Chimerix Inc (CMRX) 2015 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Chimerix' fourth-quarter and full-year 2015 financial results conference call.

(Operator Instructions).

I would now like to hand the conference over to Kevin Reeves, Vice President of Marketing.

Thank you and welcome to the Chimerix fourth-quarter and full-year 2015 financial results conference call. This morning at 7:30 Eastern time we issued a press release containing financial results and other updates for the fourth quarter and full-year 2015. The press release is available on the Company's website. You may also access today's call via webcast on the investors section of the Chimerix website: www.chimerix.com.

An archive of the webcast will be available approximately 2 hours after the conclusion of the event. On the call with me today are Michelle Berrey, President and CEO; Garrett Nichols, Chief Medical Officer; Tim Trost, Chief Financial Officer; and Linda Richardson, Chief Commercial Officer.

Before we begin I would like to reminded you that the statements made on today's call include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and are subject to risks, uncertainties and other factors including the possibility that there may not be a viable continued development path for brincidofovir and that the FDA and other regulatory authorities may not approve brincidofovir or brincidofovir [brace] regimens, and that marketing approval, if granted, may have significant limitations of their use. As a result brincidofovir may never be successfully commercialized.

In addition, Chimerix may be unable to file regulatory approval with brincidofovir with other regulatory authorities. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. You are cautioned not to rely on these forward-looking statements. These risks, uncertainties are described in detail in Chimerix' filings with the Securities and Exchange Commission including its Form 10-K filed earlier today, its most recent filed reports on Form 8-K and other documents subsequently filed with the Securities and Exchange Commission. All forward-looking statements are based on information currently available to Chimerix and Chimerix assumes no obligation to update any such forward-looking statements.

At this time I like to turn the call over to our President and CEO, Michelle Berrey.

Good morning, and thank you for joining us for the fourth quarter and full-year 2015 earnings and update call. This morning we review our performance for 2015. We also want to take this opportunity to provide you with updates to our brincidofovir development program for the treatment of adenovirus, now likely to be the indication of our first marketing applications in the US and Europe, as well as progress in our development program for smallpox.

In addition to brinci our commitment to bringing forward new medicines for CMV and BK Virus include CMX669, which has made significant progress toward a clinical study in late 2016 or early 2017. We are also moving forward with the discovery program in norovirus with selection of a clinical candidate scheduled for 2016.

As Tim will discuss in more detail later at the end of 2015 we had approximately $343 million in capital available to fund operations and we are debt-free. This capital provides the financial strength to advance brincidofovir and our earlier drug candidates and to continue to build value. At the same time we are being prudent with our available capital and made the difficult decision to undertake a 20% reduction in our workforce in January.

Let me begin by outlining some key initiatives here at Chimerix. In the first two months of 2016, we have reviewed the data from SUPPRESS, our Phase 3 trial testing brincidofovir for the prevention of CMV, stem cell transplant recipients, and have begun discussions with the FDA and foreign regulators on next steps.

As we increase our understanding of the factors that drove the outcomes in SUPPRESS, the development work that has been ongoing for the last 18 months on the IV formulation of brinci has moved to the forefront. We are committed to moving brincidofovir forward for the prevention and treatment and CMV and stem cell and solid organ transplant recipients and are evaluating options for development of oral and intravenous brincidofovir in different patient populations.

We expect to initiate clinical studies with the new intravenous or IV formulation of brincidofovir in the second half of 2016 and a Phase 2 study of brincidofovir in kidney transplant recipients at high risk of BK Virus associated disease is under development based on decreased BK viremia seen in the SUPPRESS study. With patent exclusivity through 2034 we have the opportunity to pursue indications in CMV, BK Virus and other DNA viral infections.

The most rapid path to approval is now focused on our development of brincidofovir for the treatment of adenovirus. In the next six weeks we will receive data on viral load responses and survival from the open label AdVise Study and historic controls. With the observation of a day 90 mortality of less than 40% in the approximately 100 patients with disseminated adenoviruses disease in the AdVise Study and the anticipated spring readout of the historic control data, we strongly believe that there is a near-term path forward for this antiviral.

