Prothena Corporation PLC (PRTA) 2014 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Prothena fourth-quarter 2014 financial results conference call. (Operator Instructions) As a reminder, today's conference is being recorded. I would now like to turn the conference over to Tran Nguyen, CFO for Prothena. Sir, you may begin.

Thank you, Candace. Good afternoon, everyone, and welcome to Prothena's conference call to review our fourth-quarter and full-year 2014 financial results, 2015 financial guidance, and business progress. Please review the press release we issued earlier today which is available at our website at Prothena.com, and is also attached to a Form 8-K filed today with the SEC.

On today's call are Dr. Dale Schenk, our President and Chief Executive Officer, who will discuss our 2014 highlights and corporate accomplishments; Dr. Gene Kinney, our Chief Scientific Officer and Head of Research and Development, who will review our pipeline development; and I will provide financial results for the fourth quarter and full year of 2014 and comment on our 2015 financial guidance. Finally, Dale will provide you with our upcoming milestones and then he will open the call up for Q&A.

Before we begin, I would like to remind you that during the course of today's call we will be making statements regarding Prothena's future expectations, plans, and prospects that constitute forward-looking statements under the Safe Harbor provision 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-K and Form 10-Q filed with the SEC and also the Form 10-K we will be soon filing with the SEC. We disclaim any obligation to update our forward-looking statements.

With that, I would like to turn the call over to Dale.

Thank you, Tran, and thank you all for joining us this afternoon. 2014 was a transformational year for Prothena as we initiated a late-stage clinical study, made significant progress with our three lead programs, hired and promoted key personnel and strengthened our balance sheet. As you know, Prothena is developing three novel protein immunotherapies for the potential treatment of diseases that involve amyloid or cell adhesion with patients always at the forefront of our efforts.

Our first two programs target the amyloid proteins implicated in several diseases including AL amyloidosis through NEOD001, and Parkinson's disease through PRX002, and a third program, PRX003 targets the cellular trafficking involved in psoriasis and other inflammatory diseases.

At this time, I would like to review our 2014 highlights. Our most advanced program, NEOD001 is a monoclonal antibody for the potential treatment of an orphan disease called AL amyloidosis, a grievous systemic and progressive disease that affects multiple organs and tissues within the body such as heart and kidneys. While there are three main forms of systemic amyloidosis, AL, AA, TTR amyloidosis, patients with AL amyloidosis represent the vast majority of systemic amyloidoses.

In December, we announced the initiation of the VITAL Amyloidosis Study, a global Phase 3 registrational trial for NEOD001. This Phase 3 program was supported and informed by positive data in our Phase 1/2 study and incorporates feedback from US and EU regulators as well as input from KOLs, clinical advisors, and patient advocacy groups.

Importantly, we were able to move into a Phase 3 study in less than two years after our initial IND filing, a great achievement by any standard. The VITAL amyloidosis study is designed to evaluate the effect of NEOD001 when we combine it with standard of care therapy versus standard of care alone. We believe that NEOD001 and standard of care together will produce a potentially synergistic result for the patient, given the different but complementary mechanisms of action.

[The current] standard of care these today only targets plasma cells, may be poorly tolerated, and patients often become refractory to the effect, and/or relapse. NEOD001 specifically targets the disease causing amyloid proteins that have deposited on organ tissues and are circulated in the periphery, thereby potentially improving organ function and mortality. In addition, as we reported in December, NEOD001 was found to be safe and well tolerated.

Concurrent with the VITAL amyloidosis study we continue to enroll patients with AL amyloidosis in persistent organ dysfunction in the expansion portion of the Phase 1/2 NEOD001 study. We believe the expansion phase is particularly important as we increase our safety database in this orphan disease, and the study will provide continuous data flow as we intend to report results at least once per year.

In addition, it will generate additional biomarker response data, providing the opportunity to further derisk our Phase 3 VITAL study. In December we announced that the FDA granted fast-track designation to NEOD001, making NEOD001 the first investigational immunotherapy that specifically targets the disease causing amyloid protein in AL amyloidosis to receive fast-track designation.

