Good afternoon, ladies and gentlemen, and welcome to the Dicerna Pharmaceuticals Fourth Quarter and Full Year 2019 Earnings Conference Call. At this time, all participants are in a listen-only mode. [Operator Instructions] I will now turn the call over to your host, Lauren Stival, representing Dicerna Pharmaceuticals. Please go ahead..

Thank you, operator. Good afternoon, everyone, and thank you for joining us to review Dicerna’s fourth quarter and full year 2019 financial results and operating highlights.

For anyone who has not had a chance to review our results, we issued a press release after the close of trading today, which is available under the Investors & Media tab on our website at dicerna.com.

You may also listen to this conference call via webcast on our website, which will be archived for 30 days beginning approximately two hours after this call has been completed.

Speaking on today’s call will be our President and CEO, Doug Fambrough, who will discuss our corporate progress and key milestones and provide an update on clinical development and collaboration activities. Our CFO, Jack Green will then review our fourth quarter financial results.

We also have Jim Weissman, our Chief Operating Officer; and Ralf Rosskamp, our Chief Medical Officer, available to answer questions during our Q&A session. Following our remarks, we will open the line for your questions.

I’d like to remind listeners that management will be making forward-looking statements on today’s call, including; for example, the therapeutic and commercial potential of Nedosiran, RG6346, DCR-A1AT and the GalXC platform; research and development plans and time lines, the potential for Dicerna to continue to add programs and extend the reach of our technology to additional tissues and our internal discovery research and in our collaborative programs.

Expectations related to our collaborations with Novo Nordisk, Roche, Lilly, Alexion and BI and the potential for future collaborations and Dicerna’s financial position, expectations about current or future clinical data, collaboration funding, expenses and cash usage.

Actual results may differ materially from those indicated in these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of Dicerna’s latest Forms 10-Q and 10-K filed with the SEC. Well, we may elect to update these forward-looking statements at some point in the future.

We specifically disclaim any obligation to do so if our views change. Now, I’d like to turn the call over to Doug Fambrough, Dicerna’s President and CEO.

Doug?.

Thank you, Lauren. Good afternoon, everyone, and thank you for joining us. As I reflect on 2019, I believe it was our most successful year yet.

We began 2019 primed with a great deal of momentum that accelerated over the course of the year with significant progress across our clinical development programs and our organizational growth and maturation and clearly, on the corporate collaboration front as well, both with executing on existing collaborations and striking new ones.

Among our achievements last year, we moved our lead program Nedosiran for the treatment of primary hyperoxaluria type 1, 2 and 3 into pivotal development. We completed and presented data on the PHYOX1 Phase I study last year and began dosing patients in the pivotal PHYOX2 trial, which is enrolling patients with PH1 and PH2.

Importantly, we also aligned with the FDA on a registration path to full approval of Nedosiran for treatment of both PH1 and PH2 and received breakthrough designation for PH1.

As many of you know, primary hyperoxaluria is a family of ultra-rare, life-threatening genetic disorders that cause complications in the kidneys, including recurrent kidney stones and chronic kidney disease and can lead to end-stage renal disease.

In our HBV program, we completed the healthy volunteers’ portion of the Phase I trial and began dosing patients. And in 2019, we also initiated our clinical program, which we call the SHINE program for another core development program, DCR-A1AT for the treatment of alpha-1 antitrypsin deficiency-associated liver disease.

We began dosing in healthy volunteers last fall and received orphan designation for DCR-A1AT in the EU. On the corporate front, we expanded our leadership team with several key new hires, including bringing on our Chief Commercial Officer, Rob Ciappenelli, and recruiting one of the world’s leading experts in primary hyperoxaluria, Dr.

Bernd Hopp as our Global Head of Medical Affairs. In addition to recruiting heads of HR – in addition, we recruited heads of HR, regulatory and patient advocacy amongst other key positions.

Our overall employee base expanded significantly in the past year, as we’ve put in place the key functions to enable successful execution across our core and collaborative programs and begin transitioning towards becoming a commercial stage biopharmaceutical company.

And on the collaborations front, we executed high value agreements with Novo Nordisk and Roche in the fourth quarter, providing $375 million in non-equity upfront payments that have significantly augmented our cash position. I will expand more on these in a moment.

Of equal importance, we successfully executed on our existing collaborations Lilly and Alexion. In the case of Lilly, we expect the first IND or CTA filing later this year of the first discovery program launched under that collaboration.

And Alexion exercise their options to add two additional compliment gene target programs to the collaboration, for which we received $20 million and option exercise payments. Added to the initial two, there are now a total of four target genes under our collaboration with Alexion.

Coming back to our new Roche and Novo collaborations, each of these agreements provide us with opportunities not only for future revenue from milestones and royalties, but also the ability to opt-in and share and development and commercialization of select programs.

With these opt-in features, we can retain a strong economic stake and operational involvement in key programs, giving us the opportunity to make them part of our core pipeline. With these opt-ins, the Roche and Novo collaborations set a new standard for us in assessing potential future collaborations.

These achievements over the past year have solidified our base business and represent the building blocks to our creation of a sustainable, fully integrated biopharmaceutical company with the capacity to identify, develop and commercialize new RNAi-based therapies for ourselves and our collaborative partners.

Our 2019 collaborations significantly strengthened our balance sheet, funding us into 2023. With our table nicely set, 2020 is about execution and preparing for commercial success. Starting with Nedosiran. Nedosiran is the only RNAi candidate in development for PH types 1, 2 and 3.

Using our proprietary GalXC RNAi platform technology, we rationally designed Nedosiran to target the LDHA gene, which catalyzes the final common step of oxalate production, the bad actor in PH, in not just PH1, but also PH2 and PH3.

By targeting LDHA, Nedosiran can interfere with production of the LDH enzyme preventing oxalate formation for any of the known forms of PH.

data from our first clinical trial of Nedosiran, PHYOX1 Phase I trial showed that seven of eight patients with PH1 or PH2 who were treated in the study with our three milligram per kilogram target dose achieved normal or near-normal urinary oxalate levels after just one dose of Nedosiran.

At the highest dose level of 6 milligrams per kilogram, all four patients, all PH1 achieved normal or near-normal urinary oxalate levels. Together, at the two highest doses, 11 of 12 patients or 92% achieved normal or near-normal urinary oxalate levels.