We plan to provide these data along with outcomes from our Phase 2 study and expanded access programs to the FDA so that we can discuss the potential for filing with these data sets. In the event that an additional study is required for a marketing submission in the US, we have the capital on hand and the support from the pediatric transplant community to begin the study quickly. We anticipate providing guidance on the path to approval in the US in the summer of 2016 and later in the year for Europe.

Following the recent presentation of positive data on brincidofovir's protection in the setting of a lethal rabbit pox infection, oral brincidofovir for smallpox is expected to complete the second animal efficacy study in the fourth quarter of 2016 enabling discussions with the FDA on the treatment of smallpox. We are optimistic that negotiations with BARDA for the procurement of brinci for the strategic national stockpile can reopen in the first half of 2016. We remain confident in the antiviral activity shown by brincidofovir and its significant potential as a much needed treatment option for patients with adenovirus and other DNA viral infections. I will now turn the call over to our Chief Medical Officer, Garrett Nichols, for details on the clinical development of brincidofovir in 2016.

Thank you, Michelle. I'd like to start by providing an update on our clinical trial for the treatment of adenovirus or the AdVise Study. In August of 2015 we completed enrollment of the AdVise trial, which is evaluating brincidofovir for the treatment of serious adenovirus infections in over 200 pediatric and adult patients. Patients who have undergone allogeneic stem cell transplantation are at especially high risk for developing adenovirus due to profound and persistent immunodeficiency. In this susceptible population, the development of adenovirus infection can be rapidly fatal. And it's important to note there is no approved treatment available for adenovirus.

Patients who are enrolled in the AdVise Study were placed into Cohort A, B or Cohort C based on their underlying immunodeficiency and extent of disease. Cohort A contains allogeneic stem cell transplant recipients with asymptomatic or limited adenovirus infection. Cohort B comprises allogeneic stem cell transplant recipients with disseminated adenovirus disease, and Cohort C represents other immunocompromised patients with severe adenovirus disease, including autologous stem cell transplant recipients, solid organ transplant recipients and other immunocompromised patients. All subjects enrolled in the AdVise trail received 12 weeks of open label oral brincidofovir and are followed for at least 12 weeks after completing treatment.

In December 2015 we provided an update from the AdVise setting. At the time of the report all cause mortality at day 90 remained less than 40% for the approximately 100 stem cell transplant recipients with disseminated adenovirus infection from AdVise Cohort B. Clearly this is very promising when compared to the mortality rates of up to 80% that are reported in the literature.

This spring, 24 week survival data from pediatric and adult stem cell transplant recipients enrolled in AdVise Cohort A and Cohort B will be compared with outcomes from matched historical controls from the same medical centers. As Michele noted we plan to meet with the FDA and other regulators during the summer of 2016 to review these data and to discuss any additional requirements for a proposed submission for brincidofovir for the treatment of adenovirus.

In the meantime we continue to receive and fulfill compassionate use requests for the treatment of adenovirus at a very brisk clip in both the US and Europe, highlighting the serious nature of this infection and the lack of treatment options. A new expanded access trial is opening now in order to provide access to brincidofovir while allowing us to collect outcomes associated with brincidofovir treatment in this patient population.

Next I'd like to discuss SUPPRESS and clarify a few salient points regarding this study. Number one, brincidofovir's antiviral activity was clearly demonstrated as measured by the significantly lower rate of detectable CMV in the blood compared to placebo throughout the 24 weeks of study. Number two, the failure to meet the primary endpoint was driven by the use of high-dose corticosteroids in the setting of presumed gut graft-versus-host disease. Number three, we are continuing to evaluate the subsets of high risk patients who have better outcomes in order to inform future development options. And number four, we confirm many of the key attributes brinci in this study, including its high barrier to resistance and its lack of bone marrow and kidney toxicity, attributes that distinguish it from currently available options.

We are evaluating our options for the development of both oral and intravenous brincidofovir for the prevention and treatment of CMV in stem cell transplant recipients. The development of an IV formulation of brincidofovir is progressing toward clinical testing with a first time in human study slated to begin in the second half of 2016. It's important to note that we expect the development timelines for the IV formulation will be significantly shortened based on our extensive body of data from the oral molecule. The first time in human study will give us data on concentrations of brinci in the blood that can be linked to our oral dosing program. Following this study the IV formulation could be incorporated into late stage studies in patients as soon as 2017.

