Nonclinical Safety Data Research Articles

Preclinical immunogenicity and safety of hemagglutinin-encoding modRNA influenza vaccines

Seasonal epidemics of influenza viruses are responsible for a significant global public health burden. Vaccination remains the most effective way to prevent infection; however, due to the persistence of antigenic drift, vaccines must be updated annually. The selection of vaccine strains occurs months in advance of the influenza season to allow adequate time for production in eggs. RNA vaccines offer the potential to accelerate production and improve efficacy of influenza vaccines. We leveraged the nucleoside-modified RNA (modRNA) platform technology and lipid nanoparticle formulation process of the COVID-19 mRNA vaccine (BNT162b2; Comirnaty®) to create modRNA vaccines encoding hemagglutinin (HA) (modRNA-HA) for seasonal human influenza strains and evaluated their preclinical immunogenicity and toxicity. In mice, a monovalent modRNA vaccine encoding an H1 HA demonstrated robust antibody responses, HA-specific Th1-type CD4+ T cell responses, and HA-specific CD8+ T cell responses. In rhesus and cynomolgus macaques, the vaccine exhibited durable functional antibody responses and HA-specific IFN-γ+ CD4+ T cell responses. Immunization of mice with monovalent, trivalent, and quadrivalent modRNA-HA vaccines generated functional antibody responses targeting the seasonal influenza virus(es) encoded in the vaccines that were greater than, or similar to, those of a licensed quadrivalent influenza vaccine. Monovalent and quadrivalent modRNA-HA vaccines were well-tolerated by Wistar Han rats, with no evidence of systemic toxicity. These nonclinical immunogenicity and safety data support further evaluation of the modRNA-HA vaccines in clinical studies.

An industry perspective on the FDA modernization act 2.0/3.0: Potential next steps for sponsors to reduce animal use in drug development

Abstract Pharmaceutical developers are encouraged to adopt the best practices of being purposefully thoughtful about the use of animals, seeking alternatives wherever possible. They should engage with health authorities to increase their familiarity with the methods, study designs, data outputs and the context of use for new approach methodologies (NAMs). Although current state of technology does not yet provide adequate models to fully replace in vivo studies, many models are sufficiently good for an augmented approach that will enhance our understanding of in vitro to in vivo correlations and advance the long-term goal of reducing animal use through innovative NAMs. The goal of future nonclinical safety packages is to advance the utilization of such enabling technologies towards appropriate human risk characterization. Establishing confidence in NAMs is a critical first step. For example, sponsors may include both “traditional” and NAM-based nonclinical safety data in regulatory submissions to establish confidence with health authorities. In addition, regulators should create a “safe-harbor” for hybrid nonclinical data packages to facilitate iterative learning, refinement, and implementation of NAM-based safety assessment strategies. Sponsors are urged to contribute to NAMs evolution through consortia participation, peer-reviewed publications, and documenting animal reduction in studies/programs, accelerating the eventual elimination of animal use in pharmaceutical development, as envisioned in the FDA Modernization Act 3.0.

The Vedotin Antibody-Drug Conjugate Payload Drives Platform-Based Nonclinical Safety and Pharmacokinetic Profiles.

Nonclinical safety and pharmacokinetic data for monomethyl auristatin E (MMAE) and 14 vedotin antibody-drug conjugates (ADC) were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting toxicity (DLT) or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with DLT; only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than 1 month in duration detected the same or fewer toxicities than 1-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification.

The Nonclinical Assessment of Trans-1,3,3,3-tetrafluoropropene (HFO-1234ze (E)), a Near Zero Global Warming Potential Propellant for Use in Metered Dose Inhalation Products.

HFO-1234ze (E) is proposed as a near zero global warming propellant for use in metered dose inhaled (MDI) products. This paper describes the non-clinical safety assessment in mice, rats, and dogs and supplements previously reported data (genetic toxicology, short-term toxicology, and reproductive toxicology). In all species, HFO-1234ze (E) was only detectable in blood for a short period after dosing with no evidence of accumulation. HFO-1234ze (E) was without any toxicological effects at very high doses in subchronic (13-week mouse) and chronic (39-week dog) studies. Chronic (26-week) administration to rats at very high doses was associated with an exacerbation of rodent progressive cardiomyopathy, a well-documented background finding in rodents. In a 2-generation study, extremely high doses were associated with the early euthanasia of some lactating female rats. This finding was considered to be significantly influenced by a state of negative energy balance, reflecting the specific vulnerability of rats during lactation. These findings are considered to not pose a risk to humans with typical MDI use given they occurred at doses which far exceed those expected in patients. Overall, the nonclinical safety data for HFO-1234ze (E) support its further development as an MDI propellant.

