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Report on Pharmaceutical Industry Survey of Nonclinical Statistics resources
No full textThe Nonclinical Biostatistics Leadership Forum (NCBLF) has been conducting resource surveys of Nonclinical Statistics (NCS) departments across a range of pharmaceutical companies. The purpose of these surveys is to track changes in nonclinical statistics resource allocations within the industry, and to identify emerging organizational trends. The intention is to help senior managers asses their organizational allocations relative to the industry averages and ranges. In addition, the surveys provide insights into the industry's current human resource landscape and support decision-making processes among companies with nonclinical statistics groups
Mechanisms of tumor resistance to clinically relevant KRASG12C and SHP2 inhibitor combination in preclinical models of non-small cell lung cancer
No full textAlthough KRASG12C inhibitors have shown clear clinical activity in patients with KRAS G12C mutated NSCLC and other solid tumor malignancies, the depth and durability of responses is limited by multiple mechanisms of treatment-emergent resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155. We evaluated the duration of response in a mouse model to JDQ443 ± TNO155 (± the PI3Ka inhibtor alpelisib and/or the CDK4/6 inhibitor ribociclib), and the genetic mechanisms associated with loss of response to a KRASG12C/SHP2 inhibitor combination. Antitumor responses to JDQ443 ± TNO155, with or without additional alpelisib and/or ribociclib, were assessed in cell-derived mouse xenograft models derived from the KRASG12C-mutant non-small cell lung cancer (NSCLC) line LU99. Single-agent tumor regression by JDQ443 at clinical relevant doses of 100 mg/kg in the LU99 model was on average 2 weeks and was increasingly extended (but not prevented) by JDQ443 dual-agent, triple or quadruple on-pathway combinations. Growth resumption was accompanied by increased KRASG12C gene copy number and expression. Adaptive mechanisms of resistance to KRASG12C/SHP2 co-inhibition were explored by functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles. CRISPR screening in a panel of 5 KRAS G12C-mutated cell lines identified sensitizing and rescuing genetic interactions to a KRASG12C/SHP2 inhibitor combination; FGFR1 was the strongest sensitizer, and PTEN the strongest rescuer. Consistent with this, KRASG12C/SHP2 inhibitor antiproliferative activity was strongly enhanced by PI3K inhibitors. Amplification of KRAS G12C itself and alterations of the MAPK/PI3K pathway were the predominant mechanisms of resistance to KRASG12C/SHP2 co-inhibition in this model. Biological nodes identified by CRISPR screening might provide starting points for effective combination treatment approaches
Transcriptional profiling of hepatocytes infected with the replicative form of the malaria parasite Plasmodium cynomolgi.
No full textThe zoonotic simian parasite Plasmodium cynomolgi develops into replicating schizonts and dormant hypnozoites during the infection of hepatocytes and is used as a model organism to study relapsing malaria. The transcriptional profiling of P. cynomolgi liver stages was previously reported and revealed many important biological features of the parasite but left out the host response to malaria infection.Previously published RNA sequencing data were used to quantify the expression of host genes in rhesus macaque hepatocytes infected with P. cynomolgi in comparison to either cells from uninfected samples or uninfected bystander cells.Although the dataset could not be used to resolve the transcriptional profile of hypnozoite-infected hepatocytes, it provided a snapshot of the host response to liver stage schizonts at 9-10 day post-infection and identified specific host pathways that are modulated during the exo-erythrocytic stage of P. cynomolgi.This study constitutes a valuable resource characterizing the hepatocyte response to P. cynomolgi infection and provides a framework to build on future research that aims at understanding hepatocyte-parasite interactions during relapsing malaria infection
People of TM: Video of Sarah Hemsley
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featruing stories of people in TM. No IP related content
People of TM: Video of Nasri Abdallah
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featruing stories of people in TM. No IP related content
A First-in-Human, Phase 1, Multicenter, Open-label, Dose-Escalation Study of PCA062, an Antibody-Drug Conjugate Targeting P-Cadherin, in Adult Patients with Solid Tumors
No full textBackground: This first-in-human (FIH), phase 1, multicenter, open-label study was conducted to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy, and to establish the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of PCA062 in patients with solid tumors.
Patients and methods: Adult patients with any solid tumor type and having a documented P-cadherin-positive tumor were enrolled; exceptions to P-cadherin positivity requirement were head and neck squamous cell carcinomas (HNSCC) and esophageal squamous cell carcinoma (ESCC). Dose escalation was guided by an adaptive Bayesian logistic regression model with escalation with overdose control to determine the MTD/RDE.
