Prothena Corp plc (NASDAQ:PRTA)
Q4 2015 Results Earnings Conference Call
February 18, 2016, 04:30 PM ET
Ellen Rose - IR
Dale Schenk - President and Chief Executive Officer
Gene Kinney - Chief Scientific Officer and Head of Research & Development
Tran Nguyen - Chief Financial Officer
Michael Yee - RBC Capital Markets
Andrew Peters - UBS
Kennen MacKay - Credit Suisse
Heather Behanna - Wedbush Securities
Chris Marai - Oppenheimer
Good day, ladies and gentlemen and welcome to the Prothena Fourth Quarter 2015 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session and instructions will follow at that time. [Operator Instructions] As a reminder, this conference is being recorded.
I would now like to introduce your host for today's conference Ms. Ellen Rose. Ma'am, you may begin.
Thank you, Laura, and good afternoon, everyone and welcome to Prothena's investor conference call to review our fourth quarter and full year 2015 financial results and business progress, as well as our 2016 financial guidance. Please review the press release we issued earlier today, which is available at our website at prothena.com, and is also attached to Form 8-K filed today with the SEC.
Turning to the agenda, speaking on today's call, we have Dr. Dale Schenk, our President and Chief Executive Officer, who will discuss our 2015 highlights and corporate accomplishments; Dr. Gene Kinney, our Chief Scientific Officer and Head of Research and Development, who will review our pipeline development; and Tran Nguyen, our Chief Financial Officer, who will review our financial results for the fourth quarter and full year of 2015 and 2016 financial guidance. Dale will then provide upcoming milestones and then open the call for Q&A.
Before we begin, I'd like to remind you that during the course of today's presentation, we will be making statements regarding Prothena's future expectations, plans and prospects that constitute forward-looking statements under the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements are based on estimates, projections and assumptions that may prove not to be accurate and actual results may differ materially from those anticipated due to known and unknown risks, uncertainties and other factors.
For a discussion of the risks associated with our forward-looking statements, please see our press release issued today, as well as our most recent Form 10-Q filed with the SEC and also the Form 10-K we will soon be filing with the SEC. We disclaim any obligation to update our forward-looking statements.
With that, I'd like to turn the call over to Dale.
Thank you, Ellen. And thank you all for joining this afternoon. It's really a pleasure to discuss our 2015 and recent accomplishments as it was an exceptional year. We've made meaningful advances in all of our clinical programs, including new trials and important clinical results and we've advanced our preclinical program identifying candidates for a fourth potential program.
We have raised the awareness of our programs through the publication and presentation of our clinical results and importantly, we strengthened our balance sheet with the successful completion of two equity offerings that will provide optimal flexibility for the future.
I'd like to begin with a high level review of each of our programs and corporate accomplishments. Our most advanced immunotherapy is NEOD001, a monoclonal antibody for the potential treatment of patients with AL amyloidosis. We are advancing three clinical studies for NEOD001.
First, we continue to enroll patients in the vital amyloidosis study, our Phase 3 global registrational trial in newly diagnosed treatment-naive patients with AL amyloidosis and cardiac dysfunction. This study is designed to support full global regulatory registration.
Second, we announced plans to initiate PRONTO, a Phase 2b global registration-directed study of NEOD001 in previously-treated patients with AL amyloidosis and persistent organ dysfunction.
This study was designed to align with feedback from the European Medicines Agency we received related to the VITAL Amyloidosis Study. This was as a context of a discussion regarding proBNP as a primary surrogate endpoint for conditional approval.
N-terminal proBNP response is a widely validated functional biomarker that predicts survival in patients with the AL amyloidosis. The PRONTO trial enables us to explore an accelerated path forward to address the high unmet need for therapies that improve organ function in patients with AL amyloidosis.
Demonstrating significant improvements in this key cardiac functional biomarker along with supporting trends in key secondary endpoints will expedite our development timeline and provide an additional opportunity to engage with regulators.
Third, we completed enrollment in the expansion cohort of our Phase 1/2 multiple ascending dose trial. Enrollment in the expansion cohort was increased to 42 from the original 25 patients.
This increase was driven by strong interest from patients and physicians following the positive clinical results from the Phase 1/2 multiple ascending dose portion of the NEOD001 study that were presented in oral presentations at both the ASCO and EHA congresses in June of 2015.
Next we have PRX002, our monoclonal antibody for the potential treatment of patients with Parkinson's disease and other synucleinopathies, which is the primary focus of our worldwide collaboration with Roche. We are conducting a Phase 1 multiple ascending dose study in patients with Parkinson's disease.