Development challenges for carcinogenicity risk assessments of topical drugs.

The nonclinical safety package to support development and approval of drugs intended to be administered by topical application generally follows International Council for Harmonisation multidisciplinary 3 (ICH M3) and topic specific safety (ICH S) guidances. However, some aspects of topical drug development may require case-by-case determination of nonclinical safety strategies. The necessity to conduct a dermal rodent carcinogenicity study is one such example that is not considered an obligate component of a nonclinical safety data package for drug approval. While absence of systemic exposure, as stated in ICH M3, is a primary reason to forego a dermal carcinogenicity assessment, there may also be other factors for consideration in determining the need for a life-time carcinogencity study by dermal route to aid in the overall human cancer risk assessment. We therefore reviewed nonclinical carcinogencity data packages from drugs approved by the FDA or PMDA over a ~25 year time period to evaluate outcomes of oral versus topical carcinogencity studies and to understand their utility for informing the overall human risk assessment. We also discuss various other properties of topical small molecules that could impact the decisions to conduct a dermal life-time rodent carcinogenicity study. Collectively, the need to conduct 2-year dermal carcinogenicity studies in rodents should be determined case-by-case and consider scientific factors such existing systemic toxicity and carcinogenicity study data, anticipated drug exposures in skin, skin evaluation from the chronic minipig toxicity study, and genetic toxicity profile.

Structure identification of circulating metabolites from somapacitan, a long-acting growth hormone derivative, and pharmacokinetics after single and multiple subcutaneous dosing in rats

Somapacitan is a growth hormone derivative approved for once-weekly treatment of growth hormone deficiency in adults and currently in clinical development for once-weekly dosing in children. The purpose of this study was to obtain non-clinical data from rats to support the safety evaluation of the most abundant metabolites of somapacitan in humans. The aims were to identify somapacitan metabolites and their relative proportions in rat plasma, identify the structure of abundant metabolites and measure the systemic metabolite exposure at the no-observed-adverse-effect level in the rat.After a single dose of radiolabelled somapacitan and analysis by high-performance liquid chromatography with radiochemical detection, seven somapacitan-related metabolites were detected in plasma from male rats, of which six were seen in plasma from female rats. The three most abundant metabolites (M1, M2 and M3) were structurally identified from liquid chromatography and mass spectrometry data, and a fourth metabolite (P1) was characterised from its specific retention time (lacking retention to the stationary phase) in plasma analysis with reversed-phase liquid chromatography and radiochemical detection.The metabolites were products from proteolysis of the peptide backbone in somapacitan. A deamidation product of the M1 metabolite (M1B) was also identified. Following multiple, twice-weekly dosing for 4 weeks, somapacitan was the principal plasma component up to 36 h after dosing. After 36 h, metabolites M1+M1B were the most abundant plasma components. Pharmacokinetic models were developed for somapacitan and metabolite P1 and used for steady-state assessment in the rat.Comparison of our data generated from rats with data from the parallel human study demonstrated that the most abundant metabolites were present in rats at higher levels than in humans. This study has provided non-clinical safety data that contribute to an overall safety assessment of somapacitan.

Lack of effects on female fertility and prenatal and postnatal offspring development in rats with BNT162b2, a mRNA-based COVID-19 vaccine

BNT162b2 is a vaccine developed to prevent coronavirus disease 2019 (COVID-19). BNT162b2 is a lipid nanoparticle formulated nucleoside-modified messenger RNA (mRNA) encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein locked in its prefusion conformation. A developmental and reproductive toxicity study was conducted in rats according to international regulatory guidelines. The full human BNT162b2 dose of 30 μg mRNA/dose (>300 times the human dose on a mg/kg basis) was administered intramuscularly to 44 female rats 21 and 14 days prior to mating and on gestation days 9 and 20. Half of the rats were subject to cesarean section and full fetal examination at the end of gestation, and the other half were allowed to deliver and were monitored to the end of lactation. A robust neutralizing antibody response was confirmed prior to mating and at the end of gestation and lactation. The presence of neutralizing antibodies was also confirmed in fetuses and offspring. Nonadverse effects, related to the local injection site reaction, were noted in dams as expected from other animal studies and consistent with observations in humans. There were no effects of BNT162b2 on female mating performance, fertility, or any ovarian or uterine parameters nor on embryo-fetal or postnatal survival, growth, physical development or neurofunctional development in the offspring through the end of lactation. Together with the safety profile in nonpregnant people, this ICH-compliant nonclinical safety data supports study of BNT162b2 in women of childbearing potential and pregnant and lactating women.