Investigators at the Tandem BMT Meetings were particular excited about the potential for low rates of gastrointestinal side effects based on our preclinical studies conducted to date. Intravenous brincidofovir could potentially provide a means of preventing CMV and other DNA viral reactivations in the first weeks post transplant with the opportunity to step down to oral brincidofovir at the time of hospital discharge.

Moving now to our plans for brinci in the solid organ transplant setting. Brinci's activity against other DNA viruses was an important secondary endpoint from SUPPRESS. To this end, we conducted an analysis of banked plasma from subjects during the first eight weeks following transplant or BK Virus. There was a positive trend for decreased BK Virus in the blood or BK viremia in favor of brincidofovir versus placebo, with 13% developing viremia on brinci versus 20% on placebo with a log rank P value of 0.06. This finding may be particularly relevant in kidney transplant recipients, in whom BK viremia is associated with BK Virus nephropathy with high risk of failure of the new kidney allograft. A Phase 2 study of brincidofovir in kidney transplant recipients at high risk of BK Virus associated disease is under development based on the observed decrease incidence of BK viremia from the SUPPRESS study.

In summary, Chimerix remains committed to moving brincidofovir forward as a preventative therapy for CMV in stem cell and solid organ transplant recipients. Following discussions with regulators on potential paths forward in these populations, we expect to provide a broad clinical update with development plans for each of our potential indications during the second half of 2016 beginning with clarity on our adenovirus program as early as in late summer. I will now turn the call over to our Chief Commercial Officer, Linda Richardson.

Thanks, Garrett, and good morning everyone. Given that our first indication for brincidofovir could be for the treatment of disseminated adenovirus infections, I'd like to briefly discuss our commercial activities over the past eight weeks in this area, which supplements the work we've been doing in the CMV space over the past two years. The interest in brinci as a potential treatment for serious adenovirus infections has been consistently very strong in all of our market research activities. This is driven by high mortality rates, up to four in five in infected patients in the medical literature. As well as the lack of an indicated treatment with proven efficacy.

Cidofovir has been used to treat these infections in the past but kidney toxicity is of great concern as physicians in our research have questioned Cidofovir's effectiveness in the study. By contrast, and based on data in the treatment of adenovirus infections in hundreds of patients, the risk-benefit profile for brinci appears to be different. The question is, how large is this market?

Over the past year we've seen new data coming out of preeminent transplant centers such as the Fred Hutchinson Center in Seattle highlighting the number of allogeneic transplant patients who have clear evidence of multiple DNA viral infections present in their serum samples. Less than two weeks ago at the BMT Tandem meeting additional data were presented from the Hutch that showed that DNA viral infections are frequent, persistent and associated with mortality following allogeneic HCT. These viral infections included BK, adenovirus, HHV-6, EBV and CMV, adding to the growing body of evidence that these patients are at considerable risk of infections post transplant.

Chimerix is generating additional information specifically regarding the impact of adenovirus infections and the cost associated with treating them. We are planning a series of abstracts, posters and publications. In fact, we will be sharing new data starting with the upcoming European BMT Tandem Meeting in April that will begin to highlight the healthcare burden associated with treating pediatric allogeneic stem cell transplant patients including hospitalizations and co-infections. This will complement our previous educational initiatives regarding increasing awareness of the cost and impact of CMV and DNA viral infections.

In our earlier expanded access and EIND programs as well as in the Cohort C arm of AdVise, we have provided brincidofovir to patients with serious adenovirus infections who were not allogeneic stem cell patients, including patients receiving chemotherapy, solid organ transplant recipients and others with genetic immunodeficiencies. This would suggest that the risk of serious adenovirus infections is likely underestimated and that the actual at risk patient population may be broader than current thinking, which has primarily been focused on the pediatric stem cell population.

Building awareness of the spectrum of patients who are at risk should help increase diagnosis rates. The commercial team's assessing the market size for serious adenovirus infections using a variety of data sources including hospital discharge data. We are also undertaking new primary market research with healthcare professionals using an updated blinded product profile that will include both oral and IV formulations and we'll be tracking feedback. Additionally, the possibility of being the first and only option for the treatment of adenovirus infections reframes our pricing considerations. And on a related note, we would anticipate that the probability of securing market access for this use would likely be high considering the lack of any indicated comparators.