We expect to present additional data on Nedosiran’s effect on urinary oxalate reduction over time with the initial Nedosiran multi dose data emerging from our PHYOX3 trial at the OxalEurope International Congress on March 31, 2020.

For those new to Dicerna, the PHYOX3 trial is our open-label rollover study open to any participant in our PHYOX clinical development program. The dosing regimen for PHYOX3 is identical to that of our PHYOX2 pivotal trial, which should provide some read through for what PHYOX2 data may look like.

PHYOX3 will give us the first glimpses of Nedosiran’s ability to provide long-term reduction in urinary oxalate levels to the normal or near-normal range with the potential to reduce or eliminate the need for patients to hyper hydrate. Because of the availability of data is dependent on when patients began dosing.

We expect to have more data available as the year progresses and we’ll provide a more fulsome picture of Nedosiran’s profile as the data mature. We expect to present the additional data at our planned R&D Day in August.

PHYOX2 are double-blind placebo-controlled pivotal study of Nedosiran begun last year, is a critical study in our PHYOX clinical program. PHYOX2 will include 36 patients with PH1 and PH2 and patients in this trial will remain on therapy for six months.

The primary endpoint will compare the reduction in urinary oxalate levels from baseline to measurements taken from the ends of months three through six. We continue to expect enrollment in PHYOX2 to complete in the first half of this year, putting us in position for last patient out by the end of the year.

The data from PHYOX2, together with the data across the PHYOX program are expected to support an NDA package for full approval to treat PH1 and PH2 the submission of which we are targeting for the first half of 2021, and we continue to discuss with FDA, a regulatory path forward for PH3.

Our objective, subject to FDA’s agreement would be to provide data on the Nedosiran’s effect in PH3 and seek an approval for patients with PH3. With the key clinical components of our NDA falling into place in a matter of months, preparations for commercialization are a high priority this year.

During 2019 and continuing to the present, we have made key hires in medical affairs, marketing, manufacturing and other critical areas of our business to support our evolution to a fully integrated bio pharmaceutical company with the resources to hit the ground running commercially.

We will have more to say about our commercial planning later this year. But at a high level, we expect to make Nedosiran available on a global basis. To that end, we have made the strategic decision to focus our commercial enterprise on the U.S. market and seek a collaboration partner for commercialization ex U.S.

I will not go into detail on potential partnering discussions, nor will I provide any expectations around timing or scope.

But assuming regulatory approvals, putting the right resources behind Nedosiran to ensure that it is available to the most patients worldwide fits our overarching mission to broadly enable our RNAi technology to benefit as many patients as possible. As such, securing the right arrangement for Nedosiran outside the U.S. is a high priority for us.

Moving on to the hepatitis B virus or HBV program, RG6346, formerly referred to as DCR-HBVS. RG6346 is GalXC-based therapy for the treatment of chronic HBV infection. Chronic HBV is a serious liver infection that can result in advanced liver disease or liver cancer if not treated effectively.

Chronic HBV infection claims more than 887,000 lives annually, with an estimated 292 million people infected worldwide. There are currently studying RG6346 in an ongoing placebo-controlled Phase I trial evaluating healthy volunteers as well as patients with chronic HBV infection.

Now licensed to Roche under the collaboration agreement we struck with them last year, Dicerna is responsible for completion of Phase I development after which Roche will assume its further development. We completed dosing in healthy volunteers, referred to as Group A, last year, which showed good safety and tolerability of RG6346.

In May, we began dosing patients, looking at two patient types. Those who are newly diagnosed chronics HBV patients naïve to standard of care with NUCs and who agreed to forgo initiation of new therapy for 12 weeks. These are referred to as Group B patients.

And those who have previously received treatment with NUCs and are part of a multiple ascending those Group C cohort with continued NUC treatment.

Patients in groups B and C enter into an extended follow-up observation period if they achieve reduction of hepatitis B surface antigen greater than or equal to one log from baseline and have reached the end of the formal study period, which is 12 weeks for Group B and 16 weeks for Group C.

As a reminder, this trial remains blinded, and we do not know what treatment regimen patients are receiving. That said, multiple patients have entered into the extended follow-up observation period and we are very encouraged to now have representation from both groups D and C and follow-up.

We are looking forward to results from the study in the coming months and are working with Roche to make the data available at our investor R&D Day planned for August. Our agreement with Roche encompasses RG6346 as well as additional therapies targeting human and viral genes associated with HBV infection.

For Dicerna, that means that we will be focusing not only on completing the ongoing Phase I study, but also anticipate generating new leads out of our RNAi discovery engine for HBV.

We received the $200 million upfront payment in early January and for RG6346 specifically could receive up to an additional $1.47 billion over time for the achievement of specified development, regulatory and commercial milestones, as well as royalties on potential product sales of RG6346.

One of the key features of this agreement is our ability to remain involved with RG6346 over the long haul, with the opportunity to, at our option co-fund pivotal development of RG6346 worldwide in exchange for enhanced royalties and co-promote in the U.S. products that include RG6346.

We also have the opportunity to receive additional milestones and royalties on any potential therapies that emanate from our R&D efforts, targeting multiple human and viral genes implicated in chronic HBV infection, using technology from either company. And now moving to DCR-A1AT, our second rare disease clinical candidate.

DCR-A1AT as its name implies, is being evaluated for use in patients with A1AT or alpha-1 antitrypsin deficiency and specifically for A1AT deficiency associated liver disease. A1AT deficiency is a genetic disorder that frequently causes accumulation of misfolded A1AT protein in the liver, which can cause liver damage and dysfunction.

Considered a rare disease, there are currently no approved therapies specifically designed to treat the liver manifestations of this condition. We began the first portion of our Phase I/II study of DCR-A1AT last fall and are currently dosing healthy volunteers.

This is a single ascending dose phase and will enroll up to 36 participants in as many as six cohorts. The second part is a multiple ascending dose phase in patients with confirmed A1AT deficiency associated liver disease insisting of up to 24 participants in three or fewer cohorts.

We expect to begin dosing patients with A1AT in the second half of this year. Moving now to discuss our corporate discovery collaborations. I’ll begin with our new collaboration with Novo Nordisk.