As you know, the FDA's fast-track drug development program is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose of the fast-track designation is to make important new drugs available to patients earlier. The fast-track program also provides us the ability to submit sections of the BLA for review before we submit the complete BLA. The fast-track also allows for priority review potentially shortening the standard review of the final BLA to six months.

Now, I'd like to turn to PRX002, the monoclonal antibody for the potential treatment of Parkinson's disease and other synucleinopathies. We signed a collaboration with Roche in December of 2013 and together we quickly advanced PRX002 into clinical development during 2014. We have two Phase 1 studies of this unique antibody. We have completed enrollment for the first of the Phase 1 studies in a single ascending dose trial in healthy volunteers. We expect to report data from this trial later this month in March.

In our second ongoing Phase 1 trial for PRX002 we continue to enroll patients with Parkinson's disease in this multiple ascending dose study. We expect to report data from this trial in the first half of 2016. We and Roche are excited to build awareness around this science as we believe targeting alpha-synuclein in this way holds promise to be a disease modifying treatment for Parkinson's disease.

Together with Roche, we will be conducting a symposium with a panel of scientific experts that will discuss the field's current understanding of alpha-synuclein and its role in Parkinson's disease at the upcoming Alzheimer's & Parkinson's Disease Congress, also known as AD/PD, on Saturday, March 21 in Nice, France.

For PRX003 we selected psoriasis as our initial indication to potentially demonstrate rapid proof of biology in Phase 1 and to inform our optimal clinical pathway for this unique antibody. We are very close to initiating a Phase 1 single ascending dose study for this compound, which will be conducted in healthy volunteers.

Turning to our business strategy, as you know, our mission is to create novel protein immunotherapies to transform patients' lives. We believe it is critically important to bring new disease-modifying therapies to patients in the most efficient manner possible. For our products that are focused on orphan indications or those where we have the capabilities and resources internally, we intend to develop these products through to commercialization. For our protein immunotherapies that demonstrate promise and/or efficacy in potentially larger and broad indications and that may require significantly large clinical trials in commercial footprints, we will consider partnering these indications with larger life science companies.

As we advance our clinical pipeline, we continue to build infrastructure to successfully drive development and prepare for commercialization to bring these therapies to patients around the globe. During 2014, we expanded our leadership team with the appointment of Bill Homan as our Chief Legal Officer and the promotion of Tara Nickerson as our Chief Business Officer. In addition, we strengthened our balance sheet by raising $117.4 million in net proceeds, which provides a substantial runway for the continued clinical development of our three lead programs.

Overall, we achieved a great deal in 2014. We are already on track to accelerate our progress in 2015.

At this time I'd like to turn the call over to Gene to discuss our pipeline developments. Gene?

Thanks, Dale. I'd like to take a moment to echo Dale's comments that we accomplished several significant milestones in 2014 laying an exciting foundation for progress in 2015 and beyond.

Beginning with NEOD001, in December we reported positive results from our ongoing Phase 1/2 trial where we demonstrated that NEOD001-treated patients showed favorable cardiac and renal response rates, in comparison to historical data of newly diagnosed patients treated solely with standard of care. As of September 30, 2014, NEOD001 met both primary and secondary endpoints of the Phase 1/2 study and was shown to be safe and well tolerated for patients with AL amyloidosis. There were no drug-related serious adverse events, no discontinuations due to NEOD001-related adverse events, and no dose-limiting toxicities observed.

Looking specifically at changes in indicators of organ function, patients treated with single-agent NEOD001 showed substantial cardiac and renal responses. 50% or seven of 14 cardiac evaluable patients treated with NEOD001 demonstrated a cardiac response as measured by NT-proBNP levels decreasing by more than 30% and 300 picograms per milliliter. And cardiac responders showed more NT-proBNP decline with added monthly NEOD001 infusions. This compares favorably to an expected 26.5% response rate from historical data for newly diagnosed patients treated solely with standard of care agents that are not approved specifically for AL amyloidosis.

It is important to note that increasing levels of NT-proBNP predict higher mortality rates in patients with AL amyloidosis. Conversely, decreasing NT-proBNP predicts lower mortality. Thus, we believe that the clinically meaningful decreases in NT-proBNP demonstrated following NEOD001 treatment in this Phase 1/2 study directly inform our selection of a survival-based endpoint for our Phase 3 VITAL study.