In closing, we will update our market size and potential by evaluating the impact or pre-prioritizing our order of indications. As has been shared earlier on this call, we continue to plan for possible uses of brinci in CMV prevention and treatment, in stem cell and solid organ transplant populations. As we gain more clarity on the clinical and regulatory paths forward we will continue to refine our commercial platform. Now I'd like to turn the call over to Tim.

Thank you, Linda, and good morning everyone. As Kevin mentioned in his introductory remarks earlier today we issued a press release containing our financial results for both the fourth-quarter and full-year 2015. Starting with our balance sheet, at the end of 2015 we had approximately $343 million in capital available to fund operations, we're debt-free, and had approximately 46.2 million outstanding shares of common stock.

Turning to our statement of operations, Chimerix reported a net loss of $37.8 million or $0.82 per basic and diluted share for the fourth quarter of 2015. During the same period in 2014 the Company recorded a net loss of $20.2 million or $0.52 per basic and diluted share. Revenues for the fourth quarter of 2015 increased to $3.1 million compared to $1.2 million for the same period in 2014 due to an increase in the fourth quarter of 2015 in reimbursable expenses associated with the Company's ongoing development contract with BARDA.

Research and development expenses increased to $31.6 million for the fourth quarter of 2015 compared to $15.7 million for the same period in 2014. This increase was primarily due to initiating the Company's SUSTAIN and SURPASS studies and increased headcount in activities in the Company's clinical, regulatory, development and manufacturing departments. In 2016, we will continue to have closeout costs related to SUPPRESS, SUSTAIN and SURPASS as well as costs related to reporting out-data from the AdVise study.

As we get beyond these we expect our research and development expenses to temporarily trend lower. However, following finalization of our revised development plan and our providing guidance regarding this plan we expect our research and development expenses to increase.

General and administrative expenses increased to $9.8 million for the fourth quarter of 2015 compared to $5.7 million for the same period in 2014. The increase primarily relates to costs for the originally planned 2017 commercial launch and increased headcount and activities in the Company's infrastructure functions. Looking forward to 2016, we expect our general and administrative functions to also trend downward driven primarily by a reduction in expenses related to commercial preparations. Loss from operations was $38.2 million for the fourth quarter of 2015 compared to a loss from operations of $20.2 million for the same period in 2014, due primarily to the increased research and development and general administrative expenses as previously discussed.

In light of the SUPPRESS results and delayed launch, in early 2016 we completed an approximate 20% reduction to our work force. As we work toward a new clinical and regulatory plan to be communicated in the second half of 2016, beginning in late summer with a path forward in adenovirus, we remain extremely well capitalized to make prudent and strategic clinical development and business decisions with approximately $343 million in available capital. Now I'd like to turn the call back to Michelle.

Thank you, Tim. As you've heard this morning we're continuing to evolve a better understanding of the antiviral efficacy of brincidofovir in the CMV prevention setting and are working closely with regulators to set a path forward in stem cell and solid organ populations. The availability of a new IV formulation of brinci going into clinical studies in the second half of 2016 may be particularly important in the stem cell transplant recipients who are at high risk of early viral reactivation. At the same time, we are planning to move forward with oral brincidofovir in kidney transplant recipients at increased risk of BK Virus associated disease.

In the coming weeks, we will have the survival and other outcomes data from the AdVise Study and historic controls and plan to have discussions with the FDA regarding the strength of these data in combination with our animal models, Phase 2 data and extensive numbers of patients who've received brincidofovir for adenovirus infections through our expanded access programs. We expect to provide guidance on the next steps in this program in late summer.

Our smallpox program is progressing toward a second efficacy study in an animal model, with data anticipated near year-end. We remain optimistic that negotiations with BARDA for procurement of brinci for the strategic national stockpile will reopen in 2016. Finally, we continue to bring forward molecules from our Chimerix chemical library with CMX669 moving into the clinic in late 2016 or early 2017 and a potential new clinical candidate for norovirus later this year.

Thank you for your participation in the call this morning. We will now open the call up for any questions.

(Operator Instructions)

Jessica Fye, JPMorgan.

