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A Cross Company Perspective on the Assessment of Therapeutic Protein Biotransformation
No full textUnlike small molecules (SMs), biotransformation of therapeutic proteins (TPs), except for antibody-drug conjugates (ADCs), has not been broadly investigated and included in regulatory filings. Nevertheless, there is an expanding pool of evidence suggesting that the ever increasingly diverse modalities and complexity of the TPs than the conventional monoclonal antibodies (mAbs) can significantly benefit from the insights of biotransformation into this area of therapeutics. For instance, such biotransformation analysis of the TP affords important information on its molecular stability, which may shed light into any potential impact on binding affinity, potency, pharmacokinetics, efficacy, safety and bioanalytical strategy. This white paper is intended to summarize the current practices in studying biotransformation of TPs and related findings in the biopharmaceutical industry. A key objective is to raise the awareness of this topic which remains relatively underexplored in the development of TPs. It is hopeful that continued efforts and the cumulative data could pave the way for establishing a consensus on the biotransformation assessment of TPs in the future between the industry and regulatory authorities
Absorption, Distribution, Metabolism, and Excretion (ADME) of Therapeutic Proteins: A White Paper on Current Industry Practices and Future Perspectives
No full textTherapeutics proteins (TPs) comprise a variety of modalities including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones to name a few. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subjected to different absorption, distribution, metabolism, and excretion (ADME) processes as compared to small molecules. Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group (WG) was sponsored by the Translational and ADME Sciences Leadership Group (TALG) within the Innovation and Quality (IQ) consortium with objectives to: i) better understand the current practices of ADME data generated for TPs across IQ member companies, ii) learn about their regulatory strategy and interaction experiences, and iii) provide recommendations on best practices for conducting ADME studies. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to FDA was also collated by reviewing regulatory submission packages of TPs approved between 2011-2020. This article summarizes the key learnings from the survey and an overview ADME data presented in BLAs along with future perspectives and recommendations for conducting ADME studies for internal decision making as well as regulatory submissions for TPs
Phosphine Ligand-Free Bimetallic Ni(0)Pd(0) Nanoparticles as a Catalyst for Facile, General, Sustainable, and Highly Selective 1,4-Reductions in Aqueous Micelles
No full textBy harnessing the synergy between Ni(0), Pd(0), and aqueous micelle of proline-derived PS-750-M amphiphile,
phosphine ligand-free ultrasmall nanoparticles (NPs) of Ni(0)-Pd(0) are developed for highly selective 1,4-reductions of
enones. In NP, Ni(0)-bound Pd(0) atom found to only react with most electron-deficient double bond due to electron-rich
character of Pd and fine-tuning of its d-band. Most notably, NPs contain a minimal amount of Pd (Ni:Pd = 25:1) and are highly selective without affecting the different types of N-and O-benzyl, aldehyde, nitrile, and nitro functional groups. The catalytic selectivity is investigated on a broad range of substrates, including the gram scale reaction. Control experiment reveals Ni, Pd, and micelle of PS-750-M are required for higher selectivity. The metal-micelle binding was supported by a surface-enhanced Raman spectroscopy study of NPs and their components. Optical imaging, high-resolution transmission electron microscopy (HRTEM), and energy-dispersive X-ray spectroscopy (EDX) analyses were performed to reveal the formation of NPcontaining micelle or vesicles, NPs morphology, particle size distribution, and chemical composition, while X-ray photoelectron spectroscopy (XPS) measurements unveiled the oxidation state of each metal in bimetallic NP
Democratizing data at Novartis through clinical trial data access.
No full textEnabling broad access and usage of clinical trial data within biopharmaceutical companies has historically been impeded by technical, cultural, and policy hurdles. Novartis has attempted to address this comprehensively through a program called data42; here, we explore how a diverse set of enterprise-wide stakeholders formulated a risk-based data access approach to streamline access to anonymized clinical trial data and vastly improved its use by authorized research and development (R&D) associates within the company. The result is that most Novartis clinical trial data requests, from internal associates, can now be automatically approved. The process of developing this framework and its impact on Novartis and the broader industry are explored and discussed
Novel Bruton’s tyrosine kinase inhibitor remibrutinib: Assessment of drug-drug interaction potential as a perpetrator of cytochrome P450 enzymes and drug transporters and the impact of covalent binding on possible drug interactions
No full textPurpose
Pharmacokinetic drug–drug interactions (DDIs) are investigated to ensure safety for patients receiving concomitant medications. Here, we present results of in vitro studies and a clinical study to assess the DDI potential of Bruton’s Tyrosine kinase inhibitor, remibrutinib as an inhibitor of drug-metabolising enzymes and drug transporters, and as an inducer. The pharmacokinetics of oral hormonal contraceptives (OC) in combination with remibrutinib were also evaluated. Remibrutinib is a covalent inhibitor of BTK and carries a reactive acrylamide moiety (warhead), so the potential contribution of covalent binding to observed interactions was investigated.
Methods
DDI assessment was based on initial in vitro studies, a clinical DDI study and an endogenous biomarker assessment. Beyond the potential effect on OC, the prediction of concomitant medications with remibrutinib and Cytochrome P450 (CYP) metabolism was evaluated. The impact of covalent binding was assessed by synthesising an identical reference molecule but with an inactivated warhead.
