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Edited Transcript of DRNA earnings conference call or presentation 7-Nov-19 9:30pm GMT

Q3 2019 Dicerna Pharmaceuticals Inc Earnings Call

Watertown Nov 25, 2019 (Thomson StreetEvents) -- Edited Transcript of Dicerna Pharmaceuticals Inc earnings conference call or presentation Thursday, November 7, 2019 at 9:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Douglas M. Fambrough

Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director

* James B. Weissman

Dicerna Pharmaceuticals, Inc. - Executive VP & COO

* John B. Green

Dicerna Pharmaceuticals, Inc. - CFO

* Ralf H. Rosskamp

Dicerna Pharmaceuticals, Inc. - Chief Medical Officer

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Conference Call Participants

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* Brendan Smith

Cowen and Company, LLC, Research Division - Research Analyst

* Jonathan Miller

Evercore ISI Institutional Equities, Research Division - Associate

* Keay Thomas Nakae

Chardan Capital Markets, LLC, Research Division - Senior Research Analyst of Therapeutics, Devices and Diagnostics

* Madhu Sudhan Kumar

Robert W. Baird & Co. Incorporated, Research Division - Senior Research Analyst

* Mani Foroohar

SVB Leerink LLC, Research Division - MD of Genetic Medicines & Senior Research Analyst

* Stephen Douglas Willey

Stifel, Nicolaus & Company, Incorporated, Research Division - Director

* Wing Cheung Yip

H.C. Wainwright & Co, LLC, Research Division - Research Analyst

* Lauren Stival

Stern Investor Relations, Inc. - MD

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Presentation

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Operator [1]

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Ladies and gentlemen, thank you for standing by, and welcome to the quarter 3 of 2019 earnings conference call. (Operator Instructions) And please be advised that today's conference is being recorded. (Operator Instructions)

Now I would like to hand the conference over to your first speaker today, Ms. Lauren Stival of Stern Investor Relations. Ma'am, you may begin.

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Lauren Stival, Stern Investor Relations, Inc. - MD [2]

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Thank you. Good afternoon, everyone, and thank you for joining us to review Dicerna's Third Quarter 2019 Financial Results and Operational 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 2 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 third quarter financial results. We also have Jim Weissman, our Chief Operating Officer; and Ralf Rosskamp, our Chief Medical Officer, who will be available to answer questions during Q&A.

Following our remarks, we will open the line for questions. I'd like to remind listeners that management will be making forward-looking statements on today's call, including, for example, planned and expected time line for closing of the new Roche collaboration agreement; development of DCR-PHXC, DCR-HBVS, DCR-A1AT and other pipeline programs; the timing of release of clinical data; alignment with FDA on regulatory approval requirements; the expansion of our programs into additional tissue types; expectations related to our collaborations with Roche, Lilly, Alexion and Boehringer Ingelheim; expectations for discussions and possible opportunities with potential collaborators and guidance regarding future collaboration revenue, operating expenses and cash usage. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those disclosed in the Risk Factors section of Dicerna's latest Forms 10-Q and 10-K filed with the SEC. 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, Dicerna's President and CEO. Doug?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [3]

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Thank you, Lauren. Good afternoon, everyone, and thank you for joining us. What an exciting time it is for us here at Dicerna. We are proud of the work we have accomplished over the years and particularly over the last 5 quarters as we deliver on the strategic goals we have set for ourselves. We have progressed from revealing initial proof-of-concept data in our DCR-PHXC program to starting dosing of our pivotal trial for that program. We have progressed 2 additional programs through clinical trial applications to initiate clinical development. We signed 3 major licensing deals with Roche, Lilly and Alexion. These collaborations have or will generate on closing in excess of $300 million in upfront payments to enable us to advance our wholly-owned lead rare disease programs, which are DCR-PHXC for the treatment of all forms of primary hyperoxaluria and DCR-A1AT for the treatment of alpha-1 antitrypsin deficiency-associated liver disease. We also retain an opt-in for our DCR-HBVS program for the treatment of patients with chronic hepatitis B virus infection and opt-in after proof-of-concept combination studies to co-fund pivotal development in exchange for the right to co-promote the product in the U.S. and obtain significant additional economic rights in the U.S.

