Investigational drug tracking: phases I-III and NDA submissions--Part II

The author catalogs over 800 investigational drugs/biologicals currently in Phase I, II or III clinical trials or drugs/biologicals submitted to the FDA as new drug applications. Part I of this article appeared in the September issue of Hospital Pharmacy. The list assists in predicting when new drugs will be marketed. The entries include generic/chemical name, investigational drug number, synonyms, trade names, manufacturers, clinical trial status, predicted approval year, indications or drug class, whether the drug has been developed through biotechnology, and references. Entries were gleaned from medical journals, stock market analysis publications, and the Pharmaceutical Manufacturers Association's Medicines in Development Series. The list is alphabetized by the generic/chemical name or investigational drug number and cross-indexed by the trade name and synonyms. The list reflects those drugs which were not FDA approved as of April 15, 1994. Part I concludes with the remaining alphabetical listing by generic/chemical name or investigational drug number.     

Investigational drug therapies in phase I and phase II clinical trials for alcohol use disorders

Introduction: Alcohol use disorder (AUD) is a complex psychiatric condition characterized by craving, compulsive seeking, loss of control of alcohol consumption as well as the emergence of negative emotional states during withdrawal. Despite the large socioeconomic burden of AUD, therapeutic treatment options lag behind.

Areas covered: This review covers pharmacotherapies currently in phase I/II clinical trials for the treatment of AUDs listed on clinicaltrials.gov. We discuss drug therapies that modulate monoamine, GABA/Glutamate, neuropeptide and neuroimmune systems. We examine in depth preclinical and clinical evidence of a select range of these compounds and consider their utility in treating AUDs.

Expert opinion: Current therapeutic options to treat AUD are inadequate at a population level. Currently there are 30 different compounds and one compound combination in phase I/II clinical trials for AUD. These compounds target various aspects of neurotransmitter signaling, neuroimmune modulation, and alcohol metabolism. Almost 75% of these compounds under trial are Food and Drug Administration (FDA) approved for other indications, which may save time and costs in treatment development. Further, development of therapeutics focused on genetic biomarkers and behavioral screening may improve how treatment decisions are made in the future on a case-by-case basis.     

Investigational antibody drug conjugates for solid tumors

Introduction: Despite the progress made in the past 20 years in understanding the molecular events leading to the formation of cancer, the success of targeted antitumor agents in solid tumors has lagged behind the scientific discoveries. The most difficult to treat patient segments are those with refractory solid tumors, resistant to standard chemotherapy, and novel therapeutic compounds with improved therapeutic indexes are needed. Antibody drug conjugates (ADCs) are poised to become an important class of cancer therapeutics, as evidenced by the promising objective response rates when administered as single agents to chemorefractory cancer patients.

Areas covered: The basic concept for ADCs is to combine the strengths of the two most successful classes of therapeutic compounds developed in oncology, the high selectivity of antibodies with the unrivaled potency of small molecules, with the goal to improve the therapeutic index. Currently, approximately 60 ADCs are being developed in oncology. Among them, about 20 are undergoing clinical testing, the majority of which are tubulin inhibitor-based immunoconjugates. Herein, we review ADCs targeting solid tumors, with the focus on 11 programs currently undergoing clinical development.

Expert opinion: Key challenges the ADC field is facing, including potency and safety, can be addressed effectively by introducing novel research concepts with transformational potential for ADC development.     

Investigational antibody drug conjugates for solid tumors

INTRODUCTION: Despite the progress made in the past 20 years in understanding the molecular events leading to the formation of cancer, the success of targeted antitumor agents in solid tumors has lagged behind the scientific discoveries. The most difficult to treat patient segments are those with refractory solid tumors, resistant to standard chemotherapy, and novel therapeutic compounds with improved therapeutic indexes are needed. Antibody drug conjugates (ADCs) are poised to become an important class of cancer therapeutics, as evidenced by the promising objective response rates when administered as single agents to chemorefractory cancer patients. AREAS COVERED: The basic concept for ADCs is to combine the strengths of the two most successful classes of therapeutic compounds developed in oncology, the high selectivity of antibodies with the unrivaled potency of small molecules, with the goal to improve the therapeutic index. Currently, approximately 60 ADCs are being developed in oncology. Among them, about 20 are undergoing clinical testing, the majority of which are tubulin inhibitor-based immunoconjugates. Herein, we review ADCs targeting solid tumors, with the focus on 11 programs currently undergoing clinical development. EXPERT OPINION: Key challenges the ADC field is facing, including potency and safety, can be addressed effectively by introducing novel research concepts with transformational potential for ADC development.     

