During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points. These points are typically prior to the submission of an IND, at the end of Phase 2 and before an NDA is submitted. Meetings at other times may also be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date and for the FDA to provide advice on the next phase of development. Sponsors typically use the meeting at the end of Phase 2 to discuss their Phase 2 clinical results and present their plans for the pivotal Phase 3 clinical trial that they believe will support the approval of the NDA. If a Phase 2 clinical trial is the subject of discussion at the end of Phase 2 meeting with the FDA, a sponsor may be able to request a Special Protocol Assessment, or the SPA, the purpose of which is to reach agreement with the FDA on the Phase 3 clinical trial protocol design and size that will form the primary basis for the demonstration of effectiveness in a marketing application.

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We are at a very early stage in our development efforts, our approach is unproven and we may not be able to successfully develop and commercialize any product candidates.

Hi Josh, Very nice summary of epigenetic cancer theory. Weinberg first presented that theory @ 1983 and showed demethylation of cancer cells. Major theory is cancer due to new mutations genes and minor theory due to epigenetic changes due to demethylation. Plants started @ 500 million years ago and began changing atmosphere from CO2 rich to more oxygen. Idea that original life resembled cancer from astrophysicist, (don’t remember name) but you mentioned you were big fan of his. Intuitively, hard to understand how cancer could be so metabolically robust if had to rely on de novo mutations. On the other hand, if cancer was a life form that had evolved over a billion years; then makes sense that cancer is such a robust life form. The other intuitive problem with mutation theory is as cancer becomes more undifferentiated, they all look the same. One would think if each cancer was it’s own set of new and different random mutations, cancers would all look very unique. As regards poorly differentiated cancer, microscopically, you’ve seen one cancer, you’ve seen them all. As regards continuing need for oxygen free growth; human fetus needs that ability in first week of life, until implantation in uterus and finally gets an oxygen rich blood supply. A four day old fetus looks a lot more like cancer than adult tissue.

        We base our expenses related to clinical trials on our estimates of the services received and efforts expended pursuant to contracts with multiple CROs that conduct and manage clinical trials on our behalf. The financial terms of these agreements are subject to negotiation, vary from contract to contract and may result in uneven payment flows. There may be instances in which payments made to our vendors will exceed the level of services provided and result in a prepayment of the clinical expense. Payments under some of these contracts depend on factors such as the successful enrollment of subjects and the completion of clinical trial milestones. In accruing service fees, we estimate the time period over which services will be performed, enrollment of subjects and the level of effort to be expended in each period.

“Doesn’t the FDA have to approve all changes to manufacturing before the product can be sold?” Yes, that’s correct, but generally according to the ICH Q3 model, there is a threshold for inclusion in a specification, which is the ID threshold, and another threshold for qualification UNLESS there is deemed to be some special toxicity like genotox.

Secondary endpoints based on NAS and SAF activity score, ≥2 points improvement, showed a higher proportion of patients with improvement in the Aramchol arms (600mg>400mg>placebo; P>0.05).

        We believe that, our cash and cash equivalents as of December 31, 2018, will enable us to fund our operating expenses and capital expenditure requirements through the first quarter of 2021. We have based our projections of operating capital requirements on assumptions that may prove to be incorrect and we may use all of our available capital resources sooner than we expect. Because of the numerous risks and uncertainties associated with the development and commercialization of zilucoplan and the research, development and commercialization of other potential product candidates, we are unable to estimate the exact amount of our operating capital requirements. Our future capital requirements will depend on many factors, including:

However, despite the growing need, there are currently no approved therapeutic treatments for NASH. Modification of risk factors, such as obesity and hyperlipidemia, and proper diabetic control is generally recommended for the treatment of NASH, and the standard of care includes lifestyle changes to promote weight loss, including low-calorie, low-fat diets and physical activity. Although weight loss can be potentially significant in delaying the progression of NASH, studies have shown that, for most individuals, it is generally very difficult to maintain over the long-term, even following bariatric surgery.

        If we raise funds through additional collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or to grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

Hinz, B. et al. The myofibroblast: one function, multiple origins. The American journal of pathology. 170, 1807–1816 (2007).