We reported positive Phase I, single-ascending dose study results in June 2015 in a late-breaking session at the 19th International Congress of Parkinson's Disease and Movement Disorders. Given the safety and tolerability profile seen to-date, we recently decided to add a high dose cohort to this study to inform the design and dosing levels of future clinical studies.
Our third protein immunotherapy program in clinical development is PRX003, a monoclonal antibody for the potential treatment of inflammatory diseases, including psoriasis. In June 2015, we initiated a Phase I, single-ascending dose study of PRX003 that is designed to assess the safety, tolerability, pharmacokinetics, immunogenicity and target engagement.
We also expect to initiate a Phase 1b proof-of-biology study in patients with psoriasis and look forward to discussing an initial indication to pursue based on where we believe the biology of PRX003 can provide unmet clinical need. And though early, we are excited about our evolving preclinical program targeting the amyloidogenic forms of transthyretin.
In November 2015, we presented preclinical results at the first European Congress on Hereditary TTR Amyloidosis from a series of novel confirmation-specific antibodies that selectively bind to the diseased proteins.
Turning to our corporate accomplishments, in January 2015, we appointed Dr. Anders Harfstrand to our Board. Dr. Harfstrand strengthens our Board through the strategic experience leading both entrepreneurial and large commercial organizations.
Finally, we successfully raised a total of approximately $260 million in aggregate net proceeds from two public equity offerings executed in April 2015 and January 2016. As a result, we have a very solid cash position to advance our programs through key development milestones. As you can see, it's been a very productive year across our organization.
I'd like to now turn the call over to Gene for more detail on each of these programs. Gene?
Thanks, Dale. I'd like to give a bit more detail on each of our programs beginning with NEOD001. We are developing NEOD001 for the treatment of patients with AL Amyloidosis. AL Amyloidosis is a systemic and progressive disease that often affects multiple organs and tissues within body.
While there are other types of systemic Amyloidosis, including a AA and GTR Amyloidosis, patients with AL Amyloidosis represent the majority of these systemic Amyloidosis. AL Amyloidosis affects between 30,000 to 45,000 patients in the US and Europe, with the yearly incidence rate of 10,000 to 15,000 patients.
In AL Amyloidosis, misfolded light chain proteins circulate through the body and also in accumulated in the organ tissues. The median age of onset is around 60 years old, but onset can happen at practically any age.
For the majority of patients, current treatment is limited to the off-label use of cytotoxic chemotherapeutic agents. The goal of these treatments is to control the hematologic burden, but targeting clonal plasma cells in order to decrease the production of new light chain. The cytotoxic agents are often poorly tolerated and patients may become refractory to their effect and/or relapse.
In addition, the indirect benefit of hematologic control on the underlying organ dysfunction is variable. This is an important point, since it is clear that hematologic control in the absence of organ benefit is of limited value to this patient population.
As such, there remains a significant unmet need for a well-tolerated therapy that can improve organ function and survival by directly targeting the removal of insoluble amyloid deposited on organs.
NEOD001 is an antibody that specifically targets misfolded soluble light chain as well as the deposited amyloid in vital organs such as the heart or kidneys. When AL Amyloids builds up in the heart, it leads to a progressive restrictive cardiomyopathy with associated cardiac dysfunction.
The progressive nature of this disease means that patients do not get better with our intervention and will experience progressive organ dysfunction that leads to death in many cases. For this reason, the safe and well tolerated treatment that improves or stabilizes organ function represents a significant unmet need.
We believe that NEOD001 functions by neutralizing and breaking up the misfolded light chain circulating in the blood, ameliorating the toxicity caused by soluble misfolded forms of this protein. As an immunotherapy, NEOD001 is believed to stimulate immune system to breakdown the amyloid and clear from organs.
At the American Society of Hematology annual meeting in December, we presented results of preclinical studies demonstrating the binding and clearance properties of NEOD001 and the related murine form of the antibody.
This study demonstrated that the antibody specifically recognize soluble and insoluble aggregates in organs of patients with AL Amyloidosis and promoted the clearance of insoluble aggregates by stimulating phagocytosis.
Over the course of 2015, our clinical program for NEOD001 has progressed and expanded. Our most advanced clinical trial is the VITAL Phase III Amyloidosis Study, which continues to enroll newly diagnosed treatment-naive patients with AL Amyloidosis and cardiac dysfunction.
Designed to support global regulatory registration, the VITAL Amyloidosis Study is expected to enroll approximately 230 patients who are randomized on a one-to-one basis to receive 24 milligrams per kilogram of NEOD001 or placebo with both arms of the study receiving concurrent standard of care therapy. The composite primary endpoint is event based with all-cause mortality or cardiac hospitalizations as qualifying events.