The Novo agreement, we entered into last November, surpassed each of our previous agreements in terms of overall scope, providing Nobo with rights to potentially any liver target, not subject to a current collaboration or held aside as a Dicerna proprietary program.

Structured in this way, Dicerna and Novo expect to jointly evaluate use of our GalXC technology for approximately 30 liver targets in multiple disease areas over the course of the discovery collaboration.

With GalXC’s capability to inhibit hepatocyte targets, this collaboration has the potential to deliver multiple clinical candidates for disorders including chronic liver disease, nonalcoholic steatohepatitis or NASH, type 2 diabetes, obesity and rare diseases.

We are obligated to conduct and fun discovery and preclinical development of the clinical candidate selection for each liver cell target, and Novo Nordisk will be responsible for all further development other than the first program for which we conduct IND-enabling studies.

And similar to the Roche agreement, we have the opportunity to play the long game maintaining the option to co-develop and co-commercialize two clinical stage product candidates discovered under the collaboration with the reciprocal option available to Novo for two new Dicerna liver rare disease programs.

Our two opt-in rights can be exercised up through the availability of data from the first Phase I study and the first Phase II study respectively. In other words, we can choose to opt-in after observing successful clinical proof-of-concept data substantially de-risking these programs.

We received the $175 million upfront payment in January, and Novo completed their $50 million equity investment in Dicerna at a premium in December, following HSR clearance. As with our other collaborations, we got straight to work and Novo has already selected the initial targets.

We’re eligible for another $25 million this year and in each of the coming two years for fulfilling our discovery obligations.

Longer term, we could earn up to $357.5 million per target in development, regulatory and commercialization milestone payments plus tier royalties on product sales ranging from the mid-single digits to mid-teens for programs where we did not opt-in.

Regarding our other collaborations, as I mentioned earlier, Alexion recently expanded to a total of four complement-mediated targets with their election to exercise their options for two additional targets in December. We are very pleased by the progress we have made with the initial two targets advancing to the preclinical development stage.

I believe this progress demonstrates the power of our GalXC platform to rapidly create effective molecules for development against liver targets. Finally, our collaboration with Eli Lilly, which we initiated in late 2018, is also progressing well.

This agreement is our broadest in terms of types of therapeutic areas targeted and dovetails with areas of innovation that Lilly is known for and which are our strategic importance to Lilly.

The furthest advanced of any of our collaborative programs is known as LY3561774, a candidate in preclinical studies that we are developing with Lilly for a cardiometabolic indication.

Assuming all continues to progress well, we expect an investigational new drug application or clinical trial application that is an IND or CTA, for LY3561774 late this year. DCR-CM2, the second program and that collaboration is also now in the preclinical phase for a cardiometabolic indication.

LY3561774 represents the leading edge of a wave of candidates that we expect to advance to the clinic over the next two years. Non liver candidates represent the next frontier in RNAi and is an important area of significant interest to us. Nervous system diseases and disorders are notoriously difficult to treat with traditional medications.

We believe that the precision presented by RNAi and the ability to target the disease-causing proteins of selective genes holds tremendous promise for nervous system diseases and this successful, but become one of the most significant areas of advancement in the field.

As a reminder, our collaboration with Lilly includes an exclusive collaboration in neurodegeneration and pain, while Dicerna retains the right to develop certain neurological rare disease programs. In addition to applications in the nervous system, we are exploring other disease areas that lend themselves to RNAi targeting.

We have a long way to go to proof this out, and I’m very optimistic about our chances. We expect to present our first data supporting extension of our RNAi technology to additional tissues in August at our planned R&D Day. It’s an incredibly exciting time to be at Dicerna, and I’m very happy with the progress we were making across the organization.

We have a lot going on and we have high ambitions, all of which are enabled by our ability to work of a solid financial base. For a discussion of the financials, I would now like to turn the call over to Jack Green, our CFO.

Jack?.

Thank you, Doug. I’d like to briefly walk through the key financial results and direct you to our financial results press release and annual report on Form 10-K issued today for additional details. Net loss for the fourth quarter ended December 31, 2019 was $39.7 million or $0.58 per share.

We did $18.6 million or $0.29 per share the same period in 2018. The increase in net loss was primarily driven by the increase in R&D expense period- over-period, tied to increase spending across a clinical programs and an increase in G&A due to increased spending related to commercialization preparation activities and related head count.

R&D expenses with $34.8 million for the fourth quarter of 2019, compared to $13.8 million for the same period in 2018. The $21 million increase year-over-year was primarily due to increased manufacturing costs, clinical study costs, and employee related expenses due to an increase in head count necessary to support our growth.

We expect overall research and development expenses to increase throughout 2020 and for the foreseeable future, as we ramp our clinical manufacturing activities, continued clinical activities associated with three of our core product candidates, initiated activities under the Novo and Roche agreements and continue activities under the Lilly, Alexion and BI agreements.

G&A expenses were $13.6 million for the fourth quarter 2019 compared to $7.2 million for the fourth quarter of 2018. The increase was primarily due to employee related expenses as a result of increased headcount required to support our growth as well as an increase in professional fees and consulting expenses.

We expect G&A expenses to continue to increase in 2020 as compared to 2019 largely due to investments in staffing and market readiness activities.

During the fourth quarter of 2019, we recognize $7.1 million in revenue from our collaborative arrangements with Lilly, Alexion and BI compared to $1.5 million from the BI collaboration in the fourth quarter of 2018.

As of December 31, 2019, we had we had approximately $395 million of deferred revenue on our balance sheet representing the aggregate transaction price allocable to future performance under the Company’s collaborations, which will be recognized as revenue in future periods.

Of that amount, approximately $212 million was current deferred revenue expected to be recognized as revenue in 2020, and approximately $183 million was noncurrent deferred revenue, expected to be recognized as revenue beyond 2020. Let me take a minute to walk through the components of deferred revenue by collaboration.

With the Alexion collaboration, deferred revenue totaled approximately $53 million with $27.8 million classified as current, and the remaining $25.2 million classified as long-term. We expect the majority of the deferred revenue to be recognized through the fourth quarter of 2021.

The $20 million option fee paid by Alexion for its third and fourth targets is included in the deferred revenue number at December 31, 2019. But the Lilly collaboration, deferred revenue totaled approximately $135.5 million with $63.2 million classified as current and the remaining $72.3 million classified as long-term.

