addresses important questions related to disease setting, test agents, study design, data collection, benefit/risk, and stakeholder engagement—exploring both current and future best use cases and important prerequisites for progress in this area.

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Everything in Moderation: Lessons Learned by Exploiting Moderate Replication Stress in Cancer

Cancers ◽

10.3390/cancers11091320 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1320 ◽

Cited By ~ 5

Author(s):

Nazareth ◽

Jones ◽

Gabrielli

Keyword(s):

Clinical Trials ◽

Side Effects ◽

Replication Stress ◽

Cytotoxic Chemotherapy ◽

Clinical Development ◽

Lessons Learned ◽

The Poor ◽

Damage Response ◽

Specific Vulnerability

The poor selectivity of standard cytotoxic chemotherapy regimens causes severe side-effects in patients and reduces the quality of life during treatment. Targeting cancer-specific vulnerabilities can improve response rates, increase overall survival and limit toxic side effects in patients. Oncogene-induced replication stress serves as a tumour specific vulnerability and rationale for the clinical development of inhibitors targeting the DNA damage response (DDR) kinases (CHK1, ATR, ATM and WEE1). CHK1 inhibitors (CHK1i) have served as the pilot compounds in this class and their efficacy in clinical trials as single agents has been disappointing. Initial attempts to combine CHK1i with chemotherapies agents that enhance replication stress (such as gemcitabine) were reported to be excessively toxic. More recently, it has emerged that combining CHK1i with subclinical doses of replication stress inducers is more effective, better tolerated and more compatible with immunotherapies. Here we focus on the lessons learned during the clinical development of CHK1i with the goal of improving the design of future clinical trials utilizing DDR inhibitors to target replication stress in cancer.

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