Results: Forty-seven patients were treated at 10 different dose levels of PCA062, ranging from 0.4 to 5.0 mg/kg Q2W administered as a 1-hour intravenous infusion. All enrolled patients discontinued the treatment; primary reason for discontinuation was progressive disease (78.7%). All 47 patients experienced at least one AE, of which 32 patients had a grade ≥3 AE and 37 patients experienced AEs suspected to be study drug related. The MTD of PCA062 was 3.6 mg/kg Q2W and thrombocytopenia was reported as a DLT that was attributed to the known toxicities of the DM1 payload with no P cadherin-related toxicities. PK was proportional, and no patients developed antidrug antibodies, suggesting adequate exposure at the doses tested. One patient out of 47 achieved a partial response and there was no correlation between tumor P-cadherin expression and clinical efficacy.
Conclusions: Due to limited anti-tumor activity at the maximally tolerated dose level, Novartis has terminated clinical development of PCA062 (NCT02375958)
Lipid21: Complex Lipid Membrane Simulations with AMBER.
No full textWe extend the modular AMBER lipid force field to include anionic lipids, polyunsaturated fatty acid (PUFA) lipids, and sphingomyelin, allowing the simulation of realistic cell membrane lipid compositions, including raft-like domains. Head group torsion parameters are revised, resulting in improved agreement with NMR order parameters, and hydrocarbon chain parameters are updated, providing a better match with phase transition temperature. Extensive validation runs (0.9 μs per lipid type) show good agreement with experimental measurements. Furthermore, the simulation of raft-like bilayers demonstrates the perturbing effect of increasing PUFA concentrations on cholesterol molecules. The force field derivation is consistent with the AMBER philosophy, meaning it can be easily mixed with protein, small molecule, nucleic acid, and carbohydrate force fields
Formulated oligonucleotide APIs: Regulatory aspects
No full textFormulated oligonucleotide APIs: Regulatory aspects
Authors
Christian Wetter (Roche), Chris Chorley (Biogen), Corrine Curtis, (Janssen), Nicole del Canto (Biogen), Gair Ford (AstraZeneca), Jenny Franklin (Ionis), Cinzia Gazziola (Roche), Michael T. Jones (Pfizer), Judy Lee (Novartis), Arnold McAuley (Amgen), Floor Saraber (Janssen), Audrey Scott (GSK), Janine Tom (Amgen)
The European Pharma Oligonucleotide Consortium (EPOC) [1] is a collaboration between multiple pharma companies with the aim of sharing chemistry, manufacturing, and control (CMC) knowledge as well as strategies to enable harmonization of oligonucleotide development and commercialization. The objective of the consortium is to publish science-based recommendations for the development of oligonucleotide therapeutics in a series of technical and regulatory white papers, drawing on its collective subject matter expertise and complementing that in the literature and guidelines. This public body of prior knowledge endeavors to serve as a reference for industry practice and help establish development principles for oligonucleotides. The consortium aims at being proactive and inclusive, and it anticipates initiating wider discussion on oligonucleotide CMC practice and policy, thus expediting access to these potentially life changing medicines.
Introduction
The concept of formulated APIs (also called API mixes by EMA) for oligonucleotides was described by Muslehiddinoglu et al in 2020 [2]. The publication discusses technical aspects related to formulated oligonucleotide APIs, such as their stability, manufacture, microbial control, packaging and storage. Various criteria such as supply chain, scale, dosage strengths, etc., may influence the best choice of the API form – resulting in use of either a solid API, an API in water, or a formulated API. The formulated API may be ready-to-fill, or may require further dilution or addition of excipients. Muslehiddinoglu et al left regulatory aspects out of scope of the published article; therefore, the present communication aims to complement the first manuscript and discuss relevant regulatory and GMP aspects of a formulated API. In addition, this article aims to initiate interaction and discussion with regulators to promote the use of the formulated API approach in oligonucleotide drug manufacture. The authors hope to contribute to EMA’s initiative ‘Regulatory Science to 2025 – Strategic Reflection’, in “developing expertise in novel manufacturing technologies”, “identifying bottlenecks”, and “addressing regulatory challenges” that could be overcome by “modernizing relevant regulations and guidelines”. The authors would like to propose solutions for “promoting a flexible and fit-for-purpose approach in application of GMP”, and “supporting the development of greener manufacturing technologies in line with EU’s ‘Strategic Approach to Pharmaceuticals in the Environment’” [3].