We expect the majority of the deferred revenue to be recognized through the second quarter of 2022. For the Roche collaboration, the $200 million upfront payment which was received under the contract terms in January was recorded as deferred revenue as of December 31, 2019.

Of that amount, $118 million is classified as current and expected to be recognized as revenue in 2020 primarily associated with the completion of our Phase I study of RG6346. We would expect the balance to be recognized as revenue during the remainder of the three year research term, which is extendible by an addition – by up to two years.

For the Novo collaboration, $4.2 million – the $4.2 million premium on Novo’s $50 million equity investment was included in deferred revenue at December 31, 2019.

However, the $175 million upfront payment from Novo was contingent on research deliverables achieved in January, 2020 and so is not included in the deferred revenue number at the December 31, 2019.

The $175 million upfront payment will be recorded in deferred revenue in Q1 2020 and we expect that the deferred revenue will be recognized over the five year research term, which is extendable for up – by up to two years. Finally, for the BI collaboration, deferred revenue totaled $2.2 million all classified as current.

As of December 31, 2019, we had $348.9 million in cash, cash equivalents and held-to-maturity investments compared to $302.6 million as of December 31, 2018. As mentioned, in addition to that, we received $200 million and $175 million in upfront payments from the Roche Novo agreements respectively in January 2020.

And received approximately $39 million in net proceeds from the sale of common stock to a single institutional investor under our ATM program in February 2020.

We believe that our cash, cash equivalents and held-to-maturity investments along with the upfront payments received from Novo and Roche and the proceeds from the ATM stock sale, which together total more than $750 million will be sufficient to fund our operating plan into 2023.

This plan includes our expectations to advance Nedosiran through pivotal development, regulatory filing and potential commercial launch, completing proof-of-concept studies of RG6346 in participants with HBV infection, advancing the company’s DCR-A1AT program through initial Phase I/II clinical study and initiating and conducting research and development programs with our collaborative partners.

I also want to briefly discuss the coronavirus. Like other biotechnology and RNAi companies, our supply chain relies, in part, on manufacturing capacity in China. In light of the impact of COVID-19 on China’s workforce, we’ve been closely monitoring our production schedules in China.

Based on our discussions with our suppliers, scheduled runs have remained on track so far and we are also monitoring the potential for an impact outside of China and considering appropriate actions to mitigate risk.

We’re not anticipating a supply disruption or impact on our development timelines at this point, but if circumstances change and the workforce of our suppliers is impacted or the virus’ has significant effects outside of China in the future, we could see supply delays and interruptions for some of our programs.

To mitigate supply chain risk, we are seeking to build additional safety stock in our supply chain when feasible to do so and are monitoring recommendations from the CDC.

In addition, prior to the coronavirus situation, we had already begun developing alternative supplies outside of China, key proprietary reagents, and we expect to begin supplying – we expect these to begin supplying us this calendar year. And finally, on a personal note, today we announced that I will be retiring as CFO of Dicerna in the near term.

After a 45-year finance career, I feel it’s time to move on to the next chapter. I have agreed with Doug to remain a CFO until a successor is recruited and onboard and for a transition period thereafter, and I will stay in a consulting role to assist the company beyond that transition.

I have to say that I’m very excited about the tremendous progress Dicerna has made, and I’m honored to have played a role in the company’s growth. I have a great deal of confidence in the company’s prospects and look forward to watching its future success from the sidelines as I complete my transition. With that I’ll turn the call over to Doug..

Thank you, Jack. I speak on behalf of all of us at Dicerna, when I say that it has been a pleasure working with you. Jack has been a trusted colleague and guiding hand at Dicerna for the past four years and he will be greatly missed.

As Jack noted, he will be staying on as CFO until we have a successor onboard and will remain in an advisory capacity for a period of time thereafter. We have engaged an executive recruiter and that search is now underway. Will be business as usual until we have someone in place with Jack continuing to perform his customary duties as CFO.

And while this isn’t a goodbye today, we nonetheless take this time the wish Jack well in his transition towards retirement. This will be an important year for Dicerna with multiple plan milestones and the cash resources to achieve our strategic goals.

2020 will be defined by clinical execution across our core portfolio, establishing the foundation for anticipated commercialization of Nedosiran and expanding and advancing our early-stage RNAi pipeline before ourselves and our collaborative partners. We look forward to an event-filled year and providing updates on our progress.

And with that I would now like to open the call for questions..

[Operator Instructions] Your first question comes from Steven Wiley of Stifel. Your line is now open..

Yes. Good afternoon. Thanks for taking my questions. Congratulations on a good 2019, and good luck on the transition, Jack.

A quick question, just regarding the PH3 dialogue you’re having with FDA, can you maybe just kind of provide a little bit of context around what some of the levers are involving that discussion? I know this is a fairly heterogeneous patient population with respect to disease severity.

Is there some kind of threshold here that needs to be established with respect to baseline urinary oxalate levels in order to identify the most appropriate patient population for a clinical trial? And maybe you can just talk a little bit about when you think you might have some of that regulatory clarity in hand?.

Yes. We’re happy to address PH3 situation. And for that, I’m going to pass to Ralf Rosskamp, our CMO..

Yes. Thank you very much. I think the beauty of the breakthrough designation, which we have for PH1, it allows us also to have continuous discussion with the FDA on PH2.

And as you know, at one point, we only had the approval of the FDA for full approval for PH1 and then later, we came back through the dialogue with the FDA, also having achieved full approval for PH2. This is an ultra-rare disease, and the PH3 has only been genetically confirmed 10 years.

So the issue we are facing as well with the FDA that is not the same amount of natural history data towards the progression of disease, towards the relationship between urinary oxalate and outcome. And we are working and continue to work closely with the FDA to find a regulatory path-forward. The FDA is extremely helpful.

They acknowledge that this is, in some patients, really severe disease, patients having continuous stone formation.

And we haven’t yet come to a conclusion, but I’m pretty hopeful that through our continuous discussion, what I mean continuous discussion means, since we’re having breakthrough designation, we had already a couple of telephone conference with the FDA that we’re able to come to an agreement here..