We believe our clinical data and corporate collaborations validate our GalXC platform technology. And we have only begun to scratch the surface of GalXC potential to successfully deliver RNAi therapies to both hepatic targets as well as to new tissues and therapeutic targets outside the liver. Our corporate collaborations make us a stronger company. They are not opportunistic. Rather, they represent deliberate execution of our strategy for building a fully integrated biopharmaceutical company to generate exceptional value both for patients and shareholders.

Key elements of our strategy include: first, retaining commercial rights to our lead rare disease programs where we believe the probability of clinical success is high; second, monetizing the extensive array of opportunities that we would not pursue on our own through collaborations that help us to fund development and commercialization of our rare disease programs; and third, advancing select low-risk opportunities in highly prevalent diseases, then seeking development partners to reduce and share risk while still retaining substantial economic rights in the U.S., such as co-commercialization.

Ultimately, we believe this strategy will enable us to develop commercial capabilities, first in rare diseases, which will provide a strong foundation for us to potentially move into a commercial role for more prevalent diseases. Via this strategy, we seek to retain maximum value for our shareholders while seeking to ensure the maximum number of GalXC-based programs in development across a wide array of therapeutic areas to extract the maximum therapeutic value from the GalXC platform for patients in need around the globe. This, we believe, is the best strategy for all our stakeholders, fulfilling our economic and social function.

As we rapidly progress this strategy, we continue to hire top talent and have outgrown our current laboratory and office space. We are looking forward to relocating next week to a new larger headquarters in Lexington, Massachusetts, which, along with new dedicated space for our manufacturing team in Boulder, Colorado, will continue to support execution of our strategy.

With that introduction, I'd like to now highlight the company's key advances and achievements since our last corporate update. For our DCR-PHXC program for the treatment of all types of primary hyperoxaluria, or PH, we have recently initiated dosing of patients in our PHYOX2 pivotal trial. We believe we will complete enrollment of the PHYOX2 trial by the end of the first half of 2020. As a reminder, PHYOX2 is a double-blind, placebo-controlled trial with planned enrollment of 36 patients with PH type 1 and PH type 2. Patients are to remain on therapy for 6 months. The primary endpoint of the trial compares reduction in urinary oxalate levels from baseline to measurements taken from the ends of months 3 through 6. Per protocol, DCR-PHXC is administered as a monthly fixed-dose subcutaneous injection of one milliliter volume for adult patients. Based on our interactions with the PH community, we believe a monthly fixed-dose regimen may be preferred from a compliance and convenience standpoint and may be preferable to both prescribers and patients compared to using weight-based administration. We are on track to have prefilled syringes at the projected time of product launch.

We are also currently dosing PHYOX3, an open-label rollover extension study for patients coming off various PHYOX studies, with the first patients having come off PHYOX1, a Phase I clinical study. The dosing regimen is identical to that of PHYOX2, therefore, PHYOX3 data will likely have some read-through for what PHYOX2 data may look like. We anticipate sharing PHYOX3 in the first half of 2020 as data from that trial mature.

On the regulatory front, we believe we have reached alignment with the FDA on a path to full approval for PH type 2, in addition to PH type 1, based on successfully showing substantial reduction in high baseline urinary oxalate for the PHYOX2 in the PHYOX2 trial in each patient type. This alignment with the FDA underscores the seriousness of PH type 2 as a disease and the urgency recognized by the FDA to provide an effective therapy for this high unmet medical need. As we've discussed outside of this call, the emerging natural history data for PH type 2 shows that the lifetime risk of end-stage renal disease is comparable to the lifetime risk in PH type 1.