Problem statement
Oligonucleotides are typically synthetically derived and can be isolated as a solid, in water or as formulated APIs. While available guidelines generally provide flexibility with respect to the designation of a formulated API as an API, EMA and Health Canada have set a more restrictive framework in which API-excipient mixtures can be designated as APIs in exceptional cases only. Typically API-excipient mixtures have to be designated as drug product intermediates. A guideline review is provided below.
When designating a formulated API as a drug product intermediate, the manufacturers have to fulfill drug product GMP standards for the manufacturing steps converting the API into a formulated API. The requirements for clean areas as defined in ISO 14644-1 [43] and the EU guideline to GMP, Annex 1 [5] apply. This is typically not possible in facilities designed for manufacture of oligonucleotide APIs.
Further, the designation of a formulated API as a drug product intermediate poses challenges around the shelf-life definition of the oligonucleotide drug product. Per standard requirements for chemical products, the shelf-life is defined by the start of the drug product manufacturing process, i.e., the mixing of the API with other product ingredients [6]. Storage of the formulated API for a prolonged period before further manufacture and/or filling would thereby shorten the shelf-life of the finished product upon release for market distribution.
Similar challenges have been identified when using co-processed APIs [7].
Current regulatory landscape
ICH
In the ICH Q7 [8] glossary, an API is defined as “any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product (...)”. As per ICH Q7 Q&A [9], “when a mixture is classified in the regulatory filing as an API in a region or country in which it is used in a drug product, ICH Q7 should be applied to the manufacturing of these mixtures [ICH Q7, Section 1.2, 20 – see Glossary for definition of ‘API’]”.
As per ICH Q6B [10], for biological products, the drug substance (bulk material) “may also contain excipients including other components such as buffers”.
WHO
The WHO Annex 3 on ‘Pharmaceutical development of multisource (generic) finished pharmaceutical products – points to consider’ from 2012 [11] defines an API as “Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form”.
EMA
In their Q&A document [12] the CHMP quality working party (QWP) defines an API mix as a “mixture of an API with one or more excipients”, and “the manufacture of an API mix is considered to be the first step of the manufacture of a finished product”. Further, “in certain circumstances, i.e. stability or safety reasons, the applicant can submit data on such a mixture under part 3.2.S (...).” However, “In case of an API mix prepared due to workability purposes or reasons other than safety and stability, the manufacturing steps from the addition of the excipient to the API should be described in the appropriate part of CTD 3.2.P. In addition the steps following addition of the excipient must be conducted in accordance with GMP Part I and an appropriate manufacturing authorisation”. Moreover, “a justification based only on workability reasons, e.g. to ease handling when processed into final dosage form, is not acceptable. Toxicological considerations (e.g. very potent drugs) fall under workability reasons and are not accepted as justifications.”
Canada
In their quality (chemistry and manufacturing) guidance, Health Canada states the following related to the start of drug product manufacture and possible exceptions based on safety and stability reasons [13]. The expectations are aligned with the QWP Q&A discussed above, and Health Canada encourages a discussion with their pre-market approval bureau/office.
That first processing step of the drug substance in the presence of any other substance would be considered a drug product manufacturing activity, subject to Part C, Division 2 of the Food and Drug Regulations, and would define the date from which the expiry date for the drug product would be established. (…) Sponsors having situations that might be an alternative to the above interpretation (e.g. inability to isolate the drug substance in a pure and stable form or mixing with excipients for safety or stability purposes, e.g. nitroglycerin, cholecalciferol) should discuss their case and scientific justification in advance with the pre-market approval bureau/office.”
Proposed path forward
The authors recognize that two elements need to be addressed to enable the designation of formulated APIs as APIs: First, designation of an API-excipient mixture as an API should not be justified solely by the benefits from a usability perspective [12], [13]. Second, applicants should address concerns related to the GMP standards of API manufacturing facilities [4], [5]. The following proposed path forward is intended to address these two hurdles.