Secondary endpoints include a valuation of cardiac biomarker NT-proBNP, the renal biomarker proteinuria, six-minute walk test and the quality of life survey short-form 36. We continue to open new sites and based on our current projections, we expect VITAL enrolment to be complete in the second quarter of 2017.
In October 2015, we announced plans to initiate PRONTO, a Phase 2b global registration directed randomized, double-blind, placebo-controlled trial. Whereas VITAL is enrolling newly diagnosed treatment-naive patients, PRONTO is expected to enroll approximately 100 previously treated patients with a primary diagnosis of AL Amyloidosis in cardiac dysfunction.
The primary endpoint in PRONTO is cardiac response defined by NT-proBNP best response over 12 months. Secondary supported endpoints will include the quality of life survey short form 36, the 6-minute walk test and the renal functional biomarker proteinuria. We expect to begin enrolling patients in PRONTO early in the second quarter of this year.
In clinical care today, NT-proBMP is widely incorporated into the cardiac staging of patients with AL Amyloidosis for diagnostic purposes and also used to determine the optimal treatment regimen and to predict survival based on treatment response.
Importantly, key opinion leaders agree that preventing NT-proBMP progression is the treatment objective for patients with AL Amyloidosis and cardiac involvement. Patients enrolled in PRONTO are required to have a baseline NT-proBMP level between 650 nanograms and 5,000 nanograms per liter and will have been previously treated with a plasma cell-directed off-label therapy such as the patients are organ refractory, meaning they are hematologically stable but have persistent and ongoing cardiac dysfunction. Patients will be randomized on a one-to-one basis to receive either 24 milligrams per kilogram of NEOD001 or placebo by intravenous infusion every 28 days.
The PRONTO trail is designed with 80% power to detect an absolute difference of 26.5% in NT-proBMP best response rate between the treatment and placebo groups with a two-sided alpha of 0.05. And with the initiation of the PRONTO trial, we do not currently expect to conduct an interim efficacy analysis in the VITAL study. I'd like to provide a bit more context on the endpoint of cardiac response as defined by lowering of NT-proBMP.
In a white paper submitted to regulators by the Amyloidosis Research Consortium, a group that brings together experts in the field to advance research, a compelling rationale is outlined for the use of the NT-proBMP as a surrogate functional biomarker endpoint in clinical trial in patients with AL Amyloidosis.
This functional biomarker has been evaluated following intervention in more than seven independent studies in almost 2,000 patients, a significant patient pool for a rare disease. In these studies, it has been consistently shown that NT-proBMP response predicts improved survival for patients with AL Amyloidosis.
The Amyloidosis Research Consortium has called on the FDA to adopt NT-proBMP response as a primary surrogate outcome measure to accelerate the registration of new therapeutics intended for the treatment of AL Amyloidosis.
In addition to VITAL and PRONTO, the expansion cohort of the Phase 1/2 multiple ascending dose study of NEOD001 in patients with AL Amyloidosis and persistent organ dysfunction was fully enrolled in 2015. This expansion cohort seeks to build on our understanding of the impact of NEOD001 on specific functional biomarker endpoints.
Of the 42 enrolled patients, there are 15 patients with cardiac dysfunction, 16 patients with renal dysfunction and 11 patients with peripheral neuropathy. Similar to the functional biomarkers we looked at in the previously reported Phase 1/2 result, in the expansion cohort.
We will evaluate the cardiac biomarker NT-proBNP and the renal biomarker proteinuria. In the patients where we are evaluating peripheral neuropathy, we will report results through the use of a modified lower limb neuropathy impairment score also known as the NIS-LL.
Turning next to PRX002, approximately seven million to 10 million people worldwide have Parkinson's disease today, making it the second most common neurodegenerative disease after Alzheimer’s.
There are no approved disease modifying therapies presently available. Current treatments manage the early symptoms, but importantly, do not address the underlying biology that is believed to be involved in this cause and progression of disease.
Alpha-synuclein is the protein thought to be intricately involved in the onset and progression of Parkinson's disease. Alpha-synuclein is found extensively in neurons and is a major component of pathological inclusions that characterize several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed synucleinopathies.
In June 2015, we presented results of the Phase 1 single ascending dose study in healthy volunteers that demonstrated that PRX002 was safe and well tolerated at all of those levels, meeting the primary objective of the study.
We also reported that PRX002 reduced free serum alpha-synuclein by up to 96% in these healthy volunteers. We are currently enrolling up to 80 patients in a double-blind, placebo-controlled Phase 1 multiple ascending dose study of PRX002 in patients with Parkinson's disease. Enrolled patients received three doses of PRX002 or placebo and are followed for three months after the completion of dosing.