This is Ryan on for Jessie. I appreciate you taking our questions. Could you talk a little bit more about the path forward for Adenovirus? And say if the data was a home run, I mean recognizing that the FDA doesn't seem to love historicals control studies, but given that it's a very severe disease would you still expect to do another study?

I think it's a question for us to ask of the FDA. We will be presenting the results of the study with the historical matched controls and depending on the strength of that data we will be discussing what the next steps will be. It's important to note that we have quite a history as far as treatment of Adenovirus infections concerned with patients, a number of patients who were treated in our expanded access studies. Study 350, we also have a Phase 2 study, Study 202 which we previously presented. So there's quite a wealth of data that we will be presenting to the FDA to support our activity against Adenovirus.

Could you elaborate a little bit more on what you see as sort of a path forward with the IV formulation. It sounded like you, once you do a PK dynamic study you can move into advanced later stage studies, but would you see that being sort of in combination with the oral or would it be, would you have to run independent IV studies on your own? Or separately?

I think the basic concept is that we can bridge to the exposure that we've seen from a pharmacokinetic perspective that we've achieved with oral therapy. We know the in the SUPPRESS study that oral Brincidofovir at 100mg twice weekly was an effective antiviral, so we can bridge to that exposure and if the IV therapy is associated with a lower incidence of gastrointestinal events as we expect, then we can basically achieve the same antiviral activity with an improved safety profile, particularly in those first couple of weeks after transplantation when patients are at particular risk for gastrointestinal side effects.

Just to go back to my first question, can you touch on any precedents that would support the potential for approval on AdVise alone?

There's a number of other agents that have recently been approved with smaller indications. Cresemba was an example of a study of a product that was approved for an indication for invasive Mucormycosis. That was in the context of also an approval in a head-to-head study against Voriconazole.

In the stem cell transplant treatment population recent European approvals for a drug called Defiberotide were based on the basis of historical control trials and we are aware that that study is currently up for FDA approval now as well. There's ample other examples in patients with orphan drug indications with various genetic diseases where this type of an approach has been successful.

Silma Do, Cowan and Company.

First on the rates of mortality associated with disseminated adenoviral infections, in the press release this morning you cite rates of 50% to 80%. Can you just discuss a little bit more about that range? How many data points are towards the bottom, how many are towards the top, and are there any variables that determine where the mortality rates are going to fall within that range?

Sure. So the range of outcomes associate with disseminated Adenovirus disease in stem cell transplant patients is within that range.

It just depends on the types of patients that are being treated, with adults versus pediatric patients, and really even more importantly according to the underlying transplant conditioning therapy and immunosuppressive regimens these patients receive, so at centers for example that have -- that use T-cell depletion or heavy-duty immunosuppression in order to prevent graft-versus-host disease the occurrence of Adenovirus can be very life-threatening because those individuals have a long period of time before they recover their immune responsiveness. With no approved therapies for the treatment of Adenovirus physicians have to resort to decreasing immunosuppression and the use of IV Cidofovir, which is associated with really not much in the way of efficacy but a high rate of renal toxicity and renal failure.

So within the trial sites where AdVise is being conducted, do you have enough of a variety of patients that you can match in the historical control database for all those elements, things like T-cell depletion or conditioning regiments?

That's one of the important reasons why we're matching according to center, because center specific variables will be consistent within centers, so we do believe that by doing that you're going to take account of a lot of those variables but we're still controlling for some of those key factors that are associated with a high risk of progression to mortality, such as conditioning regimen and immunosuppressive regimen in the matching procedure.

Do you have a sense -- you may have presented this, I can't recall -- to have a sense of the rates of diarrhea and the use of steroids within the patients in AdVise?

It's important to recognize that most of these patients have diarrhea at baseline because most of the patients have developed Adenovirus infections. The predominant clinical manifestation is Adenovirus enteritis.

What we've seen in our patients in the AdVise trial is that patients that are treated with Brincidofovir tend to improve in terms of their side effects as Adenovirus is being treated so they get decreased rates of diarrhea over time on the study. It's going to be an important outcome for us to look at in terms of the long-term outcomes in these patients.