For biological products, the use of formulated APIs is a generally accepted common practice, originally mandated by the stability behavior of the proteins. Oligonucleotides are generally stable in formulation; however, certain factors can impact stability. For example, the pH of the formulation strongly influences oligonucleotide degradation [14] and the addition of buffers to an oligonucleotide API can have a stability benefit. For example, Poecheim et al. showed in 2018 that buffered solutions of a model oligonucleotide API show superior stability behavior compared to the aqueous solution [15]. Furthermore, while a solid API is typically stable when stored at -20°C, the use of a buffered solution may allow storage and shipment at 2°C to 8°C or even at room temperature, which is of high relevance for oligonucleotides manufactured at a larger scale. The stability promoting properties conferred by a buffered formulation support use of formulated oligonucleotide APIs as a meaningful option.
In order to address the requirements defined in the QWP Q&A, stability data should be generated for both the API (in solid state or in water) and the formulated API under ICH long-term conditions for up to 6 months. If it can be demonstrated that the formulated API provides superior or equivalent stability behavior, the use of formulated API should be permissible. In case the stability behavior is equivalent, the authors propose that additional aspects can be considered for justification, as detailed below.
If the API is isolated as a solid, the solid API can be used for the stability comparison with the formulated API. If the API is processed further as an aqueous solution, without isolation, the API in water can be used for comparison with the formulated API.
Oligonucleotide APIs in water should not be considered as API mixtures. The oligonucleotide in water is isolated as such from the API manufacturing process, and hence water is not added as a first (and new) excipient to the final API. An oligonucleotide API in its solid state can contain up to 20% of water, and water is an integral part of the nucleic acid structure [16]. Therefore, an oligonucleotide API can be considered as an amorphous hydrate [17].
Indeed, this concept can be extended further. Downstream processing following oligonucleotide synthesis may afford an API in a solution containing so called processing salts (e.g., phosphates), which are present due to their necessity in the process. Examples could include use of a buffer to control pH, or utilization of salts from a previous chromatographic step to maintain adequate flux during UF/DF. If these components are also required as part of the drug product formulation, it should not be necessary to remove them from the API in solution, and they would consequently be part of the final composition. In such cases, an API with processing salts in water, requiring further compounding and/or dilution at the drug product stage, can be designated as an API, and not a formulated API. This is justified because the API, even if lyophilized, would not be isolated without these processing salts.
In addition to the stability and formulation considerations detailed above, a comprehensive control strategy should be implemented. The control strategy will mitigate any potential risk inherent to the management and addition of excipients as part of the formulated API manufacturing process. The elements of the control strategy include design of the manufacturing process (e.g. closed or controlled manufacturing systems), design of manufacturing facilities and utilities, and implementation of appropriate quality systems (“fit-for-purpose approach in application of GMP” [3]). They are complemented with risk assessments and implementation of risk mitigation activities (“use of risk-based approaches to manufacturing processes and control strategies” [3]), and evaluation of process validation results to ensure sufficient controls are in place. In totality, the control strategy demonstrates delivery of safe and efficacious product. In detail:
• Manufacturing facilities should be used that allow handling of excipients under appropriate GMP standards.
• Purification and final dispensing operations are typically carried out in a multi-product facility with established product segregation procedures. The facility design and controls developed should support the manufacture of low bioburden formulated APIs.
• Microbial controls incorporated into the process should assure consistent delivery of low bioburden, low endotoxin formulated API appropriate for further parenteral drug product processing. The microbial control strategy should be risk-based and include elements of facility design, process controls, personnel requirements, environmental and utility monitoring systems and procedural responses to contamination.
• Excipients used in the manufacture of drug substance could be controlled as critical raw materials. Following the standards defined in EU Directive 2001/83/EC, Annex I, Section 3.2.2.4 [18], “the specifications (of the used excipients) and their justifications shall be detailed. The analytical procedures shall be described and duly validated”. The used excipients should be handled in a facility offering an appropriate clean area concept as per ISO [4] and EU guidance on GMP [5].
• In compliance with the EMA guideline on water for pharmaceutical use, dated 2020, [19], it is proposed to use water for injection (WFI) starting with the UF/DF of the formulated oligonucleotide API, as the WFI will remain in the final medicinal product. The steps prior to UF/DF need not use WFI.
• API manufacturing process risk assessments should cover the whole process down to the formulated API: Risk assessments should show no high-risk parameters in the API manufacturing process. The downstream process must be adequately characterized and controlled to consistently produce API meeting its quality targets.
• The Quality Management System (QMS) should support all operations associated with raw material receipt/inspection, production, packaging, labeling, Quality Control testing, product disposition, release, storage, and distribution of GMP materials.