We recently decided together with Roche to add a 60 milligram per kilogram dose level cohort of patients. The addition of this cohort is intended to inform the design and dosing levels of future PRX002 clinical studies and was based in part on the safety and tolerability profile of PRX002 at lower dose levels.
With the addition of this high dose cohort, we now expect to report top line results from the multiple ascending dose study in the fourth quarter of 2016. This study will remain blinded until completion, which we expect to occur following completion of the 60 milligram per kilogram dose cohort follow-up period.
Moving to our third program in the clinic, PRX003 is humanized monoclonal antibody in development for the potential treatment of inflammatory diseases, including psoriasis. PRX003 targets melanoma cell adhesion molecule or MCAM. MCAM facilitate the movement of certain cells in the bloodstream to enter tissue and initiate a process that maybe integral to many inflammatory diseases.
This cell trafficking process has been documented in many [inflammatory] diseases including psoriasis, psoriatic arthritis, multiple sclerosis, uveitis and Behcet's disease. We believe that PRX003 may prevent adherence to and transmigration across the blood vessel wall and thereby prevent disease causing cell to spreading into tissue.
In June 2015, we initiated a Phase 1 double-blind, placebo-controlled, single ascending dose study in healthy volunteers and the top line results of this study are expected in the second quarter of this year.
Because of the visual defined nature psoriasis, we anticipate that we will be able to rapidly asses the safety, pharmacokinetics and possibly the proof-of-biology of PRX003 in a double-blind, placebo-controlled Phase 1 multiple ascending dose study in patients with psoriasis that we expect to initiate in the first half of this year. These data will further inform our strategic clinical development pathway for psoriasis or other inflammatory diseases.
The PRX003 program builds on our teams' deep scientific expertise in cell adhesion and immune-mediated disease, and we look forward to talking more about it in the coming months when we share the results of the Phase I single ascending dose study and also provide more information on the unique biology of this compound and the indications we may pursue following the proof-of-biology study in psoriasis.
Finally, we've also been active in our discovery programs. In November 2015, we presented preclinical results from the series of novel, conformation-specific antibodies that selectively bind the amyloidogenic or diseased forms of transthyretin at the First European Congress on Hereditary TTR Amyloidosis.
While our late-stage program focuses on AL amyloidosis, TTR amyloidosis represents a population that is similarly underserved and we believe our approach could make a difference in the lives of patients.
As you can see, we have a robust pipeline that remain committed to bringing new disease-modifying therapies to patients suffering from the difficult to treat and often fatal diseases.
At this time, I'd like turn the call over to Tran for a discussion of our financial results. Tran?
Thanks, Gene. First, our cash burn from operating and investing activities in 2015 was approximately $63.8 million, which was favorable and below our guidance of $66 million to $72 million.
As you know, these figures do not include the $128.6 million in net proceeds raised through our recent equity offering in January. The favorability of our actual results compared to guidance was driven primarily by lower than anticipated development expenses and to a lesser extent, higher than expected accrued liabilities.
We reported net losses of $24.2 million and $80.6 million for the fourth quarter and full year of 2015 as compared to net losses of $13.1 million and $7.2 million for the fourth quarter and full year of 2014.
Net losses per share were $0.76 and $2.66 for the fourth quarter and full year of 2015 as compared to net losses per share $0.48 and $0.29 for the fourth quarter and full year of 2014. Net loss for the fourth quarter and full year of 2015 included share-based compensation expense of $3.3 million and $10.4 million compared to $1.4 million and $5.6 million for the respective prior year period.
We reported total revenue of $307,000 and $1.6 million for the fourth quarter and full year of 2015, as compared to total revenues of $2 million and $50.9 million for the fourth quarter and full year of 2014. The difference in revenue for the fourth quarter and full year was primarily due to higher revenue earned in 2014 under our collaboration agreement with Roche.
R&D expenses totaled $17.9 million and $58.4 million for the fourth quarter and full year of 2015 as compared to $10.1 million and $38.5 million for the fourth quarter and full year of 2014.
The increase in R&D expenses was primarily due to increased external expenses related to clinical trial and higher personnel cost. R&D expenses included non-cash share-based compensation expense of $1.3 million and $4.3 million for the fourth quarter and full year of 2015 as compared $0.6 million and $2.3 million for the fourth quarter and full year of 2014.
G&A expenses totaled $6.6 million and $23.1 million for the fourth quarter and full year of 2015 as compared to $5 million and $19.1 million for the fourth quarter and full year of 2014.
