Progress 09/01/14 to 08/31/17
Outputs
Target Audience:Our company has had fruitful discussions with an international corporations in our target market. We are currently engaging them in some R&D efforts and a Joint Development Agreement that are related to Amelgo's intellectual property. Changes/Problems:One unexpected finding not mentioned elsewhere in this report was occurrence of a narrow therapeutic window for our API. This means the difference between an effective dose, and a dose that causes unwanted side effects or an ineffective dose is small. This finding has caused additonal internal discussions and possible alternative pathways to market, due to additional regulatory restrictions regarding drugs with narrow therapeutic windows. Moreover, we are re-doing some market research with this new information; with the goal of understanding the market acceptance (in on-farm practices) of a treatment that has the aforementioned property. What opportunities for training and professional development has the project provided?The Chief Scientist has, through help with the ONADE Program Manager and because of opening the iNAD, become more knowledgeable about the requirmenets and process for accomplishing and submitting all the information required for a NADA. Although, it is possible a third party will be utilized to handle regulatory affairs, having an Amelgo member with seminal knowedge has helped move the project forward. How have the results been disseminated to communities of interest?Since our technology overlaps with the academic pursuits of faculty members at the University of Wisconsin, College of Agriculture; Amelgo has involved their faculty to the degree necessary to allow for mutual benefit. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
IMPACT: Amelgo utilized the SBIR program funds to be first to develop a non-antibiotic dry cow treatment. The dry period is a necessary period of rest, where dairy cows are not milked as they approach their final weeks of gestation. Once the new calf is born, milk production recommences. The dry period is known to be one of the most critical and sensitive time periods for dairy cow health. Notably, the incidence of intramammary infection (mastitis) is markedly elevated during the dry period. Mastitis is the largest attributable cause of lost productivity, with lost revenue averaging 6-10% of total milk sales annually ($2-3 billion lost revenue). Currently, dairy herd managers face difficult choices for cows entering their dry period; (1) administer prophylactic antibiotics to reduce chance of infection or (2) gradually reduce the milking frequency and restrict food to the animals to gradually decrease milk production of cows entering the dry period. The former increases the worldwide use of antibiotics, but preserves maxiumum milk production levels longer; while the latter slowly dries the cow off which also decreases mastitis rates, but sacrifices milk production and animal welfare (feed restriction) in the process. The three major agencies of the U.S. government with responsibilities associated with food safety (USDA, FDA, CDC) have clearly articulated the concern that antibiotic use in agriculture poses threats to food safety, and to the health of agricultural workers. Moreover, industry consolidation and milk prices drive herd managers to get the most production out of their animals. This current market situation speaks to a need for a non-antibiotic treatment that can reduce mastitis risk using a mechanism that preserves animal welfare and milk production. Amelgo's strategy was to enhance the mammary gland's natural "shut-down" signals that are activated during the dry period. Accelerating these signals would reduce udder engorgement, and thus prevent mastitis. The implication and disruption to the market such a technology would cause is to reduce or eliminate the need for prophylactic antibiotics and artificial teat sealants during the dry period, while maintaining good production levels and animal health. As summarized below, the results of the field studies in dairy cows caused some reexamination of the candidate compounds, and the formulation necessary to achieve the desired effect. This has delayed our anticipated date of application for FDA approval, but the work is still ongoing. Most notably, however, when Amelgo embarked on this process 5 years ago, we were the only company pursuing a dry-off acceleration strategy (to our knowedge). Since then, at least one company has filed intellectual property (US 2014-0024670), using the dry-off acceleration concept and anecdotal stories from industry insiders indicates increasing interest in dry-off accelerants. SUMMARY OF EXPERIMENTAL RESULTS: Through Phase I SBIR efforts, Amelgo identified two candidate compounds that would fulfill the aforementioned criteria for a dry-off accelerant. This Phase II SBIR effort sought to fulfill several product development milestones in anticipation of an eventual FDA application. These included: compare the efficacy of different formulations of candidate compounds (optimized for intramammary infusion), compare the efficicacy of compound 1 versus compound 2, versus the combination of both, and determine the optimum dose for each candidate compound. Importantly, the transition from Phase I to Phase II, coincided with a transition from relying on laboratory studies to field studies utilizing commerical dairy cows. The number of experiments conducted in dairy cows was more expensive than the total size of the SBIR funds. Amelgo leveraged the SBIR funds and its intellectual property to secure additional funding from corporate collaborators through development agreementscand and the state of KY. The totality of those efforts relate to objectives 1 and 2 and will be summarized here. Objective 1: Identify the optimum dose of compound 2 in dariy cows to achieve desired dry-off effect. In a multi-purpose experiment (detailed in the interim technical report), we sought to (1) verify the dry-off accelerant effects of compound 2 in the dairy cow, (2) gather evidence that dry-off acceleration would mitigate mastitis risk, (3) monitor animal health indicators relavant to dairy farmers (leakage from udder, animal behavior etc.) and (4) utilize the data to open an investigational new animal drug application with the FDA-CVM. This field test was conducted at the University of Kentucky. The summary of this data is that as a single treatment, compound 2 did not cause a dramatic enough dry-off acceleration, resulting in the mastitits risk to be unchanged. Dry off acceleration (or lack thereof) is evidenced by monitoring plasma lactose following treatment. If dry-off acceleration is achieved, a higher level of plasma lactose would be seen post-treatment. Two-way ANOVA statisitical analysis of plasma lactose concentrations versus time, indicated no significant difference between vehicle and compound 2 treated animals. Moreover, the study design included a bacteria challenge model, which evaluates the mastitis risk. Again, no difference was seen between vehicle and compound 2 treated animals following bactierial challenge. The conclusion is that compound 2 is not a viable stand-alone dry-off accelerant. Prior to conlcusion of this study, Amelgo opened an iNAD (No. 012697) on compound 2, which ended up still being valuable because it was still a candidate to act as an enhancer to compound 1 (see objective 2). Lastly, we did learn from this experiment that the solubility characteristics of compound 2 in the preferred excipients was the key factor for determining the dose given. This dose was effective in the laboratory setting, but did not translate to the field as summarized above. This information was helpful moving forward to conduct the next field study in objective 2. Objective 2: Compare the efficacy of compound 2 versus compound 1 versus the combination of 1+2 Already being aware that compound 2 treatment alone did not translate to the field, objective 2 was simplified to comparing compound 1, versus compound 1 + an enhancing agent. The enhancing agent we initially chose to test was compound 2. Similar to objective one, a multi-purpose field test, conducted at the University of Kentucky, was designed and sought to: (1) directly compare three dry off accelerant formulations, compound 1 in formulation A versus compound 1 in formulation B versus compound 1+2 in forumation A, and (2) monitor animal health indicators relavant to dairy farmers and (3) utilize the data to discuss submission requirements pursuant to an investigational new animal drug application (No.: 012-870) with the FDA-CVM on compound 1. The results of this study indicated that compound 1, formulation A did accelerate dry-off, but that compound 1+2 in formulation A did not. This led to the conclusion that compound 2 is reversing the effect of compound 1, for reasons that are not determined. This finding eventually led to the closing of the iNAD on compound 2. Furthermore, compound 1 in formulation A was superior to compound 1 in formulation B, which focuses future efforts to utilizing formulation A.