Okay. That’s helpful. And then, Doug, I don’t want to, I guess, front run any potential R&D Day surprises here. But can you speak to the extrahepatic tissues that we might be seeing data in, when you guys kind of provide this update. I’m presuming that CNS is probably an extrahepatic tissue of interest.

But are there any other tissues here that we might want to keep an eye on?.

Thanks, Steve. You’re correct to think that CNS is going to be a front and center of that effort and we’ll be talking about that pretty extensively at the R&D Day. But for now, I’m going to decline to indicate any of the other future directions..

Okay. And then maybe just lastly for you Doug.

I guess this is probably not a question I typically ask, but I think, we’ve been getting a lot of questions around, I think some of the stock sales that happened in the latter part of 2019 and I think maybe based on the way that they were advertised or came across some of the wires, there was a little bit of confusion around those.

Can you maybe just kind of provide a little bit of more clarity around where those – where they stand right now? And I guess your continued leverage to the firm? Thanks..

Yes, thanks for bringing this up, Steve. Because I did see in the press there was a fair amount of misreporting about this. To say, as a percentage of my own options vested and unvested, the sales were about 5%. And given where we are, as I’ve talked today, this is the – I’m more bullish on the company now that and its prospects than I’ve ever been..

Okay. I appreciate the color and congrats again..

Thank you. Your next question comes from Jonathan Miller of Evercore. Your line is now open..

Hi guys. Yes, thanks for taking the question. And again congratulations to everybody on the progress last year and to you Jack, for making the transition. I’d like to start by asking a little bit more about the ramp of your commercial build-out this year.

I know you’ve already made some key hires, but how much more ramp should we be expecting and how will that develop over the course of this year?.

Yes. I’m not going to speak in a lot of quantitative detail to answer this question, but I think you can think about three phases. The first phase is bringing in a leadership tier that establishes the strategy and the scope of effort that of the build-out. And that phase, I’d say at this point is complete.

The second phase has to do with beginning in an inappropriate way to really be communicating with physicians and – to a lesser degree, but significantly communicating with payers as well to set the ground work for actual payer discussions and the marketing of the product later.

So this involves bringing in a tier of professionals who can communicate at this point in an appropriate fashion, things like the Medical Science Liaison Group. That phase is starting now and will continue through the year and through the early parts of next year.

And then the third phase is to really put the – on the ground sales force in place, ready to go as soon as, we hope, we get approval from the FDA to market. So we are very much hoping that with an NDA filing in the first half 2021 for breakthrough designation orphan disease product that we would be launching in the second half of 2021.

So 2021, we’d be putting that in place and getting training done and all the materials put together and ready to go. In terms of the scope of effort, it’s an ultra-orphan rare disease with concentrated treatment treating physician group. And so the scope of our effort, which is U.S.

focused for us, as we discussed, is going to be sized to that sort of market. I mean we are fortunate to have all the resources we need to put in place. The program, we think, is the ideal program to do this. And roughly speaking, we can have about perhaps a dozen MSOs and 20 or a couple of dozen sales force. It’s around that scale of effort.

So I hope that gives you a sense of where we are and how we’re thinking about it..

Absolutely. That’s great color. I guess the other thing I’d like to ask about is the A1AT program, which I know you’ve already got in healthy volunteers and go into patients this year.

Is there any likelihood that we could see preclinical translational data more this year, maybe at the R&D Day? And what are your expectations for top lining that initial patient data?.

This is a program that I think will significantly expand our communications on later this year. At the R&D Day, we’ll certainly give more information about the program. And I’m anticipating that we’ll be presenting healthy volunteers data at that program as we move towards the patient phase. Beyond that, I think we’ll give more timing guidance later.

But right now, we’re looking at starting to those patients in the second half. But so I’d say, mostly stay tuned for more, and we’ll be more forthcoming about that program in coming quarters..

Sure. And then just last, the one collaboration, you didn’t mention much at all was the BI collaboration, which I know moved on to another potential target last year.

Is there any news expected there? And how should we be thinking about your first and oldest?.

Yes. my script goes on long enough. So I don’t want to belabor it too much with every detail. The BI collaboration is going just fine. As you said, they shifted to a second target. That’s nothing to do with the molecule that we presented.

It had to do with their confidence in achieving the clinical endpoints they want to achieve by that mechanism of action. I’m very pleased with the molecule, and that’s reflected in their moving to ask us to do a second molecule for which they paid an option payment to have that second molecule. It’s not a replacement.

We are on track for the time lines, and it is a liver target for NASH. And the technology is very reproducible and it is reproducing and producing that target as well. It is not going to be the first thing that goes into the clinic from the collaborative partners.

And if it’s going to go in 2021, I don’t know if that’s going to be the case, then I’ll let you know. But right now, I’m having any further timing on it..

Okay. That makes sense. Thanks very much..

Thank you. Your next question comes from Mani Foroohar of SVB Leerink. Your line is now open..

Hey, thanks for taking my question. First congratulations, Jack. Doug, I feel like I haven’t seen you a long time. It’s been so long. I have a couple of questions about combination use of your partnered assets. So one about HBV, how does – how are the economic structures should Roche move forward with a triplet approach – doublet approach.

Some assets be – some elements of the combo being generics as the NUC and some being non-generic, your RNAi approach potential or core inhibitor and then elsewhere. I know you guys still have a PCSK9 asset that lives outside of your published – of your announced partnerships.

How do you think about that, either as a stand-alone asset to be partnered off for your own development or something for a potential combination use with current or future partner?.

Yes. We can address these issues. As you can imagine, the combo – expected combo nature of HBV therapy introduced some complexity into the contracting of our collaboration with Roche. I’m going to have my colleague, Jim Weissman, our COO, and the architect of our deal strategy and execution. He’s going to take those questions..

Hi, thanks for the question. This is Jim. And first of all, we were really pleased that we are in a competitive process. And when we think about – what we formally call DCR-HBVS, we really wanted to partner that with a company we thought had the bandwidth capability and the pipeline to look at a host of combinations.

We have done a lot of homework in terms of understanding the epidemiology and etiology of the disease in the various major markets around the world. For example, China, we’re really pleased that we had what we can think of as a really good level of interest from a number of players, and we were very impressed with the pipeline that Roche has.

We were also very aware of the multiple combination therapies that could be used. I think we’ve done a really good job, I can’t speak to the particulars of the deal, as you can imagine.