The increase in G&A expenses was primarily due to increases in personnel costs and legal expenses. G&A expenses included non-cash share-based compensation expense of $1.9 million and $6.1 million in the fourth quarter and full year of 2015, as compared to $0.8 million and $3.3 million for the fourth quarter and full year of 2014.
As of December 31, 2015, Prothena had $370.6 million in cash and cash equivalents and no debt. The cash figure does not include $128.6 million in net proceeds received through our recent offering in January. As of February 12, 2016 we have approximately 34.3 million ordinary shares outstanding which includes the issuance of approximately 2.6 million ordinary shares as part of the recent offering.
Now, turning to our 2016 financial guidance, we expect the full year 2016 net cash burn from operating and investing activities to be $105 million to $115 million, ending the year with approximately $388 million in cash which represents the midpoint of the range.
The estimated full year 2016 net cash burn from operating and investing activities is primarily driven by an estimated net loss of $132 million to $149 million, which includes an estimated $18 million of non-cash share-based compensation expense.
Additionally, the increase in the estimated 2016 net loss over 2015 is primarily due to clinical development cost related to the VITAL Amyloidosis Study and PRONTO trial for NEOD001, as well as increased manufacturing cost associated with our clinical and pre-clinical programs.
With that, I'll turn the call back over to Dale to summarize our upcoming milestones for 2016 and beyond. Dale?
Thank you, Tran. As we move forward into 2016, we expect a data-rich year with several important clinical milestones ahead.
For PRX003, we expect to report top line data for our ongoing Phase 1 study in the second quarter of this year and plan to initiate a second Phase 1b multiple ascending dose proof-of-biology study in patients with psoriasis in the second quarter of this year and look forward to discussing potential indications beyond psoriasis after reporting top line results in the single ascending dose study.
For NEOD001, we expect to report top line results from the expansion cohort of the Phase 1/2 study of NEOD001 in the second quarter of this year. For PRX002, we expect to report top line results from the Phase I multiple ascending dose study of PRX002 in patients with Parkinson's diseases in the fourth quarter of this year.
Looking ahead to 2017, we expect to complete enrollment in our Phase 3 VITAL Amyloidosis Study in the second quarter of 2017. We expect top line results from our Phase 2b PRONTO study in late 2017 to early 2018. We are pleased with our progress to-date and we look forward to keeping you apprised of our accomplishments in the future. Thank you for joining the call.
At this time, we open the call for questions. Operator?
[Operator Instructions] Our first question comes from Michael Yee from RBC Capital Markets. Your line is open.
Hi, thanks. Congrats on all the progress, guys. Looking forward this year, two data readouts, first on the amyloidosis study, what are you expecting out of this data and I guess, are there any reasons for it to be slightly better or slightly different than the prior Phase 1 data? And what is the peripheral neuropathy data going to tell you about the drug, does that change your thinking or increase your confidence either away on renal or cardiac amyloidosis, how do you interpret that?
And then, secondly, on the Parkinson's data, you've gone to a much higher dose now. When you report out that data, what types of things are you looking for besides safety, are you looking at biomarkers, what types of things could you talk about?
Did you have any indications of efficacy and specifically, on alpha-synuclein, we should not expect to see changes in that, correct, if we are trying to bind misfolded protein? So, can you walk us through that and help to clarify what we're looking for in these two programs? Thanks.
Yes, hi. Thanks for the questions. Obviously, on the expansion study, we look for consistency with what we've seen previously. Obviously, as you pointed out, peripheral neuropathy is a new entity. We don't have a specific expectation from that, but we look forward to it with interest.
As we've spoken about previously on our Parkinson's program, we look for information to guide us to developing a very rich and powerful Phase 2 or Phase 2/3 and as you point out, that's going to include a number of things, the amount of PRX002 in the CSF but as you pointed out, the amount of synuclein per say in CSF is probably not going to be the key features but Gene, you should elaborate on that.
No, I think that's right. Just maybe a little bit more color on first with D1 expansion data, I think Dale is exactly right. Within margin of error for a study this size, we'd expect to see cardiac and renal responses in line with what we've seen in the dose escalation part of the study.
Peripheral neuropathy, exactly as Dale mentioned, I think we were receiving some interesting anecdotal reports back during the dose escalation phase about peripheral neuropathy, we hadn't looked at it systematically in that part of the study.
So we wanted to bring a more systematic tool to bear. In general, I think both the AL as well as with TTR, as you know that literature, these patients don't generally improve with respect to the peripheral neuropathy.
So clearly what we want to do is just put a scale that's been used in Amyloidosis study to these patients and see what's happening over time. So that's all we'll be looking for peripheral neuropathy. Not a lot of case history out there, not a lot of data in this patient population per se to compare that to, but I think obviously we'll be happy with anything that looks like it might be stabilizing that progression.