The Evolution of SEND at AstraZeneca

• Insight in to AstraZeneca's business critical project to become SEND compliant in an accelerated timeframe. • Successful implementation of SEND software and processes to create in-house datasets and manage CRO data. • Over 169 CRO SEND packages reviewed, contributing to 31 submissions to the US FDA, including interim and draft datasets. • Internal quality checks were developed to mitigate variation in SEND quality. • Standardised format and controlled terms have enabled visualisation and warehousing of nonclinical safety data.

Industry experiences with immune-mediated findings in biotherapeutic nonclinical toxicology studies

With the growth of monoclonal antibodies and other proteins as major modalities in the pharmaceutical industry, there has been an increase in pharmacology and toxicity testing of biotherapeutics in animals. Animals frequently mount an immune response to human therapeutic proteins. This can result in asymptomatic anti-drug antibody formation, immune complexes that affect drug disposition and/or organ function such as kidney, cytokine release responses, fatal hypersensitivity, or a range of reactions in between. In addition, an increasing number of oncology therapeutics are being developed that enhance or directly stimulate immune responses by a variety of mechanisms, which could increase the risk of autoreactivity and an autoimmune-like syndrome in animals and humans. When evaluating the risk of biotherapeutics prior to entering the clinic, the nonclinical safety data may include any of these responses and it is critical to understand whether they represent a safety liability for humans. The DruSafe Leadership group of the IQ Consortium conducted a survey of industry to understand sponsors' experiences with these immune reactions in nonclinical studies related to both immunogenicity and pharmacologically-mediated immune perturbations. The survey covered what pathways were affected, how the immune responses were presented, how the company and health authorities interpreted the data and whether the immune responses were observed in the clinic. Additionally, the survey gathered information on association of these findings with anti-drug antibodies as well as sponsor's use of immunogenicity predictive tools. The data suggests that the ability of a biotherapeutic to activate the immune system, intended or not, plays a significant role on characteristics of the response and whether theys are translatable.

Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia.

Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells with surface expression of FLT3 protein in vivo, data from cynomolgus monkey toxicology studies with 2 bispecific T-cell engager molecules targeting FLT3 were leveraged; findings were consistent with the targeted killing of bone marrow cells expressing cell surface FLT3. Potential AMG 553-induced cytotoxicity was assessed against a wide range of normal human primary cells and cell lines; cytotoxicity was observed against FLT3-positive AML cell lines and a percentage of primary bone marrow CD34+ cells. In conclusion, the nonclinical safety data suggest that AMG 553 can target FLT3 protein on AML cells, whereas only affecting a percentage of normal hematopoietic stem and progenitor cells, supporting clinical development.

QT assessments in oncology drug development and related labels.

e14127 Background: A thorough QT (TQT) study, designed to evaluate whether a new drug excludes a small mean increase in the QTc interval (i.e., > 10 ms) which is considered to have low proarrhythmic risk, is often not feasible for oncology drugs. Alternative designs that assess the QTc changes in cancer patients are used to exclude large mean increases (i.e., > 20 ms) for drugs where the expected benefit outweighs the small proarrhythmic risk. A retrospective analysis was conducted to evaluate QT study designs and the consistency of QT labeling for oncology drugs. Methods: This analysis included FDA approved oncology drugs with QT studies reviewed by CDER’s Interdisciplinary Review Team as of 10/01/2019. Information collected included the clinical study design (i.e., TQT, alternative designs such as a sub-study in a Phase 2/3 trial), primary analysis (i.e., central tendency or concentration-QTc [CQT] analysis), QT findings at the therapeutic dose (i.e., the mean [M] and the upper bound of 90% confidence interval [UCI] of QTc changes), supportive data (i.e., nonclinical cardiac safety data, if applicable), conclusion of the QT assessment, and labeling statements in Section 12.2 (Pharmacodynamics) and Section 5 (Warnings & Precautions) of the product labels. Baseline QTc values in these alternative studies were compared to those in TQT studies across different therapeutic areas. Results: The analysis included 72 oncology drugs. The mean baseline QTc value is 411.2 ms in male patients (n = 6951) and 394.6 ms in male healthy volunteers (n = 22288), and 414.3 ms in female patients (n = 6412) and 408.8 ms in female healthy volunteers (n = 15682). Alternative study designs were used for 63 (87.5%) drugs while TQT study was only used for 9 (12.5%) drugs. CQT was used as the primary analysis for 11 (15.3%) drugs. Among the 72 product labels, 8 labels do not have QT information in Section 12.2 and 9 labels inconsistently describe the results of an alternative study. Warnings and Precautions for QT Prolongation in Section 5 of the labels were triggered by positive signals in the QT assessment or clinical trial safety monitoring experience. Conclusions: Cancer patients had higher QTc and less sex difference at baseline than healthy volunteers. QT labeling consistency in Section 12.2 could be improved by standardizing the description of study results based on QT study designs. Disclaimer: The contents reflect the views of the authors and should not be construed to represent the FDA's views or policies.