But in looking through what the various combinations could be, how many agents there might be, the types of agents, whether it would be multiple GalXC molecules or GalXC molecule with other modalities, we thought it through, and I’m very pleased with where we ended up. I know that’s only a partial answer to your question. You like those details.

I think you just have to rest assured, we’re very aware of it. And I think we did a good job on that..

Yes. To be a little bit more specific, right? The royalty does reflect the percentage of value that the RNAi component brings to the combo. But we have guardrails in the contract that ensure that the value attributed to the RNA portion represents a very substantial fraction of the value of the combination.

And a widely available and expensive generic cannot be considered to be bringing a lot of the value to a combination. So, I think we protect – appropriately protected our economic interests in that complex calculation of how to attribute value in a combo..

Thank you, Doug. And then on PCSK9, of course, the transaction that caught everybody’s attention between The Medicines Company and Novartis is important. We’ve long had a strategy around PCSK9, and we’re weighing our options at this time.

We’ve got incoming interest, and we’re thinking what would be the most appropriate way forward with our PCSK9 leads..

Great. Thanks, guys. And one quick follow-up regarding the PHYOX program.

Have you guys dosed any Japanese patients that will be required for a potential JNDA? Or is that something you’d expect to happen in the hands of your future geographic partner?.

We have not, to date, dosed any patients in Japan. Having said that, is our expectation that amongst the 36 patients will be patients from Japan. And it is our hope that we can support filing and market entry in Japan as expeditiously as possible, just as we’re seeking in the United States.

And so if we put more generally, Japan is part of the current PHYOX2 pivotal program..

Great. Thanks. I’ll hop back. Thank you..

Your next question comes from Yaron Werber of Cowen. Your line is now open..

All right. Thanks for taking my questions. So Doug, I was just going to ask about a couple of things relating to PHYOX3 and the open label. You mentioned that this is going to be the first long-term data that we’re now looking at reduction in urinary oxalate levels.

And sort of – and understanding is how low one can go and whether one can go lower than the sort of the lower end of normal, and so maybe a thought on that.

And then what would you expect to see in terms of the need to reduce levels to eliminate the need to hyper hydrate? And is there any historical data that you can point it to kind of give us a guide as to what to expect? Thank you..

Ralf, can you address those things?.

Yes, thank you very much.

So first of all, PHYOX3, the primary endpoint is annual decline in renal function because the ultimate goal, of course, in those patients is by reducing the calcium oxalate excretion from the liver and by reducing the amount of calcification that you at least stabilize the renal function because those patients, as you know, ending up in end-stage renal disease and renal transplantation.

And therefore, this is a long-term three-year study with the endpoint reduction – with the endpoint being estimated GFR. Having said that, of course, we are continuing to measure oxalate in the urine because it gives us a good readout what the amount of suppression of oxalate production in the liver will be.

And when it comes to a hyperhydration, I think and the protocol states that at the time when patients, on two consecutive visits, reached near-normal or normal concentrations, then they get weaned off of their hydration therapy. That’s the ultimate goal.

That’s the ultimate goal, which you want to achieve that those patients can lead to normalize that they don’t have to bring this huge amount of water – potassium citrate. So what we then believe will have also an outcome on the quality of life measures in this study as well.

So yes, we plan to reduce hyperhydration of those patients when they reach the normal, near-normal concentration. Concentrations of less than 30% or 50% would not be enough to get patients to that point that you can wean them off their hyperhydration therapy.

Does that address your question?.

Yes. It did. So, thank you. And then the second question has to do with maybe, Doug, it’s been understanding of the A1AT program. The timing has slipped a little bit into the second half? And just an understanding is it relating what, was it trial design? I mean the initial phases in healthy volunteers.

So is it relating to the subsequent part of the study? Or is it related to manufacturing? And maybe just give us a little bit of a sense kind of where you are in the program in terms of timing to progressing it onwards?.

There was a little bit of healthy volunteer slippage associated with holidays. And other than that, I mean the program is largely on track..

Okay..

Yes. I agree..

Go ahead..

Please go ahead..

Yes, it’s – it hasn’t really – from our perspective, really clicked a lot. There were some – as we started last year with the coming December and vacation period. And yes, this is a healthy volunteer part here takes longer than, for instance, in our Nedosiran, where we could, in parallel, treat patients and healthy volunteers and then go in patients.

But because of the concern of regulatory agencies around possible lung injuries, therefore, this program in itself goes a little slower than the Nedosiran program. And therefore, the time lines are more extended than in our other program, but nothing really unusual here..

Great. Thanks for the clarification. And maybe, just a final question.

So as you think ahead in terms of how to differentiate this program, can you give us any inkling maybe clinically, how would you go about that?.

I think that all I can say on that is that we do tend to focus on the most severe patients. That’s the highest unmet medical need and the most, I believe, likely to actually get treated when identified, and there’s product available. Other than that, we do expect to say more about this program later this year..

Thank you..

Your next question comes from Ed Arce of H.C. Wainwright & Co. Your line is now open..

Hi, everyone. Thanks for taking my questions. And let me add my congrats on a very filled 2019 with lots of progress. So, a couple of questions for me. First, on Nedosiran, regarding your PHYOX3 open-label trial given the identical design and the potential for read-through on your pivotal.

I’m just wondering if you could perhaps – and I realize this was partly answered previously.

But if you could perhaps give us any more detail around what trends of aspects are going to be? What we can expect from the readout, perhaps in terms of, not just potency, but sustained potency over time and any sort of steady state or anything along those lines?.

Yes. Thanks, Ed. This is Ralf. The only data we have made available so far, a single dose data. So this will be our first time, as Doug said, in one month from now at the OxalEurope data, where we will get a limited first lands in multi-dose data look like in patients and with our monthly regimen, our fixed-dose regimen of 170 or 136 milligrams.

So what you can expect is really to see the amount of urinary oxalate.

And of course, since we’re expecting to have maximum effect around three months that was – we learned from our Phase I study, we would expect to see a sustained reduction in urinary oxalate over time, which then would lead to – as discussed with the previous question, to near-normal concentration would lead to weaning of the hydration therapy.

Does that address your question?.

Yes. that does. Thanks, Ralf. I appreciate that. And then switching gears to your HBV program. Obviously, as you mentioned, you’ve got both patients that had entered the study NUC experience as well as naive patients, all of whom have now continued on the rollover after having achieved one log of reduction or more.