How do you interpret that data, Gene, because there is no placebo and that sort of a…
Right, so do we need to redo it with a grain of salt, I mean, do you expect responses or do you expect it to be stable? You are going to report this endpoint, How do you interpret that because…
Yes, I mean, we'll report the data Mike, putting it into context of what you're saying, and I think it is difficult in this population because there's not a lot of case history out there. There are a couple of older published papers and they all said the same thing, which is that the neuropathy is relatively relentless and persistent even in the phase of other organs improving.
But frankly there's not like well-controlled natural history data that we can compare it against. So I think what we'll be looking for is what's happening over a period of time, we know in TTR over time that anything is less than about two point worsening is considered a response in that disease state. So we will be looking along the same lines.
I think, on the Parkinson's disease, I don't have much more to add above and beyond what Dale said. I think that obviously we've been pretty consistent in that thing. We most want to see is how much of the drug actually gets into the central compartment.
For us, the drug getting into the central compartment and understanding how our drug interacts with that network [ph] pathogenic species, as you say, allows us to very accurately model doses to select moving forward into what's called a more efficacy focused clinical studies in the future.
And so I think, clearly we want to see that. The nice part about being able to move to a higher dose from our perspective is that it takes that number, whatever that number is in terms of how much of the antibody gets into this central department and it moves it away from a go, no-go decision on the program.
In other words you can't possibly ever get enough drug into the brain and more into a place where what are the right doses to pick moving forward, so it moves it from kind of go, no-go to a dose selections base, because obviously if we can continue to push the dose, regardless of what that percent number is, higher is higher, right, so which is good.
Higher is higher. Got it. Thank you, guys.
Okay. Thank you, Mike.
And our next question comes from Andrew Peters from UBS. Your line is open.
Hey, guys. Thanks for taking my questions. So first one on VITAL, just appreciate the update kind of on enrollment, seems like it's within your expectations that you laid out when the trial was started. Just want to understand how that could possibly change, say if the data in the second quarter from the expansion cohort are particularly strong?
Did you see any change in enrollment timing on number of patients coming in once the ASCO data were updated? I know you've said in the past that the expansion cohort benefited from kind of that increased knowledge and interest from the prior disclosure. So just want to understand, is it possible that 2017 estimate can still prove conservative?
Yes. It’s a good question. I mean, I think you're right, after we presented, or I should say, our investigators presented data at ASCO and EHA last year, we did see an up tick in interest and that was really evident in the expansion cohort, the data we'll be talking about here in the next quarter.
In VITAL, it's little bit of a different story because remember in VITAL it is newly diagnosed treatment naive patients. So these are patients we will be pulling from the new incidence as opposed from the prevalent population.
And so I think anything that's done that increases awareness and I think enthusiasm around the program always have an opportunity to increase enrollment and help us to enroll the study, just because it increases awareness.
That said, second quarter 2017 is our best estimate today, it's within the guidance, as you say that we previously provided. It is our base case, clearly, we'll continue to pull all the levers we can to make sure that study enrolls as expeditiously as possible.
And then just a follow-up on the VITAL. Has the event rate from a mortality or cardiovascular event perspective, has that differed at all from your expectations from what you've seen so far in the patients on study and how does that kind of play into your expectations for final readout update?
I think you'd previously said, followed 12 months to 18 months once was the last patient is enrolled, is that still consistent with how you're thinking about it?
Yes. So we're still, guiding to 12 months to 18 months past last patient in, I think right now we don't have enough information to change that. Obviously, if at any point the data changes, such that the timing is outside of those goal post, one direction or the other we'll certainly come back and re-guide. But I think for now, it's a bit too early to talk about event rates.
Okay. And then just a quick one on the Parkinson's side, just wanted to check in with the work that you're doing with the Michael J. Fox Foundation on the biomarker side. Is that something that we could expect to see if and when a Phase 2 study is started?
How could those biomarkers be incorporated into a study and what's just the progress both from a trial perspective and any sort of discussions that the foundation may have had with regulators? Thanks.
Yes. So Michael J. Fox, and I said - we have a - I think it's clear that we've had a long relationship with the Michael J. Fox Foundation, very, very good scientists over there, been doing wonderful work there. There are different initiatives looking at both for dermal – for dermal [ph] symptoms as well biomarkers, I think it's been really a game changer for the work we're doing here with PRX002.
What we've done in this agreement that we signed with them last year was really too more formalize that relationship so that we could in a more formal way, actually push certain science or studies through the process and actually evaluate how well they might work in a clinical setting with respect to looking at disease modification or markers target engagement in terms of alpha-synuclein and moving and what have you.