In addition to the cardiac responses we demonstrated a clinically relevant response in a second organ. Approximately 43% or six of 14 renal evaluable patients demonstrated a best renal response defined by a greater than 30% decrease in proteinuria in the absence of eGFR progression. Historical controls would suggest that only approximately 24% of newly diagnosed patients demonstrate a renal response when treated with standard of care.

The results of this study support and inform our initiation of the VITAL amyloidosis study, our global Phase 3 registrational trial for NEOD001. The VITAL study is now targeting enrollment of approximately 230 newly diagnosed treatment naive patients with AL amyloidosis and cardiac dysfunction.

Patients enrolled in the VITAL study will be randomized at a one-to-one ratio to receive either 24 milligrams per kilogram of NEOD001 or placebo. All patients in the trial will also receive standard of care consisting of chemotherapeutic and/or oncologic agents. Note that in our Phase 1/2 study patients with persistent organ dysfunction following prior plasma cell directed therapy were treated with NEOD001 alone.

Since current nonapproved standard of care treatments target a component of the disease pathway that is discrete from and complementary to NEOD001, we believe that by adding NEOD001 to standard of care in a newly diagnosed treatment naive patient population that patients will have the opportunity to experience the clinical benefit associated with standard of care, in addition to the effects provided by NEOD001 and its associated favorable safety profile to date.

The primary composite endpoint of the VITAL study consists of all-cause mortality or cardiac hospitalization. We believe that this event driven endpoint will allow us to establish a definitive measurable clinical benefit for patients treated with NEOD001 and standard of care compared to those treated with standard of care alone.

Because of the unique nature of this clinical study for the AL amyloidosis community, we will also be collecting multiple secondary endpoint measures including NT-proBNP and 6-minute walk test data as markers of cardiac function and levels of proteinuria as a marker of renal function. In addition, we will be using two quality-of-life surveys. We expect enrollment to take approximately 18 to 30 months with the last patient in followed for 12 to 18 months. As you would expect, this timeline is highly dependent upon both recruitment and subsequent event rate.

We do have the option to review the data on an interim basis to assess the primary endpoint for efficacy and futility. In addition to the VITAL amyloidosis study, the multiple dose and expansion portions of the Phase 1/2 study of NEOD001 are ongoing. In the expansion Phase, we are targeting enrollment of 25 additional patients with AL amyloidosis and persistent organ dysfunction, specifically 10 patients with cardiac dysfunction, 10 patients with renal dysfunction, and 5 patients with peripheral neuropathy. We expect to present new analyses from this study at least annually at appropriate medical conferences beginning this year.

As part of our commitment to patients with systemic amyloidosis and to gain insight into the patient experience, we recently collaborated with the Amyloidosis Foundation to conduct a 16 question survey of more than 500 participants consisting of both patients and family members. The results of this analysis were recently presented at the Eighth Annual Rare Disease Day at the National Institute of Health.

These survey data demonstrated that diagnosis of AL amyloidosis required three or more physician visits in almost 70% of the respondents. More than 75% were ultimately diagnosed by a specialist, namely a hematologist/oncologist, nephrologist, or cardiologist. And while the majority of respondents indicated they were not knowledgeable about clinical trials for their disease, almost half stated that they would consider enrolling in a clinical trial if informed.

Of note the Amyloidosis Foundation estimated that there were approximately 10,000 to 15,000 new cases of AL amyloidosis diagnosed annually in the United States and EU. Based on these incident data, the Amyloidosis Foundation also estimates that approximately 30,000 to 45,000 patients are living with AL amyloidosis in the US and EU today.

We believe data from this and other studies can help to identify areas where diagnosis is delayed or missed and, ultimately, help to educate physicians, patients, and the community to encourage the early accurate diagnosis of amyloidosis to improve disease management and survival outcomes.

Turning to PRX002, in April 2014 Roche dosed the first subject in our Phase 1 single ascending dose study in healthy volunteers. This is a randomized double-blind placebo-controlled study designed to assess the safety, tolerability, pharmacokinetic, immunogenicity, and pharmacodynamic properties of PRX002. Enrollment of 40 subjects is now complete with results from the Phase 1 single ascending dose study expected later this month.