On the commercial side, we're still struggling to figure how many patients have life-threatening adenoviral disease each year in the United States. I know you talked about doing some work. Do you have any preliminary figures that you could share?

I think we're trying to triangulate so we are looking at a variety of data sources. I think you can get a false read if you only rely on your own market research where people can understate or overstate what they think is the incident.

So we are looking at hospital discharge data and codes. There's some government information, et cetera. We are pulling that all together.

We did a large quant study earlier primarily focused on Europe, but that I think it would be imprudent to speak totally until we refine that forecast, but we're trying to triangulate with different sources.

Katherine Xu, William Blair.

I'm just wondering with regards to AdVise, the primary endpoint is survival at 180 days, right?

The primary endpoint in the study is time to mortality in the Cohort B patients, in the patients with disseminated disease and then in the Cohort A patients, it's time to either the development of progressive Adenovirus infection or mortality.

So in Cohort B, I thought it was, landmark's analysis 180 days following treatments. Is that not the case, or is it just the Kaplan-Meier curve analysis?

Patients are followed out to 24 weeks after their last dose of therapy. The analysis that we're going to be performing is going to be all patients through 24 weeks, so that's 12 weeks of therapy and 12 weeks of follow-up. Again, the primary endpoint of the study is the time to event analysis.

At the midyear FDA meeting you're going to look at the 12-plus-12 data?

Correct.

And then so when 12-plus-24 comes and there's going to be another discussion, or is it going to be any change to that or?

I think it's going to be an important conversation to have with the FDA as to what the path forward will be based on that data set. Difficult to speculate. It depends on what the data shows, so we're really looking forward to having that data but what we do know is that at day 90 in the Cohort B patients we were still seeing a less than 40% mortality.

As we get the 24 week data and importantly we get that matched control data, we will have a better idea about our path forward. But really in terms of communicating outside of the Company, we really want to have those conversations with regulators before we really discuss what those next steps are going to be.

Can you, Garrett, explain the steroid use pattern in Adenovirus treatment and management?

Sure. I think that one of the important concepts is that in the Adenovirus treatment study the median day of start of drug is later than is the case in a prophylaxis study in SUPPRESS, so we started on average at day 15 in SUPPRESS. The median start date for Adenovirus in the AdVise trial is around day 60. So it's later than is the case in SUPPRESS.

Accordingly a lot of these patients will have developed graft-versus-host disease already and already be on therapy for graft-versus-host disease, indeed that's a risk factor for developing Adenovirus disease in the first place. In the setting of Adenovirus infection, especially severe Adenovirus infection, physicians tend to manage a patient by decreasing immunosuppression rather than increasing immunosuppression in an attempt to get the Adenovirus infection under control. So they will rapidly taper immunosuppression, and really that's a very different situation than what we've witnessed with SUPPRESS when patients were being presumptively treated for graft-versus-host disease continued on Brincidofovir and had immunosuppression increased in the setting of continued diarrhea.

That was helpful. I just have a question on the antiviral activity of Brinci. So from SUPPRESS during that treatment period of 14 weeks, and you have 24% versus 38%, so that was kind of short of the planned 50% reduction. And I know you cut the BK Virus by reading against13% versus 20%, lower but I don't know whether that's within or meeting expectations, and of course when it gets to the clinical outcome there was no difference.

So I'm just curious with this kind of data did this kind of meet your expectations in terms of NTR activity, or where they short of expectation, any thought there?

I think that clearly what we know is that these patients were pretty heavily immunosuppressed on the Brincidofovir regimen. So the use of corticosteroids was eightfold higher just through the first 100 days after transplantation and this may account for some of the reason of the decreased efficacy.

We still had a very potent antiviral effect in the first 14 weeks and indeed it was carried through to the full 24 weeks of study where patients who were treated with Brinci had lower rates of CMB reactivation overall, and that was still statistically significant with a P value 0.01 through week 24. That said, I think that as we look at our treatment going forward we're hopeful that a number of different things from education of physicians to potentially the use of IV therapy will decrease the incidence of diarrhea and specifically the management of patients with high risk corticosteroids such that we're able to improve upon antiviral efficacy going forward.

Yigal Nochomovitz, Citigroup.