We have, as I've said in the past, loaded up, I think the multiple ascending dose study with a number of biomarkers with the three-month treatment regimen, obviously, we're not suggesting that there is a high probability that those will move in a direction that implies anything about disease modification. It takes a little bit longer than that disease progression in Parkinson's disease using the tools we have today.
That said, we do think it's a great opportunity to operationally derisk some of those biomarkers, to sort to understand fundamentally how they function in the context of a clinical study. And to be able to then use the ones that have the most promise or introduce new ones into Phase 2 studies or Phase 2/3 studies where we might be able to look more at clinical outcomes, efficacy types of outcomes, thinking about treatments maybe a little bit longer than three months.
Okay. Great. Thank you.
Our next question comes from Kennen MacKay from Credit Suisse. Your line is open.
Hi. Thanks so much for taking my questions. Just moving back to the VITAL trial, I was wondering if you could comment on how many centers are open and whether your calculations are based more on increased uptake in the currently only open centers or from expansion in the number of centers?
Yes. I mean so I can tell you that if you're going to -- to go clinical trials (inaudible) today, which is always a lagging indicator, because it's not uptake as often as we'd like, there are about 70 plus centers listed.
And I think what I would expect is that we are enrolling well at the centers that we have open, we still have some centers to open, we're not done with that process yet. So I think it will be a combination of both realizing the benefit in terms of enrollment of the centers that are open, but also then continuing to open centers in multiple geographies.
Okay, got it. And then maybe just moving to the extension data that we'll see in Q2 or 1, we've previously seen about a 57% improvement in cardiac dysfunction patients and a 60% benefit in renal dysfunction patients. Do you have any sense of how we could expect those numbers change?
And a portion of the patients that had moved from the multiple ascending dose into the expansion had received an increase in dose, is that right. So could we expect sort of an increase in responses there?
Yes, let me be very clear. The multiple ascending dose patients are not the same patients at the expansion patients. So no patients moved into the expansion cohort from the original part of the study. It is - so just to be really clear, there's two components to the Phase 1/2 study, component A, is the dose escalation component, these are the data that we've talked about at ASCO and EHA last year.
In that component, the study patients did come into the study at different dose levels, but all patients were escalated to 24 milligrams per kilogram at a certain time point I think we had all patients escalated as of December, if I remember right.
The expansion cohort with the new cohorted patients that we began enrolling last year, completed enrollment of last year, that group is a 42 new patients, again, 15 with cardiac dysfunction, 16 with renal dysfunction, and 11 with peripheral neuropathy, so there's no overlap there.
In terms of what we expect, I mean I think obviously within error, we have to account for 1 standard deviation or 2, but within that we expect the rates to be with inline of what we've seen in the past.
One of things that we did with the expansion cohort was made sure that we didn't lock the database and read that out until the last patient had at least nine months of treatment and that was based on observations from the first part of the study, where all patients had responded at least as of that last February data cut has responded within the first nine months of treatment. So again, we expect to see rates within error margin or margin of error about same rate.
Got it. Okay, terrific. Thanks so much for taking my questions.
Our next question comes from Heather Behanna from Wedbush Securities. Your line is open.
Great. Thanks for taking the question, I've got a couple. The first one on PRONTO, I'm just curious what has been the guiding factor for enrollment, and if you could just remind us of how many centers you're planning for that study?
You mean to get the participation in? Is that you're asking, Heather?
Yes. So I mean it's just the normal work that has to be done. I mean, obviously, when we announced the study, when we made the decision to move forward last October, and I think even at that time, we indicated that we probably be into this year before we got patients enrolled.
We're doing all the things we need to do there. We've got getting all of the countries open, getting all the sites open, getting everybody under contract. So there's a lot to work, the operational work that needs to be done. In terms of the number of sites, we're expecting somewhere in the 25 to 35 range.
Those will be a subset of the VITAL sites, which has actually helped us to some extent with respect to contract language and what have you, since we have some familiarity with those sites and are working with those sites for other programs. So we think that makes a lot of sense, particularly in as much as a reminder, PRONTO is patients that have previously received standard of care, whereas is VITAL is treatment-naive newly diagnosed. So there is no competition for patients at the same site.
Great. That’s helpful. And then just a quick question VITAL. Is there any color you can give us on just through the base line characteristics you're seeing of people enrolling, is it sort of lines up as far as severity or staging occasions that you've seen in the literature as a whole?