In July 2014, following confirmation of the initial safety and tolerability in healthy volunteers, we together with Roche began a concurrent multiple ascending dose Phase 1 study of PRX002 in patients with Parkinson's disease. This is a randomized double-blind placebo-controlled trial that is enrolling approximately 60 patients with Parkinson's disease at multiple centers across the United States.

This study is designed to evaluate the safety, tolerability, pharmacokinetic, immunogenicity, and pharmacodynamic properties of PRX002 in addition to multiple clinical and exploratory biomarkers. These patients are enrolled in escalating dose cohorts of PRX002 or placebo, and all patients will receive three monthly doses and will be followed for a total of approximately 6 months.

Taking a step back, I'd like to discuss our excitement around PRX002. PRX002 targets alpha-synuclein, a protein found extensively in neurons and many studies suggest it plays an important role in multiple nerve degenerative disorders, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, together characterized as synucleinopathies.

The synuclein protein can misfold and aggregate to form toxic assemblies. There is genetic evidence synuclein plays an important role on the onset and progression of Parkinson's disease. There is also increasing evidence that disease causing forms of alpha-synuclein can be propagated and transmitted from neuron to neuron, resulting in an infection like spread of the neuronal death.

We hypothesized that by targeting alpha-synuclein with PRX002 it may be possible to stop or delay the progression of these devastating diseases, and it is our intent to test this hypothesis through our clinical program.

Our third antibody, PRX003, is targeting the melanoma cell adhesion molecule, also known as MCAM. MCAM is a molecule that allows certain cells traveling in the blood stream to leave the circulation and enter tissues, a process that may be integral to many inflammatory diseases.

MCAM functions like Velcro hook and loop fasteners, allowing cells to stick to blood vessel wall and then migrate into the adjacent tissue to initiate or maintain a pathogenic inflammatory process. This cellular transmigration process has been documented in many inflammatory diseases including psoriasis, psoriatic arthritis, multiple sclerosis, sarcoidosis, 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 cells from spreading into the tissue. We expect to initiate a Phase 1 single ascending dose study in healthy volunteers in the first half of 2015, and while there are numerous potential target indications for this compound, we've selected psoriasis as our initial development focus.

We believe that because of the visual defined nature of psoriasis we will be able to rapidly assess the safety, pharmacokinetic, and possibly the proof of biology of PRX003, allowing these data to then further inform our strategic clinical development pathway for psoriasis and/or other inflammatory disorders.

In summary, with data from our NEOD001 and PRX002 programs, multiple planned presentations at medical conferences, and advancement of all pipeline programs, we look forward to making further progress in our goal to positively transform patients' lives by meeting several meaningful planned catalysts in 2015.

At this time, I'd like to turn the call over to Tran for a discussion of our financial results. Tran?

Thanks, Gene. First, our cash burn from operating activities in 2014 was approximately $1 million compared to guidance of $7 million to $12 million, and includes a total of $45 million in upfront and clinical milestone payments through our collaboration with Roche for PRX002 in 2014. As you know, these figures do not include the $117.4 million in net proceeds raised through our equity offering in 2014. 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 $13.1 million and $7.2 million for the fourth quarter and full year of 2014, respectively, as compared to net losses of $11.1 million and $41 million for the fourth quarter and full year of 2013, respectively. Net losses per share were $0.48 and $0.29 for the fourth quarter and full year of 2014, respectively, as compared to net losses per share of $0.52 and $2.20 for the fourth quarter and full year of 2013, respectively.

Net loss for the fourth quarter and full year of 2014 included share-based compensation expense of $1.4 million and $5.6 million, respectively, compared to $1.1 million and $3.1 million for the respective prior period. We reported total revenue of $2 million and $50.9 million for the fourth quarter and full year of 2014 respectively as compared to total revenue of $0.2 million and $0.7 million for the fourth quarter and full year of 2013, respectively. The increase was primarily due to $1.9 million and $50.3 million in collaboration revenue recognized in relation to the PRX002 collaboration with Roche in the fourth quarter and full year of 2014.