Results
Overall, the study revealed minor DDIs with limited clinical relevance for remibrutinib with CYP enzymes and drug transporters. Interestingly, the reactive warhead of remibrutinib had no impact on CYP enzyme and transporter inhibition, including time-dependent inhibition of CYP3A4, but may increase the induction potential of remibrutinib.
Observed inhibition of metabolic enzymes indicated that remibrutinib is a weak inhibitor of CYP3A4 and CYP2C9 and is not a clinically relevant inhibitor of uptake and efflux transporters, with the exception of intestinal P-glycoprotein and breast cancer resistance protein inhibition. .
Conclusion
Oral contraceptives may be safely administered and are effective when given with pharmacologically relevant doses of remibrutinib
Phase Ib/II study of ceritinib in combination with ribociclib in patients with ALK-rearranged non-small cell lung cancer.
No full textPreclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non-small cell lung cancer (NSCLC).This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy.Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300-450 mg/day) and ribociclib (range, 100-300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4-57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5-25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5-25.1). Safety profile of the combination therapy was consistent with single-agent safety data.Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC
Model-based dose selection to inform translational clinical oncology development of WNT974, a first-in-class Porcupine inhibitor.
No full textWNT974 is a potent, selective, and orally bioavailable first-in-class inhibitor of Porcupine, a membrane-bound O-acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose-escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5-45 mg WNT974 were studied, however, the protocol-defined maximum tolerated dose (MTD) was not established based on dose-limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model-based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure-response analyses of a target-inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure-response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model-based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development
How agarose gels surrounding PLGA implants limit swelling and slow down drug release.
No full textThe aim of this study was to better understand to which extent and in which way the presence of an agarose gel (mimicking living tissue) around a PLGA [poly(lactic-co-glycolic acid)] implant affects the resulting drug release kinetics. Ibuprofen-loaded implants were prepared by hot melt extrusion. Drug release was measured upon exposure to phosphate buffer pH 7.4 in Eppendorf tubes, as well as upon inclusion into an agarose gel which was exposed to phosphate buffer pH 7.4 in an Eppendorf tube or in a transwell plate. Dynamic changes in the implants' dry & wet mass and dimensions were monitored gravimetrically and by optical macroscopy. Implant erosion and polymer degradation were observed by SEM and GPC. Different pH indicators were used to measure pH changes in the bulk fluids, gels and within the implants during drug release. Ibuprofen release was bi-phasic in all cases: A zero order release phase (~20% of the dose) was followed by a more rapid, final drug release phase. Interestingly, the presence of the hydrogel delayed the onset of the 2nd release phase. This could be attributed to the sterical hindrance of implant swelling: After a certain lag time, the degrading PLGA matrix becomes sufficiently hydrophilic and mechanically instable to allow for the penetration of substantial amounts of water into the system. This fundamentally changes the conditions for drug release: The latter becomes much more mobile and is more rapidly released. A gel surrounding the implant mechanically hinders system swelling and, thus, slows down drug release. These observations also strengthen the hypothesis of the "orchestrating" role of PLGA swelling for the control of drug release and can help developing more realistic in vitro release set-ups
The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug.
No full textChronic myeloid leukemia (CML) is driven by the constitutive activity of the BCR-ABL1 fusion oncoprotein. Despite the great success of drugs that target the BCR-ABL1 ATP-binding site in transforming CML into a manageable disease, emerging resistance point mutations impair inhibitor binding, thereby limiting the effectiveness of these drugs. Recently, allosteric inhibitors that interact with the ABL1 myristate-binding site have been shown to awaken an endogenous regulatory mechanism and reset full-length BCR-ABL1 into an inactive assembled state. The discovery and development of these allosteric inhibitors demonstrates an in-depth understanding of the fundamental regulatory mechanisms of kinases. In this review, we illustrate the structural basis of c-ABL1's dynamic regulation of autoinhibition and activation, discuss the discovery of allosteric inhibitors and the characterization of their mechanism of action, present the therapeutic potential of dual binding to delay the development of mutation-driven acquired resistance, and suggest key lessons learned from this program
Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis
No full textDiarrhoeal disease caused by Cryptosporidium is a major cause of
morbidity and mortality in young and malnourished children from low- and
middle-income countries, with no vaccine or efective treatment. Here
we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor,
designed to be active at the infection site in the gastrointestinal tract
and undergo rapid metabolism in the liver. By using mutational analysis
and crystal structure, we show that EDI048 binds to highly conserved
amino acid residues in the ATP-binding site. EDI048 is orally efcacious
in an immunocompromised mouse model despite negligible circulating
concentrations, thus demonstrating that gastrointestinal exposure is
necessary and sufcient for efcacy. In neonatal calves, a clinical model
of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of
diarrhoea and signifcant reduction in faecal oocyst shedding. Safety and
pharmacological studies demonstrated predictable metabolism and low
systemic exposure of EDI048, providing a substantial safety margin required
for a paediatric indication. EDI048 is a promising clinical candidate for the
treatment of life-threatening paediatric cryptosporidiosis