Yes. So I think what we're doing in that study is we're stratifying by level cardiac involvement using the different cardiac staging approaches. So obviously, the assumption is, there is four stages there if you use the Mayo staging criteria.
So the assumption there obviously is that for whatever patients we get in, we'll make sure that they're randomly distributed, but in terms of any early read on baseline demographics, we don't have data to share today.
Yes, and I'd say its worth mentioning of - in the VITAL study relative to PRONTO, remember with VITAL like a - with PRONTO it’s like our Phase 1/2 where the patients obviously had already gone through treatment, so they tend to be better off. I think in VITAL we're going to see a large range of that because they're newly diagnosed, just like it was in a real world setting.
Great. That’s helpful. And then, I just had a quick question for Tran on the SG&A expense that kind of bumps up this quarter. I'm sorry if I missed it. Moving forward, should we expect things to sort of even out a little bit or we are going to see a greater increase again as we move into 2016?
Well, given that we've increased our cash burn guidance to $105 million to $115 million, you should definitely see an increase in OpEx. That being said, it's driven 80% by R&D and then 20% by G&A. So, clearly, still very focused on R&D activities and from that perspective, that's also primarily driven by activities around NEOD001.
Perfect. Thank you.
Our next question comes from Chris Marai from Oppenheimer. Your line is open.
Good afternoon, guys. Thanks for taking the question. So, really just on the next readout for NEOD001, I was wondering if you could help us understand what evidence we'd have from those readouts that would suggest you removing, I guess, the amyloid plaques from tissue.
Very specifically, I know you presented some data at ASH in that regard. But is there any way we can look at either a comparison between your responses in renal patients versus cardiac or maybe even data from the peripheral neuropathy patients that would suggest we're actually removing the plaques from the tissue? Thanks.
Well, I think, - yes, we've spoken about is not great imaging agents for the tissues that we happen to be looking at. We were looking at spleen or liver would be much easier and keep in mind too it could be that we're removing soluble aggregates and that's leading a big piece of the way for the improvement, although as we've often said in renal we think its likely due to removal of the aggregates. There is not a simple way to do it – it was in a good way right now...
Yes, I agree. I mean, there is no imaging agent that we can use today widely that would allow us to look at that specifically but I think Dale's point is right on the mark, which is, the more soluble forms of these toxic light chain conformations, our thoughts play overall at the level of the heart and so a number of groups now show that there is a cardiotoxic effect of these soluble forms of misfold light chain, but at least in the kidney, that doesn't appear to be the case. At least, there is no evidence to suggest that's the case.
So, I believe that most people feel that the deposition of the amyloid in the kidneys is what leads to the dysfunction of the kidney and so clearly they'll be seeing improvement there certainly gave me some comfort that how to do you get to that improvement, it seems like the most likely scenario is through removal of amyloid and some restructuring that allows for that proteinuria to go down. So we expect consistent with removal of amyloid, although it's not a direct measurement, but it is consistent with the mechanism of action.
As you mentioned, we showed at ASH last year that if you really just plaque amyloid from patients into a dish and put macrophage in with there, you don't see macrophage engage, they don't see the amyloid quite frankly as all that for, but when you cook that NEOD001, they do engage and they do phagocytose that amyloid and that's what we'd expect.
This are native amino acid sequences, the immune system doesn't recognize this forum but when we introduce the kind of protein immunotherapy concept, we can get those immune cells actually do their job, which is what we're going for.
So, right now [indiscernible] the agents aren't ready for humans, but actually there are some efforts ongoing in the field in general and maybe several years from now, they will be there.
Got it. And then you'd expect that to be sort of a time dependent sort of outcome at the patient level? So deepening of sort of renal response or even cardiac response overtime beyond maybe what you would be for a plasma directed therapy?
Yes, and there was some data presented at ASH in December, actually at the Untangling Amyloidosis Symposium there. It was a case study shown by Dr. Morie Gertz from the Mayo Clinic, but actually he was showing a patient who was - had pretty reasonable levels of proteinuria, about 5 grams of protein for 24 hour urine collection, at baseline had been 40 months since last chemotherapeutic response.
And that patient came in this study and I think at the data point in December, that patient was down to about 0.8 grams per day. So and that trend had continued as that patient continued to receive D1. So, to your point, I think we do have some evidence out there that suggest that, that's probably happening.
And I am showing no further questions at this time. I will like to turn the call back over to Dr. Dale Schenk for closing remarks.
Okay. Thank you for joining us this afternoon. We appreciate your interest in Prothena and our clinical development programs. Over the coming months, we look forward to sharing new data in program advancements that we expect to propel our programs towards potential commercial availability for patients. Thank you.
Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program. You may all disconnect. Everyone have a great day.
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