Investigational drugs in Phase I and Phase II for Levodopa-induced dyskinesias

Introduction: Prolonged treatment of Parkinson’s disease (PD) with levodopa (L-DOPA) results in motor complications, including motor fluctuations and involuntary movements known as L-DOPA induced dyskinesias (LIDs). LIDs represent an additional cause of disability for PD patients and a major challenge for the clinical neurologist. Preclinical research has provided invaluable insights into the molecular and neural substrates of LIDs, identifying a number of potential targets for new anti-dyskinetic strategies.

Areas covered: This review article is centered on drugs currently in Phase I and II clinical trials for LIDs and their relative pharmacological targets, which include glutamate, acetylcholine, serotonin, adrenergic receptors and additional targets of potential therapeutic interest.

Expert opinion: LIDs are sustained by complex molecular and neurobiological mechanisms that are difficult to disentangle or target, unless one or more prevalent mechanisms are identified. In this context, the role of the serotonergic system and mGluR5 glutamate receptors seem to stand out. Interesting results have been obtained, for example, with partial 5-HT1A/5-HT1B receptor agonist eltoprazine and mGluR5 negative allosteric modulator dipraglurant. Confirmation of these results through large-scale, Phase III clinical trials will be needed, to obtain new pharmacological tools that may be used to optimize the treatment of PD patients with motor complications.     

Real-time multiple-particle tracking: applications to drug and gene delivery

Complex biological environments, such as the cell cytoplasm or the mucus lining the airways of the lungs, can pose significant barriers to efficient therapeutic drug and gene delivery. Biological barriers are particularly important in controlled drug delivery applications that utilize a large carrier particle, such as a liposome or a polymer micro- or nanosphere. The dynamic transport of particulate drug and gene delivery vehicles through these barriers is poorly understood, having been primarily studied with static methods in the past. Recently, the transport of synthetic drug and gene carriers has been investigated quantitatively with real-time particle tracking technology, providing new insight into particle behavior in complex biological environments that is guiding rational improvements in particle design. This review briefly highlights basic principles of particle tracking and its application to elucidate important phenomena that limit effective particulate drug and gene delivery.     

Investigational drugs in phase I and phase II clinical trials for thalassemia

Introduction: Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials.

Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials. A phase III clinical trial is currently ongoing. Ruxolitinib, a Jak2 inhibitor, has been tested to limit stress erythropoiesis in a phase II clinical trial. In addition, improvement in iron chelation has been developed. Moreover, several trials of gene therapy are currently active in different countries with different lentiviral vectors.

Expert opinion: The most promising molecules are the activin receptor ligand traps. Together with gene therapy these could be an alternative to bone marrow transplant, aiming towards a curative strategy. The main limit to gene therapy seems to be the conditioning regimen, thus an in vivo gene therapy would be more suitable. At pre-clinical level gene editing is showing extremely encouraging results.     

Investigational HIV integrase inhibitors in phase I and phase II clinical trials

Introduction: To date, three HIV integrase strand transfer inhibitors (INSTIs), i.e. raltegravir, elvitegravir and dolutegravir, have been approved for clinical use. Recent research has focused on new integrase inhibitors including those targeting non-catalytic sites of HIV integrase.

Areas covered: This paper reviews two investigational INSTIs in phase I and II clinical trials, bictegravir (BIC) and cabotegravir (CAB), as well as an investigational noncatalytic integrase inhibitor (NCINI) termed BI 224436.

Expert opinion: Data from phase I and II clinical trials demonstrate that CAB has good efficacy and is well-tolerated. CAB is promising because it can be formulated both orally and as a long-acting (LA) injectable for treatment and prevention of HIV infection. Since LA-CAB formulation offers the possibility of favourable dosing, it may help individuals who struggle with adherence issues. BIC also represents a promising safe, effective and well-tolerated drug that can be administered as a single once-daily regimen in coformulation with emtricitabine and tenofovir alafenamide (FTC/TAF). Ongoing phase III trials should clarify optimal doses and reveal the potential clinical advantages of these new drugs and formulations over other current regimens. Exploration of novel HIV integrase inhibitors acting through mechanisms different from those of INSTIs is still needed.     

