No abstract

The prophylactic effect of in-feed medication with oxytetracycline was tested by using an Actinobacillus pleuropneumoniae aerosol challenge model. Groups of 10 conventional pigs were provided with feed containing 400, 800, 1200 or 1600 mg oxytetracycline/kg and fed ad libitum. After six days of medication the pigs were challenged and clinical signs were recorded. Two groups of four unmedicated pigs served as controls and were euthanased 36 to 48 hours after challenge and dissected. The feed medication was continued for nine days after the challenge, and the different treatment groups were then moved to separate accommodation where they were mixed with seronegative tracer pigs. The steady state concentrations of oxytetracycline in the pigs' serum after six days medication with feed containing 400, 800, 1200 or 1600 mg oxytetracycline/kg ranged from 0.07 to 0.13, 0.21 to 0.46, 0.27 to 0.46 and 0.35 to 0.56 microgram/ml, respectively. One of the eight unmedicated control pigs died, and the other seven showed signs of pleuropneumonia post mortem. Medication with feed containing 400 mg and 800 mg oxytetracycline/kg failed to prevent pleuropneumonia in the challenged pigs, and the mortality rates in these groups were two out of 10 and one out of nine pigs, respectively. All the pigs given feed containing 1200 and 1600 mg oxytetracycline/kg survived and only two of the pigs in the first treatment group showed mild clinical signs. No clinical signs were observed in the tracer pigs which were mixed with the pigs medicated with 400, 800 or 1200 mg oxytetracycline/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Background MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody under development to prevent RSV infection in infants. A model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinically relevant endpoints (e.g. incidence rates) in humans, including lower respiratory tract infection (LRI) in infants, was presented previously. This model accounted for variable exposure to RSV over the course of the season through a force-of-infection (FOI) function modulating the overall risk of RSV infection over time. The objective of the current work was to determine whether variations in regional seasonality would impact the efficacy of a clinical trial evaluating MK-1654. Methods A FOI function to describe the degree of RSV exposure as a function of time was created by fitting epidemiological data to a Gaussian function added to a constant baseline value. Clinical trial simulations were conducted using the MBMA to predict seasonal incidence rates (IR) of RSV medically attended lower-respiratory tract infection (MALRI) and efficacies for a range of MK-1654 doses in both temperate and tropical regions. Results Epidemiological data was well captured by the FOI function. Clinical trial simulations indicated that seasonal IRs of RSV were sensitive to differences in the FOI represented by temperate and tropical regions; however, there was no substantial impact on efficacies across MK-1654 dose levels. Consistent with predictions for a temperate climate, MK-1654, when administered at the start of the RSV season in a region with a tropical climate, was also predicted to maintain high efficacy ( > 75%) for the prevention of RSV MALRI for 150 days. Conclusion Simulations indicated that while FOI is a substantial driver of overall RSV incidence rates, MK-1654 efficacy in a late-stage clinical trial is likely to be high, regardless of regional variations in RSV. Disclosures Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Jos Lommerse, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Brian M. Maas, PharmD, Merck & Co., Inc. (Employee, Shareholder) Jingxian Chen, PhD, Merck & Co., Inc. (Employee, Shareholder) Francesco Bellanti, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Li Qin, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Han Witjes, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Philippe Pierrillas, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Radha Railkar, PhD, Merck & Co., Inc. (Employee, Shareholder) Antonios O. Aliprantis, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Kalpit A. Vora, PhD, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Luzelena Caro, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

Background MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) with an extended half-life in late development to prevent RSV infection in infants. Neutralizing mAbs, like MK-1654, have great potential for prophylaxis against viral infection. However, well-validated approaches for clinical dose and efficacy predictions are lacking. Methods Summary-level literature data from RSV prevention studies were used in a model-based meta-analysis (MBMA) to describe the relationship between RSV incidence rates and serum neutralizing antibody (SNA) titer. The model was validated using viral challenge experiments in cotton rats and phase 3 RSV-A efficacy results in infants for an anti-RSV F mAb, REGN-2222. A phase 2b human RSV challenge study (HCS) in adults was also conducted with MK-1654. Participants (N=70) received 100, 200, 300, or 900 mg of MK-1564 or placebo and were challenged intranasally with RSV 29 days later. RSV viral load and symptomatic infection were monitored. Data from the HCS were compared to model predictions. The MBMA was used to predict efficacy of MK-1654 in a virtual population of pre- and full- term infants. Results The relationship between SNA titer and RSV incidence rate defined using the viral load data from the cotton rat approximated the relationship identified for infants from the clinical MBMA. The MBMA was quantitatively consistent with the phase 3 efficacy results against RSV A for REGN-2222. In the HCS, RSV nasal viral load measured by RT-qPCR and quantitative culture as well as symptomatic infections were decreased in MK-1654 recipients compared to placebo. Incidence rates of RSV infection in the HCS were also consistent with MBMA predictions. The model-based clinical trial simulations for MK-1654 indicated a high probability of substantial efficacy against RSV-associated medically attended lower respiratory tract infection ( >75% for 5 months) for doses ≥75 mg. Conclusion Our MBMA successfully quantified the relationship between RSV SNA and clinically relevant endpoints, including lower respiratory tract infection in infants. MBMA-based efficacy predictions support continued development of the MK-1654 antibody for the prevention of RSV in infants. Disclosures Brian M. Maas, PharmD, Merck & Co., Inc. (Employee, Shareholder) Jos Lommerse, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Radha Railkar, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Luzelena Caro, PhD, Merck & Co., Inc. (Employee, Shareholder) Jingxian Chen, PhD, Merck & Co., Inc. (Employee, Shareholder) Wen Liu, MPH, Merck & Co., Inc. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Qinlei Huang, MS, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Li Qin, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Jie Meng, MSc, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Han Witjes, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Emilie Schindler, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Benjamin Guiastrennec, PharmD, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Francesco Bellanti, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Daniel Spellman, PhD, Merck & Co., Inc. (Employee, Shareholder) Brad Roadcap, MS, Merck & Co., Inc. (Employee, Shareholder) Amy Espeseth, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Aubrey Stoch, MD, Merck & Co., Inc. (Employee, Shareholder) Eseng Lai, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Kalpit A. Vora, PhD, Merck & Co., Inc. (Employee, Shareholder) Antonios O. Aliprantis, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)