R&D expenses totaled $10.1 million and $38.5 million for the fourth quarter and full year of 2014, as compared to $5.6 million and $26.1 million for the fourth quarter and full year of 2013. The increase in R&D expenses was primarily due to increased external expenses related to product manufacturing and clinical trials and higher personnel costs. R&D expenses included non-cash share-based compensation expense of $0.6 million and $2.3 million for the fourth quarter and full year 2014, as compared to $0.4 million and $1 million for the fourth quarter and full year 2013.

G&A expenses totaled $5 million and $19.1 million for the fourth quarter and full year of 2014, as compared to $5.3 million and $15.1 million for the fourth quarter and full year of 2013. The increase in G&A expenses was primarily due to increases in personnel costs and higher consulting expenses for the fourth quarter and full year of 2014. G&A expenses included non-cash share-based compensation expense of $0.8 million and $3.3 million for the fourth quarter and full year of 2014, as compared to $0.7 million and $2.1 million for the fourth quarter and full year of 2013.

As part of the February 2014 public offering, Perrigo sold its full position of approximately 3.2 million ordinary shares of Prothena. We are pleased to have helped diversify our shareholder base with this successful offering. As of December 31, 2014, Prothena had $293.6 million in cash and cash equivalents, which includes approximately $117.4 million of net proceeds from our successful 2014 public offering. We have no debt and approximately 27.4 million ordinary shares outstanding.

Now turning to our 2015 financial guidance, the Company expects the full year 2015 net cash burn from operating and investing activities to be $66 million to $72 million, ending the year with approximately $225 million in cash, which represents the midpoint. The estimated full-year 2015 net cash burn from operating activities and investment activities is primarily driven by an estimated net loss of $77 million to $83 million, which includes approximately $9 million of non-cash share-based compensation expense.

Additionally, the estimated 2015 net loss is primarily due to clinical development costs related to the VITAL amyloidosis study for NEOD001, increasing clinical manufacturing and trial expenses associated with PRX002, and clinical development costs related to PRX003 as well as costs related to further advancement of its discovery program.

With that, I'll turn to call back over to Dale to summarize our upcoming milestones for 2015 and beyond. Dale?

Thank you, Tran. Looking ahead, we intend to report new data from the expansion phase portion of our NEOD001 Phase 1/2 trial at a medical conference later this year and annually moving forward. We expect data from our single ascending dose trial of PRX002 later this month in March as well as data from the multiple ascending dose trial in the first half of 2016. Finally, we expect to initiate the Phase 1 single ascending dose trial for our third program, PRX003, in the first half of 2015 and the multiple ascending dose study in 2016 to potentially provide rapid proof of biology in Phase 1.

At this time I would like to open the call for questions. Operator, please?

(Operator Instructions) Michael Yee, RBC Capital Markets.

Hi. Thanks. This is John on behalf of Michael Yee. For PRX002, could you just help us put into context the data we will see this month? I understand it's Phase 1 in healthy, so primary aim is safety and PK, but with biomarker measures such as knockdown and alpha-synuclein in the periphery, I'm just curious how much knockdown in your view is clinically meaningful?

And just bigger picture, Gene briefly laid out why you guys are excited with this approach, but how validated is the alpha-synuclein hypothesis in Parkinson's? Is it any different from the amyloid beta hypothesis in Alzheimer's? And has other drugs shown knockdown of alpha-synuclein? Thanks.

Thanks, John, for the question. This is Gene. So let me start with just the Phase 1 single ascending dose data. So, obviously, this a single agent ascending dose study, so single infusion of PRX002 in a population of healthy volunteer subjects. Obviously, the primary outcome measure, as you accurately point out, is going to be safety and tolerability. Obviously, we will also be very interested in the pharmacokinetics of the molecule.

We are capturing some biomarkers in this study. It's somewhat limited in terms of what we can look at because it is a non-disease population, but I think one thing we can look at and are eager to look at is how the antibody PRX002 is actually engaging with the target in vivo and what kind of modulation there.

I think a key question, obviously, in the field -- and we can talk about the validation of alpha-synuclein as a target in a second here -- but as you go after alpha-synuclein obviously the first thing you want to know is that you can do so in a safe and well-tolerated manner at doses that actually modulate the peptide and the protein. So that's an important learning that I think we can get out of the single dose study.