• Process validation of the formulated API manufacturing process must be performed to ensure the process consistently meets its quality targets.
The requirements for formulated APIs detailed above will provide sufficient controls to permit their production at the site of API manufacture.
The authors would like to comment on the fact that a justification for using formulated APIs based only on workability reasons, e.g., to ease handling prior to processing into the final dosage form, is not currently accepted by EMA. Specifically, advantages of a formulated API, such as reduced environmental impact (“support the development of greener manufacturing technologies” [3]) and security of supply could also be considered when justifying the chosen formulated API approach. In addition, if the use of a formulated API affords a demonstrable benefit to the quality of the API and/or drug product, factors other than stability could be considered as appropriate justification. These could include improvements in purity or yield, or introduction of innovative manufacturing processes enhancing the state of the art.
In general, lyophilization is defined as a stabilizing process in which the sample is frozen followed by a reduction of the solvent content by sublimation and then by desorption to values that will no longer allow biological growth or chemical reactions [20]. If microbial growth can be controlled using measures discussed above, and lyophilization is not needed for suppression of degradation, then lyophilization essentially represents additional handling steps and a stress to the API. It is furthermore a highly energy-consuming unit operation. Unless there are clear benefits for transportation and supply chain (see detailed discussion by Muslehiddinoglu et al [2]), skipping the lyophilzation step is in alignment with the aspiration to promote greener manufacturing approaches [3].
As noted in the QWP Q&A [12], “for APIs of an explosive nature the use of an API mix may be justified, and an appropriate explanation is considered sufficient”. Therefore, if powder explosivity data on the API demonstrate a potential safety hazard to pharmaceutical operators, it may be necessary to keep the API in solution during the process, leading to either a partially or fully formulated API, or else an API in water or containing processing salts, as the most pragmatic solution.
Some additional selected aspects are briefly discussed below to promote further alignment.
Regulatory documentation
The location of formulated API-specific information in module 3 of the CTD is provided in Table 1 below. Other locations in the application may be possible in alignment with ICH M4Q [21].
Table 1: Formulated API-specific information and location in module 3 of CTD
CTD section Content Comment
3.2.S.2.2 Description of formulated API manufacture: Oligonucleotide (solid phase) synthesis, cleavage, purification, potential coupling to obtain conjugates, ultrafiltration/diafiltration, concentration, potential annealing, concentration, mixing with excipients Used processing salts (remaining in the drug product) and excipients should be listed in 3.2.P.1 [12]. Their contribution to the drug product composition should be provided.
3.2.S.2.3 Specifications of the materials used to manufacture the formulated API should be provided in this section. This includes the used excipients. Used processing salts and excipients and reference to relevant standards will also be provided in 3.2.P.1
3.2.S.2.6 Justification of formulated API approach, including comparative stability data demonstrating favorable behavior of formulated API compared to API in solid state/in water. Other quality-based justifications (e.g., improvement in overall purity of final drug product) could also be included in this section.
Summary of API manufacturing process risk assessments and process characterization studies to ensure process robustness, including API formulation consistency and microbial attributes. Extractable and leachable substances (if in bags), endotoxin clearance, excipient selection, and API container closure integrity.
Other aspects, such as environmental impact, safety, supply security benefits
Safety-based if this is the principal justification for the API mix. Tight linkage with discussion provided in 3.2.P.2
3.2.S.7.x Re-test period, storage conditions and stability data of the formulated API Information on the formulated API (which is the designated API). Comparative stability data is provided in 3.2.S.2.6
3.2.P.1 Composition, including processing salts and excipients added to the drug substance when manufacturing the formulated API Processing salts and excipients used in the manufacture of the formulated API contribute to the composition of the finished product and should be listed on the label
3.2.P.2.1 Justification of choice and level of excipient Discussion expected to be linked to discussion in 3.2.S.2.6 (e.g., for selected buffers)
When a partially formulated API is used, the choice and level of excipient used in the drug product manufacture should be justified.