Just wondering about how you see the differences in those patient groups? And how you might think about reporting that ultimately later this year at your R&D Day in terms of stratification of patients? Thanks..

Well, we’ll talk about Group B and Group C as distinct groups at our R&D Day. The Group C is very comparable to what other companies have conducted in their Phase I. And for those inclined to parse the comparisons that provides reasonably similar fruit in order to be comparing with others.

Group B is a little bit different, and we’re not aware of a similar study from one of our peer companies, but it has a couple of things that we think make it very relevant to us. One, as a single dose with no other pharmaceutical intervention, we get a good pharmacodynamic curve for the effect of our drug.

And that enables modeling and simulation in a more straightforward fashion than trying to do that with multi-dose data. And that will help us inform how to do dose regimens going forward.

And second, perhaps a little bit more of a subtle point or forward-thinking point, the vast majority of chronic HBV patients are not diagnosed, not currently being treated. And there will need to be a treatment decision made when they are freshly diagnosed.

And so that patient Group actually represents – Group B patient group actually represents a large majority of the addressable population. And so we wanted to get an initial look at what happens when you start dosing those patients with an RNAi therapy without the complication of what other therapies have – can potentially impact the virus.

So, there are multiple goals that we’re trying to address with Group B, and we look forward to separately talking about the data from those two groups and trying whatever conclusions the data support..

Great. That’s very helpful, Doug. Thank you for that. And then I’ll just add, Jack, congratulations on a long finance career, and I wish you all the best in your retirement..

Thank you, Ed. I appreciate it..

Your next question comes from Robyn Karnauskas of SunTrust. Your line is now open..

Hi. This is Nicole on for Robyn. So, just a few questions here.

So, as you start hearing more about the extrahepatic targets later in the year, can you help us understand the hurdles of delivering RNAi to other tissues? And with going after, for example, other targets in CNS or muscle and immune cells, what are the nuances in the biology that people aren’t fully appreciating about the GalNAc platform that you guys have?.

Yes. Hi, Nicole. I’m happy to address that. Unfortunately, my colleague Bob, is not Bob, is not here because he could certainly do – Bob Brown, our CSO, would do more justice to this than I believe I can. But I can give some insight.

And first thing I would say is you need to recognize that hepatocytes represent a special and I believe best case for RNAi delivery for two reasons. The first reason is the abundance of the ASGPR receptor, that GalNAc binds to on the surface of the hepatocytes in the frequency with which it internalize.

It provides a conveyor belt into the cell that is – there’s no other system that has that level of flux that we’re aware of in the body anywhere else. And the second thing is, it does appear to be a unique biology as hepatocyte. They’re based in serum and as part of their role and physiology to take stuff up and deal with it.

And I think that in – via mechanism that I can’t articulate, and I don’t think it’s fully understood, does make them more amenable to the uptake of, I think, great many things and nucleic acids amongst them.

And so I think with that biology you had the – it stands to reason that hepatocytes would be the first thing that was effectively conquered, if you will, by technology for RNAi.

In optimizing for hepatocytes, where the real gains came from, was it stabilizing the molecule so that once they were internalized, they survive what is enzymatically and chemically harsh internalization environment and actually make it to the silencing complex in the cytoplasm.

And we have, I think, done a very good job protecting our molecules from destruction along that path. Now, that protection should pay the same benefits in all other cell types that it pays in hepatocytes. And I think generally, it gets us closer to workable solution in all other cell types.

Going forward, we will be doing two types of things to the molecules to enable delivery to other tissues. One is identifying and utilizing other receptors in the same way we utilize the ASGPR for GalNAc-mediated delivery.

And the second is using – particularly, the extended region of our molecule that is unique to the Dicerna platform, using that as a platform for modifying the overall chemistry of the molecule, things such as its lipophilicity, its overall charge to mass balance in order to make it an easier chemical task to cross into cells.

In the nervous system, specifically where a lot of our extrahepatic work is, and we’ll talk a lot about at our R&D Day, it is particularly that second element that is driving our success in nervous system delivery to date.

But in other tissues you’re facing a situation, where you don’t have the same flux of receptor-mediated internalization, and you don’t have the base directly in serum. And as I said, this general proclivity to take stuff up that hepatocytes have.

I think it’s likely hepatocytes will represent the peak of performance for RNAi, and it’s likely that higher doses will need to be used in other tissues to achieve comparable results.

Having said that, I think it’s quite remarkable that a 1 ml dose enables monthly administration and that’s heavy dosing for our Nedosiran program and certainly could have opted for a quarterly administration with subcutaneous. That’s remarkable from a pharmaceutical properties perspective. Far, far in excess of your average antibody.

So I think there’s a lot of room to dose higher up and effectively achieve delivery to other issues.

So I hope that more or less addresses the question?.

Yes, definitely. Thank you so much and thanks for taking my question..

Your next question comes from Madhu Kumar of Baird. Your line is now open..

Hey, guys. Thanks for taking our questions. I will also say congratulations to Jack as he moves on. Our first question relates to PHYOX2 the pivotal trial.

So thinking about PH1 versus PH2, is there an expectation that the trial is really comparing across both types of PHs, where drug has to be placebo just overall? Or is there a notion that you have to win both in PH1 and PH2?.

Yes. Thank you for the question. This is Ralf, again. It’s – the analysis will be PH1 and PH2 against placebo. So there is nothing to assume that – and we have shown this in the single-dose study that there is a difference in the response to PH1 or PH2.

Remember, in both – even in PH3, the ultimate step of the production of oxalate in the liver goes through the LDHA enzyme, and we are blocking this. So there’s no reason to believe that there is a difference, and therefore, our primary analysis will be the combination of PH1 and PH2 patients against placebo..

Okay. And then next question is relating to the commercial landscape, the competitive landscape in PH type 1, specifically. So kind of looking at what’s out there, it’s not reasonable to expect there will be another competitor out in the market ahead of you guys.

So how do you think about differentiation, and particularly because of the broader utility of the dose range, do you imagine that price is a potential lever for you as a second engine, specifically in PH1?.

Thanks for question, Madhu. We think that the differentiation is based on the broader applicability of the molecule, the broad amount of safety data associated with LDHA from the human genetic experience.