In terms of the validation of alpha-synuclein, maybe I can just say a few words and then Dale may want to chime in here, because he's done a lot of this validation work. But certainly, we think there is both good genetic as well as pathologic evidence suggesting that alpha-synuclein is a significant player in both the onset and progression of Parkinson's disease and related synucleinopathies.

Certainly there's genetic evidence suggesting duplication, triplication or mutation of alpha-synuclein will -- or I should say the genes that code for alpha-synuclein will lead to early onset Parkinson's disease. We also know that in idiopathic cases of Parkinson's disease the pathology is really almost defined by alpha-synuclein pathology and inclusions. We think there is actually very substantial genetic evidence as well as pathological evidence. But maybe, Dale, you care to comment further on that?

Yes, you mentioned that -- note that we have a siren in the background -- sorry about that ?- you asked about the amyloid. I think the story with Parkinson's and synuclein is actually simpler. There's no debate about which protein in Parkinson's -- everybody seems to be converging on synuclein. Also synuclein is in the neuron as opposed to outside of the neuron, thereby causing damage directly to the neuron itself.

And then finally, one thing that is easier to tackle in Parkinson's than in Alzheimer's is there is a peripheral component -- a clear peripheral component in Parkinson's disease with synuclein and synucleinopathies that can be interrogated and investigated. And I won't echo the stuff that Gene just said about the genetics and other pathologies. Pretty clear-cut.

Great. But just following up on that point, so has there been other drugs that have shown knockdown in alpha-synuclein, whether it's in the brain or the periphery? And then just following up more on that point, so at what point would we know or would you know that the alpha-synuclein hypothesis is no longer a hypothesis and real? I'm just wondering are we going to have to wait years and hundreds of millions of dollars after Phase 3 to finally know, like Alzheimer's disease, or is there a stage in Phase 2 and other functional endpoints that may give you clear signal? Thanks.

So, John, let me first address the first part of your question about knockdown of synuclein. Certainly, we can speak to nonclinical data, right, where I think there are multiple models of alpha-synuclein over expressing, transgenic mice, for example, where you see high levels of alpha-synuclein expressed chronically. You see pathologies in the brains of those animals and, ultimately, dysfunction in those animals that is related to that alpha-synuclein pathology.

And certainly, and we have published a lot of this work, notably with Eliezer Masliah at UCSD. And in that work I think it's pretty clear that these antibodies that we use, particularly those that target alpha-synuclein in the right place -- and there are wrong places to target alpha-synuclein -- that they have very good impact in terms of reducing the pathology but also preserving against those functional deficits. So I think there's good evidence certainly from the nonclinical data -- Dale, if you want to mention maybe some of the clinical work?

Yes. There's not too much on the clinical side. For path of immunotherapy, we are the trailblazers, which is a place we like to be. And so, we will have to wait and see. But to answer your question about the process, again, I think every disease is different and I'll echo what I said earlier. That Parkinson's is a peripheral component that can be investigated much more easily -- no such thing exists in Alzheimer's.

So Parkinson's we are going to most likely have pretty clear-cut biomarker data. And I mean that when I say we, and the field in general, too, will have available to it long before -- sorry, as a stepping stone into the other movement endpoints. The process will be simpler and more direct and more measurable.

Okay. Great. Thank you.

Jason Kantor, Credit Suisse.

As you think about rolling out additional data from the AL amyloidosis study, is there a specific conference that you are going to target annually? Should we think about ASH? Or is this something that's going to vary from year to year or is this something that can be fairly predictable?

Jason, I think there are the usual suspects in terms of conferences particularly around hematology. You are talking about obviously ASH, EHA, ASCO, and there's probably some others as well you can think about. As a rule, we wouldn't say exactly which conferences, because obviously there's a submission process and acceptance of the abstract process that needs to take place for each of these conferences. On a case-by-case basis as we knew we were going to present, we'd actually put out a note ahead of time to make sure that anyone that was interested in coming to the conference and taking a look at the data had an opportunity to do that. But it would be premature to actually specifically name a single conference because it would be ahead of the process of submission and acceptance.