On the Phase 2 Brinci study and kidney transplant that you are planning, could you talk a bit more about how you're going to screen patients for high risk of BK reactivation? I guess it wasn't clear to me based on our work that you could sort of know a priori who would be more likely to reactivate BK, and then can you give any more details on the Phase 2 design in terms of whether it's going to be randomized and if so what you're going to compare to?

Thanks, Yigal. So we are looking at a number of different options and these could include particular patients that are particularly high risk for BK Virus infection owing to the high levels of immunosuppressions that are used. So some of these characteristics could be patients with donor reactive antibodies that would be a very, very high risk for BK Virus reactivation, in which case a randomized controlled study against active Valganciclovir could be contemplated, but there's also we know that BK Virus is actively screened for in these patients. Either in the blood, so looking for BK viremia, or in the urine looking for BK shedding in the urine.

Both of which perceive the development of BK Virus nephropathy and therefore because there's nothing to do for those patients, I study that randomized patients either Brincidofovir or placebo could be contemplated in a Phase 2 design.

When might we know what that trial looks like?

I think that these conversations are ongoing with our solid organ transplant physicians and we probably will be able to provide further guidance in the middle of the year.

Okay. I actually had a question on the new molecule 669 versus Brinci. Can you just spend a few minutes discussing how the 669 profile differs from Brinci in terms of breadth and depth of antiviral activity, potency, and also are you able to say at this point whether you think that the 669 might offer a better chance of not having a diarrhea side effect versus Brinci?

Good question, Yigal. On CMX669 it does have a different profile than Brinci. It is not as broad an antiviral but does have very potent efficacy in-vitro against CMB and BK Virus.

The dosing of 669 is likely to be more frequent than Brinci, and because of that it may be a better antiviral to begin in the context of active CMB infection, because you can get to study state much more quickly with a drug that has a shorter half-life. We've not seen evidence of GI side effects in our preclinical models and as you're aware the preclinical studies with oral Brinci did give us an indication of the likely GI side effects that we have seen in a number of patients who are on oral Brinci. Like the IV formulation of Brinci they were not see evidence of GI toxicity with CMX669.

Again as Garrett was alluding to, as we learn more about these patients who are at high risk for BK or who already have early evidence of reactivation of BK that may be a population that is already self-selecting for the advantages that CMX669 could bring. The solid organ transplant recipients and in particular the kidney transplant patients don't seem to have the breadth of the multiple DNA viral infections that stem cell transplants recipients have, so again that population could be a better first choice for us.

As we're continuing to explore the patient populations and understand more about the BK Virus predictors, those patient populations may be our likely first choice for patients with unmet medical needs. As we get into the clinical studies with 669 we'll better understand the dosing frequency but much more likely to be a daily dose, once daily dose, than what we saw for Brinci with twice weekly dosing or even once weekly dosing.

Thank you. Michelle, on the smallpox negotiations with BARDA, could you just clarify how that process works? It wasn't clear to me that the discussions were closed or that they needed to be reopened, and if it's still the Corporate goal that you'll expect a contract this year?

Yes. Very much still a Corporate goal. The proposal that we had submitted again for the request for response, and then last summer we submitted a proposal in August of 2015, but because the federal budget was not fully funded because there were not monies available within BARDA toward the end of the fiscal year at the end of September, we were not able to come to complete negotiations on that. As you may remember, there were some ongoing discussions about our 2016 federal budget but now with the 2016 federal budget approved and having gone through the various committees, we do know that BARDA has their 2016 budget. We are hopeful that we can thus reopen the negotiations.

Because we -- the proposal that we submitted was only available to be negotiated for 60 days, so that expired at the end of September. So that's why the reopened, with air quotes, negotiation, we would need to update some of those dates for manufacture of the drug and we are still in a position where if we can get to a final negotiation in the first half or so of 2016 that could allow us to begin to provide drug to the stockpile in the later part of 2017.

Just a reminder, too, that we did recently present the full data from our rabbit pox efficacy model which is one of our two pivotal studies for smallpox under the FDA's animal rule, and we saw 100% survival in that lethal model when Brincidofovir was begun immediately upon confirmation of infection and continue to see statistically significant improved survival than the dosing began 24 or 48 hours after confirmation of infection. Because the rabbit pox duration of infection is about half the duration for smallpox. It means that you have more of an opportunity to begin Brinci in the setting of a potential smallpox outbreak or bio weapon event.