And importantly, our dosing regimen, which we think maximizes convenience while providing a safety and redundancy for a self-administered chronic indication. We also had incorporated in our protocol the ability to wean off of the disease management hyperhydration and other aspects of disease management and actually have that’s part of the protocol.

So, those are the levers that we look to for differentiation. We don’t consider pricing, at this point, a productive way to drive differentiation..

Okay, great. And one last one about the alpha-1 antitrypsin program. So considering a competitor program is going to have these early data in A1AT, liver disease patients later this year.

What would you envision you can learn in that trial that you could incorporate into your own studies in A1AT patients?.

Well, we look forward to seeing data emerge in the field. And I think the data you’re referring to, the most interesting element will be paired biopsies of a relatively short period of time, which may give some indication of slope of change associated with histology.

And that could impact thinking, although I think our thinking is fairly advanced on what our pivotal trial would look like on our front..

And finally, to that end, do you think the changes in A1AT ZZ globule information are more largely a function of equilibrium from circulating A1AT? Or is it a function of hepatocyte turnover or a mix of both?.

Well, I think it’s a little bit of a stretch to say hepatocyte makes a whole bunch of misfolded protein, I think, that accreted and then taken back up by the same cells to form a globule. I would tend to think you would cut out the middle man there.

So I find it a little bit implausible that the driver of globule formation is re-uptake by hepatocytes of circulating A1AT. Having said that, I understand there’s evidence for exchange, and there may be a contribution to globules, but we’re in the absence of very specific molecular data, which would be extremely hard to collect.

But intuitively, I think you would expect the globule to be based on misfolded protein that aggregates after synthesis before secretion..

Well, I guess you’re thinking more along the lines of does the blockade of synthesis lead to a shift in equilibrium out not as much a shift in from the outside. But if you blockade synthesis will that cause a reduction kind of through an equilibrium shift into circulation. But whatever it is we’ll all find out soon enough.

So, thanks so much for your questions..

Okay..

Thank you. Your next question is from Mayank Mamtani of B. Riley FBR. Your line is now open..

Thanks for taking my questions and congrats on a very successful 2019 and wishing the best to Jack for his next chapter. Two questions, mostly clarifying for DCR-HBVS. Can you talk to how many patients are in the different cohorts? It seems like 56 patients across 18 cohorts, if I’m not mistaken.

And maybe clarify, have you gone up to the 12 mg per kg dose and I mean that the R&D update, would you have the multiple dose data? And the second part was the coronavirus exposure.

Could you maybe talk to if there are sites in Asia? And if you’re talking beyond just the supply chain issue?.

Yes. So, for the first part of the question on HBV, we have fully completed Group A, a healthy volunteers that includes all dose levels, including the 12 mpk, and the drug was well tolerated at all dose levels for HBV. Group B is eight patients, and that breaks down to three-placebo patients and five-drug patients.

Group C is 18 patients, six each in three cohorts and in – within each cohort, there are four patients that get treated with active compound and two patients on placebo.

So there the – does that cover the relevant numbers you’re looking for?.

Yes.

And the R&D update would have all the data, the multiple dose included?.

That’s correct. For the – what we anticipate will be in August R&D Day that will allow us to have the full planned, studied evaluation for every patient in all the groups..

There might still be follow-up. So as you know, they go into this condition of follow-up once at months for more than one log reduction. So that might still be ongoing, but we’ll show all the data up to months’ fall of antibody. And of course, we’ll show the follow-up period in some of the patients where we have. Yes. Whatever we have..

Whatever we have, yes. Relative to coronavirus, yes, we do have sites in Asia in the HBV program. Hong Kong, for example, is a major contributor.

Have we completed dosing yet, Ralf, in Group C?.

No. We haven’t completed, but we have not seen an impact. So as I see, we are closely monitoring those patients continuously going to screening to get dosed, and those who are dosed and have a monthly visit or they have follow-up visit, they come to those visit.

So we haven’t seen any impact so far on patients not enrolled into the study, not coming to their scheduled visits..

Yes. We are right at the tail-end of enrolling this. We’re in the main phase of enrollment of the of the highest dose cohort. It is conceivable in scenarios that it may be difficult to get follow-up visits. But right now, we don’t have an impact.

And until authorities tell people, they can’t go back to the hospitals for a follow-up, then we anticipate follow-up visits will occur..

That’s great to hear. And hopefully, that last thing is not the scenario. And then a follow-up on the cardiometabolic disease.

Collaboration that you have Lilly and Novo specifically, is alcoholic liver disease part of any of those? And then more broadly, can you – like when can we learn anything specific about these targets? And could you confirm if like the most advanced ones are “first-in-class?”.

We’re really limited into what we can share about our partners’ targets and indications and need to take our lead from them on what they want to disclose. So beyond general that their cardiometabolic targets and their stage of development, I really can’t share beyond that, unfortunately.

I would say that alcoholic liver disease is within the scope of both the Lilly collaboration and the Novo collaboration..

Great. Thanks for taking my questions..

Thank you. Your last question comes from Keay Nakae of Chardan. Your line is now open..

Yes. Thank you. Just a point of clarification on the extension part, extended follow-up for HBV.

How far out do the Bs and Cs go if they have the one log reduction and qualify for that?.

Well, currently, the protocol says six months, but we have filed or in the process of filing a protocol amendment because we have patients reaching this point, and we want to continue to follow them up.

So we have a protocol amendment with regulatory agency, which extends the six months conditional follow-up through another year in case, for instance, somebody would zero at a clearance, and we want to follow-up how long the log reduction goes because we only know, it’s more than one log reduction.

And we don’t even know whether it continues to be two log reduction or 1.1 log reduction or even a clearance, we don’t know because we are lined at, and therefore, we want to continue the follow-up until we do this planned interim analysis for the R&D Day, where we then can actually see the actual log reductions..

Okay, very good. That’s all I have. Thanks..

There are currently no more questions. I will now turn the call back to Doug for closing remarks..

I want to thank everyone for joining us today in reviewing our fourth quarter financial results and our milestones for 2020. It’s going to be an exciting year, and we’ll keep you all updated on our future calls. Thank you very much..

Ladies and gentlemen, this concludes today’s conference call. You may now disconnect..