Moving on to our HBV program, we are particularly excited by our recent collaboration with Roche. Unlike our discovery stage collaborations, our HBV collaboration with Roche includes an option for us to co-fund pivotal development of DCR-HBVS in exchange for enhanced U.S. royalties and the right to co-promote the product in the U.S. Importantly, we can exercise the option at the initiation of pivotal development. Meaning that we do not bear development costs until the Phase II proof-of-concept combination studies conducted by Roche have generated data that support moving forward with pivotal trials. We believe this substantially derisks any future investment we may make in the treatment of HBV infection and is a distinguishing feature of our collaboration relative to comparable collaborations by others.

The Roche collaboration includes discovery stage work for additional HBV gene targets and human liver gene targets relevant to the treatment of HBV. Under this discovery aspect of the collaboration, both companies will seek to discover potential products and the best candidates will be moved forward for development with Dicerna participating regardless of which company generates the candidate that is advanced. Upon closing, we will receive a $200 million upfront payment and up to $1.47 billion in potential milestone payments based on development, approval and commercial sales of DCR-HBVS, plus royalties up to the mid-teens globally. If we exercise the co-fund option, we are eligible for increased royalties in the U.S. from the high 20s to mid-30s percentages. Dicerna will complete the ongoing Phase I trial, after which Roche is responsible for future development of DCR-HBVS.

We are confident in our approach and that DCR-HBVS may be competitive with current candidates in development in its ability to show strong reduction in levels of circulating HBV S antigen. With our collaboration signed, we are shifting our R&D Day timing to roughly mid-year 2020 when Phase I data from all planned cohorts will be available.

However, we already have some information that is perhaps indicative of the activity of DCR-HBVS in patients. Multiple patients from Group C, the first cohort of HBV patients in our Phase I trial, have entered the extension phase of the study, which only occurs if a patient has achieved a 1 log or greater reduction in circulating S antigen at the end of month 4. Not all patients from the first cohort have reached this point in the study. And not all patients who have reached month 4 have been eligible for the extension. As a reminder, there are 6 patients in each cohort, only 4 of whom received drug and the other 2 received placebo. Thus, the information we have so far is consistent with a greater than one log reduction in circulating S antigen in at least some treated patients. But let me stress that, at this point, we do not know which patients are receiving drug and which are receiving placebo, and neither ourselves nor Roche have seen any quantitative data from this trial.

As a reminder, the Group C portion of our Phase I trial has 3 dose level cohorts at 1.5, 3.0 and 6.0 milligrams per kilogram. And each cohort will enroll 6 patients, 2 of whom will receive placebo. We are currently enrolling cohort 2 of that trial, which is the 3.0 milligram per kilogram dose level. We are also enrolling Group B of the trial in which NUC-naive patients receive a single 3.0 milligram per kilogram dose of HBVS. The Group A portion of the study, which enrolled healthy volunteers, is complete.

Moving to our third GalXC clinical stage program, which targets alpha-1 antitrypsin deficiency-associated liver disease. A1AT liver disease is an inherited disorder that results from 2 copies of the mutated Z form of the A1AT gene, causing accumulation of misfolded A1AT protein in the liver, which can cause liver damage and dysfunction. We filed our clinical trial application for a Phase I/II trial with the Swedish Medical Products Agency, or MPA, in July and are tracking nicely with our previous guidance of beginning the study this quarter, with a plan to begin dosing healthy volunteers imminently.

As a reminder, the first phase is a single ascending dose phase in healthy volunteers, enrolling up to 36 participants in as many as 6 cohorts. The second phase is a multiple ascending dose phase in patients with confirmed A1AT deficiency-associated liver disease, consisting of up to 24 participants in 3 or fewer cohorts.

We select our wholly-owned candidates like DCR-A1AT and DCR-PHXC based on unmet medical need and what we believe is a high probability of clinical success relative to industry averages. We have committed to a fourth internal program meeting our criteria, which appears on our pipeline, but we are unlikely to disclose the target of that program prior to reaching the clinical phase. We continue to evaluate additional targets, both in and outside the liver for internal program nomination.

Briefly touching on our collaborations. We're pleased with the progress we're making. