In-Vivo. [***] Commercial Supply Agreement. If (a) NVS is Manufacturing such In-Vivo [***] Product for use outside the U.S. and (b) no Designated CMO is, at such time, able to (or within a timely manner would be capable of) Manufacture and supply such In-Vivo [***] Products, then at HMI’s request and at the appropriate time directed by the JMC, the Parties will negotiate in good faith a definitive supply agreement for NVS to supply to HMI In-Vivo [***] Products for Commercialization in the U.S. in accordance with this Agreement (“In-Vivo [***] Commercial Supply Agreement”) along with a quality assurance agreement covering quality related obligations of such supply (“In-Vivo [***] Quality Assurance Agreement”) (which In-Vivo [***] Quality Assurance Agreement will contain terms related to NVS’ rights and obligations as the Manufacturer of such In-Vivo [***] Product as well as terms related to each Party’s rights and obligations as the Regulatory Responsible Party for such In-Vivo [***] Product, including each Party’s respective review, comment, and approval rights thereunder). The In-Vivo [***] Commercial Supply Agreement and In-Vivo [***] Quality Assurance Agreement will provide for customary terms and conditions, including forecasting, ordering, delivery, manufacturing costs, termination at will rights for both Parties with reasonable advance notice periods, reasonable volume caps with a mechanism to address adjustments to such cap over time, technical criteria to be met, payment, and supply, and will be consistent with the terms of this Agreement. The transfer price paid by HMI for In-Vivo [***] Products under the In-Vivo [***] Commercial Supply Agreement shall be equal to [***]. If the Parties are unable to agree upon the terms of the In-Vivo [***] Commercial Supply Agreement, then neither Party will be obligated to enter into such agreement, and NVS will not be obligated to Manufacture In-Vivo [***] Products under the In-Vivo [***] Commercial Supply Agreement until the Parties reach agreement on the terms of such agreement.
In-Vivo. [***] Commercialization Activities. Each Party will provide the other Party with reasonable cooperation, support, and assistance requested by the other Party, at the requesting Party’s expense, with respect to preparing such Party’s Commercialization plan for In-Vivo [***] Products in order to coordinate Commercialization with respect to such In-Vivo [***] Products throughout the Territory; provided, that any such cooperation, support, and assistance shall be limited to that permitted under Applicable Law.
In-Vivo. There few studies which have simulated in vivo tooth wear in human subjects, or aetiological tooth wear factors. This may be because in vivo simulation of tooth wear is limited by ethical considerations as tooth wear, by its very nature, is an irreversible damaging process to the dental hard tissues. However the initial surface softening is reversible and future studies may be able to simulate the initial erosion lesion which is then assessed and repaired in vivo however the assessment techniques are currently not discriminating enough for this type of research. Xxxxx et al (2006) investigated the effect of stannous fluoride and sodium fluoride toothpastes on enamel erosion in a study which simulated acid erosion, by passing diluted citric acid over healthy anterior teeth of human subjects, using a peristaltic pump. The calcium content in the citric acid applied before and after the treatment with toothpaste was measured and the authors concluded that the stannous fluoride toothpaste markedly reduced the enamel dissolution of teeth in vivo, whereas the NaF toothpaste provided no protection (Xxxxx et al., 2006). Xxxxxxxx et al (1997b) compared the effects of a xxxxx meal versus a high fat content meal taken with alcohol on GOR measured by oesophageal and oral pH and found that pathological levels of GOR were provoked by the high fat meal in 6 of the 12 subjects whereas the xxxxx meal provoked pathological levels of reflux in only two out of the twelve subjects. Moreover, there was a significantly lower pH in the anterior palatal region of the oral cavity after consumption of the high fat content meal (Xxxxxxxx et al., 1997b). If an erosive challenge were to be simulated in vivo, use of an acidic gel may reduce unnecessary exposure of enamel/dentine to damage by reducing the flow rate of an erosive challenge over tooth surfaces, which are not of interest to the measurement technique, to nil (Xxxxxxx et al., 2005). Localisation of the erosive challenge would also have the secondary advantage of allowing a split-mouth or even split-tooth design to be employed. One area which is potentially under-researched in the field of dental erosion is the role of biological factors such as saliva and the acquired dental salivary pellicle in modifying the erosive wear process in vivo (Xxxx et al., 2006b). Therefore, immediate saliva analysis could be included for in vivo models which would reduce the changes in the salivary pH that occur during storage of the saliva (Xxxxx...
In-Vivo. KPL-716 was well tolerated in multi-dose 7-week and 26-week primate toxicity studies. In the 7-week toxicity study, cynomolgus monkeys were dosed once every other week with either an intravenous (IV) bolus injection of up to 500 mg/kg KPL-716 or a subcutaneous (SC) injection of 300 mg/kg KPL-716, for a total of 3 doses. The multi-dose, 7-week, preclinical toxicology study in cynomolgus monkeys revealed no specific toxicities, and the no observed adverse effect levels (NOAELs) for systemic toxicity were 500 mg/kg for IV administration and 300 mg/kg for SC administration. For further details, refer to the IB. In the chronic toxicology study, weekly administration of KPL-716 by IV bolus injection or SC at doses up to 200 mg/kg IV/SC for 26 weeks (27 total doses) was well tolerated in cynomolgus monkeys. Based on these results under the conditions and duration of the study provided in the final report, the NOAEL was considered to be 200 mg/kg IV/SC, the highest dose tested. A low level of anti-drug antibody (ADA) response was noted in the toxicity study, which was not unexpected because KPL-716 is a fully-human antibody. The magnitude of the ADA response was judged to be insufficient to impact toxicokinetic evaluations.