Publications
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Progress 09/01/15 to 08/31/16
Outputs
Target Audience:Our company has had fruitful discussions with two international corporations in our target market. We are currently engaging one of them in some R&D efforts that are related to Amelgo's intellectual property. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?For our technicians, they are recent graduates of the University of Kentucky's College of Agriculture. Every experience they've had, both in the laboratory and out in the field, has developed their resume/CV further than what it was initially. Moreover, the PD and AR of the project, through discussions with the CVM and others, has learned the process and pitfalls to submitting a successful new animal drug application. How have the results been disseminated to communities of interest?
Nothing Reported
What do you plan to do during the next reporting period to accomplish the goals?We intend to scale up the next animal study, that addresses objective 2. To do this, we will "rent" instead of purchase cows; thereby returning them to their owner and to milk production. To do this, we must first establish an authorization from the FDA (under our iNAD) and a withdrawal period. This is in progress.
Impacts
What was accomplished under these goals?
FROM 2014-15 ANNUAL REPORT: Under objective 1, we have accomplished milestone 1A, which involved laboratory testing of the active pharmaceutical ingredient by two technicians on staff (accounting for the 1.5 FTE). Upon completion of their work, we began preparations for and have very recently finished milestone 1B. We are collaborating with the University of Kentucky on the field tests in 1C. In addition to contracting the on-site staff at UK, we will also have our two technicians participating and running the field study. This study will commence and finish sometime in early Q4 of 2015. Lastly, we have set a timeline and made appropriate financial arrangements to accomplish milestone 1F in October of 2015. To this end we have several ongoing communications with the Office of New Animal Drug Evaluation (ONADE) at the Center for Veterinary Medicine (CVM). 2015-16 ACCOMPLISHMENTS: We have completed all the milestones for objective 1. The interim technical report summarized the findings from field tests that were done in collaboration with the University of KY. Also, we opened an iNAD in October of 2015. We will be opening another iNAD in October of 2016. Regarding Objective 2, we have partially completed all four of the milestones. To elaborate, due to cost of purchasing a healthy, high-producing dairy cow for experimental use, the study we recently completed, addressing Objective 2 was at a much smaller scale than what is needed. However, having identified the best formulation and dose, we intend to scale up the next animal study. To do this, we will "rent" instead of purchase cows; thereby returning them to their owner. To do this, we amust first establish an authorization from the FDA and a withdrawal period. This is in progress.
Publications
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Progress 09/01/14 to 08/31/15
Outputs
Target Audience:
Nothing Reported
Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?For our technicians, they are both recent graduates of the University of Kentucky's College of Agriculture. Every experience they've had, both in the laboratory and out in the field, has developed their resume/CV further than what it was initially. Moreover, the PD of the project, through discussions with the CVM and others, has learned the process and pitfalls to submitting a successful new animal drug application. Lastly, the CEO, Nelson Horseman, recently completed the LARTA administered commericialization program. The program provided guidance and excellent support for commericialization strategies relevant to Amelgo. How have the results been disseminated to communities of interest?
Nothing Reported
What do you plan to do during the next reporting period to accomplish the goals?During the next reporting period, we will have accomplished all the items under objective 1, and begun the planning and initial staging for objective 2. To this end, it is possible that the PD may apply for a no-cost extension of this award finish completion of objective 2.
Impacts
What was accomplished under these goals?
Under objective 1, we have accomplished milestone 1A, which involved laboratory testing of the active pharmaceutical ingredient by two technicians on staff (accounting for the 1.5 FTE). Upon completion of their work, we began preparations for and have very recently finished milestone 1B. We are collaborating with the University of Kentucky on the field tests in 1C. In addition to contracting the on-site staff at UK, we will also have our two technicians participating and running the field study. This study will commence and finish sometime in early Q4 of 2015. Lastly, we have set a timeline and made appropriate financial arrangements to accomplish milestone 1F in October of 2015. To this end we have several ongoing communications with the Office of New Animal Drug Evaluation (ONADE) at the Center for Veterinary Medicine (CVM).
Publications
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