Current and future approaches to nonclinical cardiovascular safety assessment

Our goal is to accurately predict all types of cardiovascular events in patients utilising nonclinical cardiovascular safety data. In the past two decades, cardiovascular safety science has primarily focused on events associated with the electrocardiogram. Broadening out to other cardiovascular parameters, we share real-life case studies that highlight our progress towards improved and better-informed project progression based upon use of disease models, mechanism-based translation and structure-function relationships. To fulfil this goal, further advances in patient-relevant humanised models will be required to enable cardiovascular safety science to keep pace with the ever-changing landscape of novel therapeutic paradigms.

Nonclinical safety assessment of AMG 553, an investigational anti-FLT3 CAR-T therapy.

7032 Background: FMS-like tyrosine kinase 3 (FLT3) is a tyrosine-protein kinase involved in hematopoiesis. In acute myeloid leukemia (AML), higher FLT3 transcript levels, independent of the presence of FLT3 mutations, correlate with higher leukocyte counts and higher degrees of bone marrow infiltration by leukemic cells. FLT3 protein is detectable on the cell surface of more than 80% of leukemia isolates from adult AML patients whereas FLT3 mutations are present only in approximately one third of patients. AMG 553 is a novel, investigational, adoptive cellular immunotherapy for the treatment of relapsed refractory AML, consisting of autologous T cells genetically modified ex vivo to express a transmembrane chimeric antigen receptor (CAR) to target FLT3 protein on the surface of AML cells irrespective of FLT3 mutational status. Methods: The nonclinical safety evaluation of AMG 553 includes assessment of FLT3 expression in normal tissues; in vitro assessment of cytotoxicity against human cells with or without FLT3 expression; toxicology studies in cynomolgus monkeys administered autologous T-cells transduced with an anti-FLT3 CAR or administered anti-FLT3 bi-specific T-cell engager (BiTE) antibodies. Results: Assessment of FLT3 expression in normal tissues indicates that FLT3 protein is detected on the cell surface of a subpopulation of human bone marrow hematopoietic stem and progenitor cells; expression in other tissues is cytoplasmic and not anticipated to be accessible to AMG 553. AMG 553-induced cytotoxicity was only observed in a percentage of primary bone marrow CD34+ cells. There was no evidence of CAR-T cell-mediated toxicity, expansion, or persistence in cynomolgus monkeys likely due to restricted cell surface FLT3 protein expression in healthy animals which demonstrates the limited value of such studies for this target. All findings in toxicology studies with anti-FLT3 BiTEs were consistent with the targeted killing of cells expressing FLT3 on the plasma membrane. Conclusions: The nonclinical safety data support AMG 553 as a novel therapeutic to target FLT3 protein on AML cells irrespective of FLT3 mutational status, while only affecting a percentage of normal hematopoietic stem and progenitor cells.

Development of pain therapies targeting nerve growth factor signal transduction and the strategies used to resolve safety issues.

Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpected joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in animals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learnings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety.