3.2.P.2.5 Microbial attributes and control
Microbial attributes discussion in 3.2.P.2 should also include the excipient used in the formulated API in relation to the microbial attributes relevant to the final drug product Tight linkage with information provided in 3.2.S.2.6
3.2.P.3.2 Batch formula of drug product manufacture, starting from the formulated API Formulated API amount, any additional excipients, and/or WFI added as part of DP manufacture
3.2.P.3.3 Description of drug product filling process The drug product manufacturing process consists of the potential addition of further excipients to the formulated API, sterile filtration and aseptic filling. Thawing/equilibration may not be needed if formulated API can be stored at room temperature
3.2.P.8.1 Definition of shelf-life and storage condition Shelf-life starts with the first step of the drug product manufacturing process, i.e., the use of the formulated API
Characterization of API
It is proposed to characterize the API at the stage where it is most suitable. For example, for siRNAs, it may be best to run certain characterization tests at the single strand stage and some others at an annealed stage. For certain parameters of formulated oligonucleotide API, characterization using the solid API may be preferred, for other parameters using dissolved API may be appropriate, and certain tests, like stereogenic composition, can only be performed during synthesis development studies, and not as an end-product test. Therefore, flexible approaches using scientific reasoning can be justified.
A discussion should be provided in section 3.2.S.3.1 if processing salts and excipients added to the formulated API have an impact on the characterization.
Control strategy
Release of API
Release testing per CTD section 3.2.S.4.1 should be performed using the formulated API. The formulated API should be analyzed for identity and content (or relative concentration in final API mix) of excipients used in its manufacture. As proposed above in the section on characterization, certain release tests may be performed upstream in lieu of testing of the formulated API. In addition, the use of Process Analytical Technology (PAT), e.g. for real-time confirmation of sequence identity, may be implemented as part of the synthesis.
Drug product manufacture
The start of the drug product manufacture
A genome-wide association study of serum proteins reveals shared loci with common diseases
No full textWith the growing number of genetic association studies, the genotype-phenotype atlas has
become increasingly more complex, yet the functional consequences of most disease
associated alleles is not understood. The measurement of protein level variation in solid
tissues and biofluids integrated with genetic variants offers a path to deeper functional
insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing
4,035 independent associations between genetic variants and 2,091 serum proteins, of which
36% are previously unreported. The majority of both cis- and trans-acting genetic signals are
unique for a single protein, although our results also highlight numerous highly pleiotropic
genetic effects on protein levels and demonstrate that a protein’s genetic association profile
reflects certain characteristics of the protein, including its location in protein networks, tissue
specificity and intolerance to loss of function mutations. Integrating protein measurements
with deep phenotyping of the cohort, we observe substantial enrichment of phenotype
associations for serum proteins regulated by established GWAS loci, and offer new insights
into the interplay between genetics, serum protein levels and complex disease
Pharmacokinetic Drug Interactions of Asciminib With the Sensitive Cytochrome P450 Probe Substrates Midazolam, Warfarin and Repaglinide in Healthy Volunteers
No full textAsciminib, a novel agent being investigated in chronic myeloid leukemia, is a first-in-class BCR-ABL1 inhibitor that works by STAMP (Specifically Targeting the ABL Myristoyl Pocket) and therefore differs from approved ATP-competitive tyrosine kinase inhibitors. In vitro, asciminib has shown reversible inhibition of cytochrome P450 (CYP) 3A4/5, CYP2C9 and CYP2C8. This phase 1, open-label, 2-stage study in healthy volunteers evaluated the effect of asciminib (40 mg twice daily at steady-state) as a potential perpetrator on single-dose pharmacokinetics of a 2-drug cocktail containing midazolam (CYP3A substrate) and warfarin (CYP2C9 substrate) in stage 1 (n=22), and of repaglinide (CYP2C8 substrate) in stage 2 (n=25). For midazolam plus asciminib vs midazolam, geometric mean (Gmean) ratios (90% confidence interval) for midazolam AUCinf and Cmax were 1.28 (1.15, 1.43) and 1.11 (0.96-1.28), respectively. For warfarin plus asciminib vs warfarin, Gmean ratios for S-warfarin AUCinf and Cmax were 1.41 (1.37, 1.45) and 1.08 (1.04, 1.13). Results for R-warfarin were in line with those for S-warfarin. For repaglinide plus asciminib vs repaglinide, Gmean ratios for AUCinf and Cmax were 1.08 (1.02, 1.14) and 1.14 (1.01-1.28), respectively. The treatments were generally well tolerated, and the asciminib safety profile was consistent with previous reports with asciminib monotherapy. Overall, the results indicate that asciminib (40 mg twice daily) is a weak inhibitor of CYP3A and CYP2C9 and has no effect on CYP2C8