One final question if I could, you made a comment in the press release on potential BV activities. Is that something that's more of an exploratory nature for this year or is the goal to transact some sort of deal for an in-licensing this year?

That has continued to be exploratory. We've actually been looking at BV opportunities over the last 1 1/2 years or so but are continuing to look at potential opportunities for complementary molecules for Brinci given our patient populations with both stem cell, solid organ and other immunocompromised patients. So really not much more detail available at this point but it is something that we are actively looking at.

Andrew Peters, UBS.

I just wanted to kind of tease out a couple more on the solid organ transplant Phase 2. It seems that one of the options that you are thinking is looking at end points like BK nephropathy. I just wanted to understand really how achievable or easy of an endpoint is that given that it's a relatively infrequent adverse event just given the larger landscape of transplant.

So how would you be able to sort of tease out a meaningful effect there? Would you just be looking for trends in improvement or is that something you think you could kind of tease out a statistically significant result?

Thanks for the question. I think there are intermediate endpoints before you get to BK nephropathy that would be useful to look at. So week one could look at high risk patients and look at endpoints of BK Virus in the urine or BK Virus in the blood as intermediate endpoints, or one could screen for patients who develop for example BK Virus in the urine and treat those individuals in order to prevent the development of BK Virus in the blood. So I don't think that we necessarily -- you're correct that if you did a study that was looking for BK nephropathy as an endpoint that's more of a Phase 3 clinical endpoint type of a study and was one of the end points that we were looking at in the Phase 3 program.

What we're looking at in Phase 2 is evidence of activity against BK Virus and protection of the patients from development of progressive BK Virus or BK Virus progression in those individuals. So it just depends on the design that we end up arriving at but there are several options that have intermediate steps before one gets to BK nephropathy.

Great. Just another BK-related question. So I know that the data that you've presented from SUPPRESS so far have been relatively early. I think it was eight weeks or so on the viremia side. As you get additional data points coming out, would that change your view at all on kind of the impact or the effect of Brinci on BK viremia, or is it the fact that the earlier data may actually tell you a bit more in terms of antiviral activity just because of the potential compounding of the steroids?

I think that's one of the reasons that we ended up doing the first eight weeks was to as much as possible remove some of that compounding effect. We do plan to do further analyses of plasma samples later in the time points and then those data would be -- would need to be analyzed in the context of increasing immunosuppression. So I think that we've kind of hit the highlight as far as the initial activity but further data points will be very useful for us to take a look at as well.

Geoff Meacham, Barclays.

This is Carter on for Geoff, thanks for taking our question. Assuming AdVise and the match control data are supportive, what role should we be thinking the EAP dataset will play, and maybe you can just remind us on how large that sample size should be by the time you go before regulators.

The expanded access protocol is being opened primarily to provide access to Brincidofovir but it does give us the opportunity to capture data from patients. As you know emergency IND, individual IND access, does not give us an opportunity to collect data from these patients and so this is an opportunity for us to develop further experience with regards to Brinci.

At this point we are fulfilling roughly 7 requests per week, and so over time this is going to be a pretty significant increase in the data set as we continue to collect patients in the opening expanded access program. But we also have the old study 350 which had quite a few patients who were treated for Adenovirus as well that complements the dataset that we will have from AdVise.

That concludes our question-and-answer session for today. I would like to turn the conference back over to Chimerix's management for any additional comments.

Thank you very much for joining us this morning. We hope this was helpful in clarifying some of our forward-looking design considerations and timing on particular the Adenovirus indication availability of data in later spring with meetings planned with the FDA and other regulators later in the year. But we hope by Summer we will be able to provide you with guidance on where we are with Adenovirus and any potential next steps that were discussed with the FDA.

We also hope to be bringing you data on IV Brincidofovir with a first in human study scheduled in the second half of 2016 and again those data -- that should lead us to quickly get back into treatment of patients with CMB, BK or other patient populations in particular that have a need for IV for prevention in very early stem cell transplant patients. Again, thank you for your support and appreciate your joining us this morning. Thank you.

Thank you. Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program, and you may now disconnect. Everyone, have a good day.