Carcinogenicity assessment of the Hedgehog pathway inhibitor, vismodegib in Tg.rasH2 mice and Sprague-Dawley rats

Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0.1-fold and ≥0.6-fold, respectively, of the steady-state exposure (AUC0–24h) of the recommended human dose. No malignant tumors were identified in either species. Overall, the totality of pharmacology and nonclinical safety data (lack of genotoxicity, in vitro secondary pharmacological binding, and immunoregulatory effects, and limited effects on the endocrine system) suggests that the development of the benign hair follicle tumors may be related to pharmacologically-mediated disruption of hair follicle morphogenesis, although the exact mechanism of tumorigenesis is unclear. Hair follicle tumors have not been reported in vismodegib-treated patients. The relevance of this finding in rats to patients is uncertain.

How Much Nonclinical Safety Data Are Required for a Clinical Study in Ophthalmology?

Planning the nonclinical development program for an ophthalmic product requires first an understanding of how the drug will be used in the clinic-topical, injected, relatively short duration of testing, chronic testing, and what is already known about the drug. In some cases, when the drug is being repurposed or reformulated to allow for the same or different route of ocular administration, the requirements will be very different than for a first-in-class, novel drug. In general, ICH guidances have relatively little direction with respect to ophthalmology. Sponsors are encouraged to make use of meetings with the FDA, particularly for unusual situations, given this lack of specific ICH direction. In this article we describe the range of nonclinical studies required in our experience-pharmacology, pharmacokinetics and toxicology, with attention to the stage of clinical development and duration of treatment. As well, we discuss the coordination of effort with pharmaceutics researchers on drug substance and drug product.

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report

This is a report on a 2-day joint meeting between the British Society of Toxicological Pathology (BSTP) and the Safety Pharmacology Society (SPS) held in the UK in November 2013. Drug induced adverse effects on the cardiovascular system are associated with the attrition of more marketed and candidate drugs than any other safety issue. The objectives of this meeting were to foster inter-disciplinary approaches to address cardiovascular risk assessment, improve understanding of the respective disciplines, and increase awareness of new technologies. These aims were achieved. This well attended meeting covered both ‘purely functional’ cardiovascular adverse effects of drugs (e.g., electrophysiological and haemodynamic changes) as well as adverse effects encompassing both functional and pathological changes. Most of the presentations focused on nonclinical safety data, with information on translation to human where known. To reflect the content of the presentations we have cited key references and review articles.

Abstract 1752: Nonclinical safety and pharmacokinetics of Sym004: A synergistic anti-EGF receptor antibody mixture

Abstract Epidermal growth factor receptor (EGFR) is a well validated oncology target for monoclonal antibodies (mAb's). Symphogen is developing a novel and more efficacious anti-EGFR therapy to treat cancer patients with EGFR-dependent tumors. Sym004 is a recombinant antibody product consisting of a 1:1 mixture of two chimeric IgG1 mAb's targeting non-overlapping epitopes of EGFR. Preclinical proof-of-concept studies have shown that the Sym004 mixture is superior to existing anti-EGFR mAb's currently in clinical use (1). The nonclinical safety data of Sym004 are presented. The studies were designed to evaluate toxicity and pharmacokinetics of Sym004 as well as the individual antibodies comprising Sym004. No apparent accumulation was observed upon weekly dosing of Sym004 to non-human primates for eight consecutive weeks, whereas, a prolonged half life and accumulation were noted for both of the individual antibodies if these were administered alone. Weekly administration of Sym004 to non-human primates was well tolerated although dose limiting toxicity was observed in a dose-range-finding toxicology study. In a head-to-head comparison with the licensed anti-EGFR mAb, cetuximab (Erbitux®), weekly administration of Sym004 did not induce any distinct or novel adverse findings in the animals. However, and in accordance with the enhanced pharmacological profile of Sym004, an accelerated onset of anticipated anti-EGFR-mediated effects (skin rash and liquid faeces) was observed compared to cetuximab. None or only minor effects were observed in the animals treated with the individual antibodies comprising Sym004. All experimental observations, except a single case of rash, showed reversibility during the 4-week treatment free recovery period. In tissue cross reactivity studies, Sym004 had a staining pattern similar to cetuximab in a full tissue panel from both human and non human primates. In conclusion, Sym004 is considered to be safe, and the nonclinical safety data supported the initiation of the currently ongoing Phase I/II trial. 1. Pedersen MW et al. Cancer Res; 70(2) January 15, 2010 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1752. doi:10.1158/1538-7445.AM2011-1752

Abstract 2656: Ethical considerations in evaluating targeted anticancer drug candidates in healthy volunteers – safety and risk assessments