Investigational drugs in phase I and phase II clinical trials for hereditary angioedema

Introduction: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare bradykinin-mediated disease characterized by recurrent subcutaneous and/or submucosal angioedematous attacks (HAE attacks), which occur unpredictably. The recurrent HAE attacks do not respond to conventional treatments, and may evolve into a life-threatening condition; therefore, special therapy is required.

Areas covered: The agents used so far for the acute management of HAE attacks act by blocking the release of bradykinin, or its binding to its receptor. By contrast, the investigational medicinal products under evaluation in Phase I and II clinical trials are targeted at the prevention of HAE attacks. Chemically, these new drugs are small synthetic molecules, oligonucleotides, or antibodies, which inhibit either kallikrein, or Factor XII.

Expert opinion: The key considerations for the development of new medicinal products include more straightforward dosing, self-administration, longer duration of action, and keeping the patient attack-free. This review summarizes the status and the findings of the currently ongoing Phase I and Phase II clinical trials of C1-INH-HAE.     

Investigational study of tamoxifen phase I metabolites using chromatographic and spectroscopic analytical techniques

A comprehensive overview is presented of currently known phase I metabolites of tamoxifen consisting of their systematic name and molecular structure. Reference standards are utilized to elucidate the MS(n) fragmentation patterns of these metabolites using a linear ion trap mass spectrometer. UV-absorption spectra are recorded and absorption maxima are defined. Serum extracts from ten breast cancer patients receiving 40mg tamoxifen once daily were qualitatively analyzed for tamoxifen phase I metabolites using a liquid chromatography-tandem mass spectrometry set-up. In total, 19 metabolites have been identified in these serum samples. Additionally a synthetic method for the preparation of the putative metabolite 3',4'-dihydroxytamoxifen is described.     

Particle tracking in drug and gene delivery research: State-of-the-art applications and methods

Particle tracking is a powerful microscopy technique to quantify the motion of individual particles at high spatial and temporal resolution in complex fluids and biological specimens. Particle tracking's applications and impact in drug and gene delivery research have greatly increased during the last decade. Thanks to advances in hardware and software, this technique is now more accessible than ever, and can be reliably automated to enable rapid processing of large data sets, thereby further enhancing the role that particle tracking will play in drug and gene delivery studies in the future. We begin this review by discussing particle tracking-based advances in characterizing extracellular and cellular barriers to therapeutic nanoparticles and in characterizing nanoparticle size and stability. To facilitate wider adoption of the technique, we then present a user-friendly review of state-of-the-art automated particle tracking algorithms and methods of analysis. We conclude by reviewing technological developments for next-generation particle tracking methods, and we survey future research directions in drug and gene delivery where particle tracking may be useful.     

Pharmacy database for tracking drug costs and utilization.

A pharmacy database for tracking drug costs and physician prescribing trends is described. Accuracy problems plagued data systems used to make drug-use-policy decisions at a tertiary care teaching hospital because of structural deficiencies within the systems and their nonclinical orientation. To resolve these problems, a programmer analyst, a clinical supervisor, and a clinical pharmacist developed a hierarchical database of drug costs. The database was designed to be valid for tracking drug costs according to patterns of clinical use. Internal controls were created that could identify and correct cost-tabulation errors arising within the ordering, order-entry, and billing processes. The database was able to tabulate drug costs according to the clinical service on which the patient was being treated at the time so that reports could compare aggregate prescribing trends from one time period to another for the same service. Similarly, the database could track and report drug use by disease or financial classification. Flagging elements were introduced to the database for cancer chemotherapy and antimicrobial drug products to enable reporting by these categories and by therapeutic subcategories within the antimicrobial category. Routine monthly reports were distributed to end users. Development of a database for tracking drug costs and utilization allowed a teaching hospital to derive the cost of medications from billing-charge information and to report data to health care professionals on the basis of important factors like clinical services.     

Investigational drugs for the treatment of cancer cachexia: a focus on phase I and phase II clinical trials

Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue.

Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life.

Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.