GSK2982772 is a highly selective inhibitor of receptor‐interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first‐in‐human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo‐controlled, double‐blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1‐120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open‐label relative bioavailability study comparing 20‐mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24‐hour period for the 60‐mg and 120‐mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.

TPS9119 Background: The toxicity profile of the third-generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib makes it an attractive backbone for combination with other targeted agents, possibly overcoming acquired resistance mechanisms. Combination with a MET-inhibitor is an intuitive approach as MET-amplification was identified as the most common mechanism of resistance to osimertinib in preliminary ctDNA data from the Phase III FLAURA (15% of pts) and AURA3 (19% of pts) studies. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI that had an acceptable safety profile when combined with osimertinib in the Phase Ib TATTON study, providing the basis for this Phase II SAVANNAH study (NCT03778229). Other mechanisms of acquired resistance to osimertinib, including secondary EGFR mutations (e.g. C797S), RAS/RAF activation, and oncogenic gene fusions, provide additional opportunities for developing osimertinib-based combinations. Methods: Eligible pts will have histologically/cytologically confirmed EGFR-mutant NSCLC, and MET+ disease by central FISH, central IHC, or local NGS (retrospectively confirmed by central FISH/IHC). Pts must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Pts will receive osimertinib 80 mg plus weight-based dosing with savolitinib 300 or 600 mg PO QD, in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in pts who are MET+ by central FISH. Secondary endpoints include: ORR ( MET+ by central IHC and all pts); progression-free survival, overall survival, duration of response, percent change in tumor size, HRQoL, and EGFR mutation ctDNA clearance ( MET+ by central FISH, central IHC, and all pts); safety, and pharmacokinetics (all pts). Based on the TATTON study, we anticipate enrolling ~172 MET+ pts to include ≥117 pts with MET+ disease by central FISH. Enrolment began in Q1 2019. Ongoing development of complementary trials targeting other osimertinib resistance mechanisms will also be discussed. Clinical trial information: NCT03778229.

The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, GSK2315698, Ro 63-8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti-SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure-response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first-in-human study with anti-SAP antibodies.

bHistorically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [C max ]), the time above the MIC (t > MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.

Background and Purpose: Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent, and highly MET receptor TK inhibitor. This series of studies aimed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to link inhibition of MET phosphorylation (pMET) by savolitinib with anti-tumour activity.Experimental Approach: Cell line-derived xenograft (CDX) experiments using human lung cancer (EBC-1) and gastric cancer (MKN-45) cells were conducted in athymic nude mice using a variety of doses and schedules of savolitinib. Tumour pMET changes and growth inhibition were calculated after 28 days. Population PK/PD techniques were used to construct a PK/PD model for savolitinib. Key Results: Savolitinib showed dose-and dose frequency-dependent anti-tumour activity in the CDX models, with more frequent, lower dosing schedules (e.g., twice daily) being more effective than intermittent, higher dosing schedules (e.g., 4 days on/3 days off or 2 days on/5 days off). There was a clear exposure-response relationship, with maximal suppression of pMET of >90%. Data from additional CDX and patient-derived xenograft (PDX) models overlapped, allowing calculation of a single EC 50 of 0.38 ngÁml −1 . Tumour growth modelling demonstrated that prolonged, high levels of pMET inhibition (>90%) were required for tumour stasis and regression in the models. Conclusion and Implications:High and persistent levels of MET inhibition by savolitinib were needed for optimal monotherapy anti-tumour activity in preclinical models. The modelling framework developed here can be used to translate tumour growth inhibition from the mouse to human and thus guide choice of clinical dose and schedule.