Abstract Background: Biopharmaceutical and clinical pharmacology studies are typically conducted in healthy volunteers with few exceptions, such as for anti-cancer drugs. Traditional chemotherapies are too toxic to be studied in healthy volunteers. However, even for targeted anti-cancer drugs that often have mild to moderate toxicity profiles that don't expose healthy volunteers to extra risks, studies have rarely been conducted in the population. Navitoclax (ABT-263) is an orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in several Phase 1 studies in cancer patients. The need to evaluate multiple formulations and the difficulty in recruiting patients made it critical to evaluate the possibility of recruiting healthy volunteers to support formulation development. Methods: Nonclinical safety data and clinical data from Phase 1 studies in cancer patients were evaluated extensively by a multi-functional team to determine the subject inclusion criteria, the maximally recommended dose, and a risk management plan. The protocol, safety evaluation and recommendations were reviewed and approved by the Drug Safety Evaluation Committee at Abbott. Results: In nonclinical studies, navitoclax was not genotoxic; it caused testicular toxicity, and dose-dependent thrombocytopenia (TCP) and lymphopenia, which are all expected from inhibition of Bcl-2 targets. In Phase 1 single-agent studies in cancer patients, the most frequent, dose-limiting toxicity was TCP. Nonclinical safety data supported a single dose ≤30 mg navitoclax in healthy volunteers. Furthermore, evaluation of clinical safety data, TCP dose-response and lymphopenia data supported administration of a navitoclax dose ≤100 mg in a single-dose, multiple-period crossover study in healthy female volunteers of non-childbearing potential. Two relative bioavailability (BA) studies in healthy female subjects with non-child bearing potential (N=12 each) were conducted sequentially and successfully, the first at a 25 mg dose and the second at a 100 mg dose. Compared to similar studies in cancer patients, on average, each study in healthy volunteers saved 3.5 months. A well-informed decision to select a Phase 2 formulation was made on the basis of limited data in patients and high-quality data in healthy volunteers. Conclusion: The case study illustrated that targeted anti-cancer drugs can be studied in healthy volunteers with careful assessment of both clinical/nonclinical data and by putting appropriate risk management plan in place. When feasible, BA studies in healthy volunteers avoid delaying potentially active treatments to cancer patients. Such studies also provide high-quality bioavailability data in a timelier and inexpensive fashion compared to similar studies in cancer patients, and they don't impose risks beyond the minimal levels that are standard in healthy volunteer studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2656. doi:10.1158/1538-7445.AM2011-2656

Non-clinical Post-Marketing Commitments for newly licenced pharmaceuticals

There are clear minimum requirements for non-clinical (toxicology) studies which are needed prior to human exposure to a potential new pharmaceutical and additional studies are needed in an ongoing manner to support clinical development and marketing [ICH, 2009. ICH M3(R2) Non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95). Adopted June 2009, effective December 2009.] The pharmaceutical industry is under increasing pressure to reduce costs and reduce, refine and replace the use of animals, as far as possible. Hence any increase in regulatory requirements for non-clinical safety data could have a significant impact both on the economic and ethical considerations of drug development. It is, therefore, of interest that further non-clinical studies are required by the Regulatory Authorities for a small but increasing proportion of drug product applications at the marketing approval/data review stage. These studies are known as Post-Marketing Commitments (PMCs). Available information on non-clinical PMCs was collated using drug product information from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA), resulting in a combined data set of 162 studies. Non-clinical PMCs comprised 9.8% and 6.5% of total PMCs for products authorised by the EMEA (Centralised Procedure) and FDA, respectively. Non-clinical PMCs increased with increasing date of approval, despite increased regulatory information available to guide Applicants. Furthermore, the increase reflected an increased proportion of applications with non-clinical PMCs, not an increase in overall numbers of applications. There was no clear correspondence between the publication dates of relevant guidelines and increases in specific non-clinical PMC study types, when the data were analysed by non-clinical study category, target population/indication or compound class. Possible exceptions were some photocarcinogenicity and juvenile toxicity studies. For many non-clinical PMCs relevant guidance existed in the concurrent regulatory information. Hence these PMCs could have been predicted based on known pharmacology, indication and route/duration of administration. Conclusion. Some increases in non-clinical PMCs were attributed to increased non-clinical data requirements from the Regulators. However, strategic deferrals by the Applicant, unintended omissions due to poor regulatory intelligence and overall differences in risk perception between Regulators and Applicants account for a significant proportion of the non-clinical PMCs.