And this symposium that you are hosting or participating in, what's the expectation for what could come out of that? Is that going to be a place where new clinical data is going to be released or talked about? Or this is just highlighting the mechanism of action and the unmet need and such?

So the intent of the symposium at AD/PD, which is being jointly sponsored by ourselves and Roche, is really to focus on the role of alpha-synuclein in Parkinson's disease as well as other synucleinopathies. Really from a molecular basis all the way through to kind of a therapeutic intervention basis -- that's the primary focus.

Okay. Thanks.

Chris Marai, Oppenheimer.

Just really quick on VITAL, I was wondering how you think perhaps the current standard of care might impact immune response and, therefore, potentially impact your treatment in combination. With respect to that, in your view how much of your benefit do you think is due to sort of ADCC or other immune mediated aspects versus say structural factors or antibody binding resulting in structural changes that allow for plaque to dissolve or become dislodged? Thanks.

Thanks, Chris, for the question. So let me just start a little bit with the mechanism of action of D1. As I think we've talked about pretty extensively in the past, we believe that there are two kind of aggregated species of light chain that have been implicated in this disease, at least with respect to toxicity in the disease. There are soluble aggregated forms and then the insoluble aggregated forms. Soluble aggregated forms are probably a little bit more of a labile form, if you will, a bit easier to disrupt to neutralize the toxicity after interaction with an antibody.

But, as you point out, kind of as a general statement in the field of amyloid, there's some interesting literature suggesting that if you have the insoluble form, the so-called fibrils or amyloid itself, really that's a poor substrate for macrophage phagocytosis optimization. But what can happen is after you actually engage that material with an antibody through interaction with Fc gamma receptors, you tend to switch those macrophage into a phenotype, which is dominated by phagocytosis. So, we think that that is certainly a relevant mechanism of action with respect to removal of amyloid from tissue.

The chemotherapeutic agents that are standard of care certainly impact the immune system in a general way. I think our read of the data around phagocytosis, specifically, the macrophage function is that it's a little bit more mixed in terms of what you might expect there. And so, our general feeling is we think NEOD001 as a standalone agent in the Phase 1/2 program has demonstrated, I think, very nice effect by our evaluation of the data in a, quote-unquote, organ refractory patient population.

And we think that by combining that with any benefit of a very complementary biology, i.e. turning down the production of new light chain from those plasma clones, that we should see a very complementary effect which should be additive or even synergistic in nature and then comparing that obviously to the standard of care alone. So we are not overly concerned by that, but we do think it's certainly an important mechanism.

Okay. Great. And just with respect to PRX003, the psoriasis trials, maybe remind us, how many patients is that and when do we expect data? Sorry if I missed it. Thanks.

We haven't talked about the design of that study yet, but I think we have said that we expect the first study to be a single ascending dose study in healthy volunteers. And so that's a pretty straightforward design and approach.

And we've also said that we would initiate the sequential MAD in 2016, so that will give you a sense of when that (SAD) would read out. There, of course, the primary would probably be safety tolerability, PK immunogenicity from a secondary perspective. We'll be looking at exploratory in terms of pharmacodynamic properties, too.

Yes, absolutely.

And would you be looking at -- these are all in healthy volunteers or would you be looking at this in any patients with psoriasis? Thanks.

So we anticipate that we would look at pharmacodynamic effects in both healthy volunteers as well as in multiple dose study in patients.

Thanks. Thank you, guys. Congrats on the quarter.

Heather Behanna, Wedbush.

Thanks for taking the question. Just a follow-up on 003 -- if you could just talk a little bit about the IL17 antibodies in psoriasis, and sort of what your expectation might be or what you are thinking of going in with 003 considering its mechanism in comparison.

Thanks, Heather. Great question. So obviously we are encouraged by the anti-IL17 data particularly in psoriasis. I think it really indicates that IL17 is playing a very important role in that disease. Where we are differentiated, I think, in terms of approach is that we're really going after the TH17 cells themselves, right? So the signature cytokine of the TH17 cells is certainly IL17, but that is not the only cytokine that is released by those cells. I point out to IL22 as another example.

So the point being that these TH17 cells release multiple cytokines which likely stimulate multiple pro-inflammatory pathways. And so it's no surprise then that there are a number of inflammatory disorders where perhaps if the contribution of IL17 and some of these other cytokines may be differentially important, you could expect to have a broader impact.

And so we are quite excited about the opportunity space there, but at the same time in a strategic manner we think that moving forward with psoriasis in the first instance, given the visible and nature of the actual disease and the ability to see proof of biology relatively quickly, provides an opportunity not only to provide benefit potentially to psoriasis patients maybe in a way that's differentiated from IL17, but also allows us strategically to derisk the program in the molecule in a relatively expeditious way.

And then on the backend of that, assuming that the drug is safe, well tolerated, and shows the expected proof of biology, we would really open up the opportunity space to additional areas of inflammation beyond that which may or may not be served well by the anti-IL17 approaches.

I would just add you might expect differences in pharmacodynamics, right? Because in one case you're getting rid of a cytokine and in the second case you're getting rid of the source.

Great. Thank you.

(Operator Instructions) Bert Hazlett, Ladenburg.

Thanks. A lot has been asked and answered but just following up on the 003 question. So is it fair to summarize that once you get to the proof of principle or at least a demonstration of biologic activity in the psoriasis model that psoriasis will likely not be the primary indication that's sought? Or is that too strong a statement?

I think that's too strong a statement. Obviously, what we would look to do in a positive scenario is first compare the activity with expectations. I think obviously there has to be added benefit to patients with psoriasis to move forward. You are going to want to do that certainly analysis. But we are not excluding the possibility that there may be added or differential benefit over and above the anti-IL17.

That said, I think the probably bigger impact is you'd start to ask the question of what else in addition to psoriasis you could start to think about? Again, maybe in a manner that's differentiated, maybe in areas where the anti-IL17's haven't shown as robust of a response as has been seen in the psoriasis study.

I think you have to be very thoughtful and strategic in the general inflammatory disease space. We've been through this before with Tysabri in the sense that we will take all the data that we have. As Gene said, we will look carefully at psoriasis but we will also look at both potential orphan and very, very broad indications -- large indications as well to try to position PRX003 going forward. It's a very interesting antibody.

Thank you for that. And just shifting back to 001 and the VITAL study. The 18 to 30 months seems like, given the urgency that's necessitated with the condition, it seems like maybe that's a long time for enrollment. Can you just speak to that and talk about maybe some of the concerns that you might have or the benefits that you might have to be able to swing enrollment either toward the 18 months or toward the 30 months?

Absolutely, Bert. If we are going to try and swing enrollment we are not going to try and swing it to the 30 month (multiple speakers).

Fair enough. (laughter)

I'll tell you that. All that said, it's a very important question. And I think it's a pretty wide range and we recognize that. The challenge is pretty obvious here. This is an orphan disease for which there is no real precedent for this type of study so we've done our best estimating. We've certainly looked at trials in other orphan disease spaces not excluding obviously other systemic amyloidoses. We've also done all the proper homework that you are supposed to do in terms of site surveys and what have you, talked to a number of KOLs.

So these are our best estimates today. I think it's probably fair to say that as we continue to gain experience in this space we certainly desire to tighten up this guidance. I wouldn't expect that until at the earliest later this year but potentially into next year as well. But our hope, certainly, is to -- with real experience under our belt to be able to kind of move this guidance to a closer number in the future.

Thank you for that. Is there a particular geography that you feel strongly about that you are pushing things toward? Or is it really more global in nature?

No, this is a global trial. I think we said back at December 2 when we talked about this that we were anticipating opening somewhere around 50 to 60 sites, primarily in North America and Europe is where we are focused in the first instance.

Okay. Thank you very much. Congratulations on the progress.

And I am showing no further questions at this time. I'd like to turn the conference back over to Dr. Dale Schenk for any closing remarks.

Okay. Thank you, everyone, and in conclusion I would like to reiterate our enthusiasm for this important time in Prothena's evolution. We believe the year ahead will be filled with many important events to progress our programs forward. Thank you for your continued support. Thanks, everyone.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude today's program, and you may all disconnect. Have a great day, everyone.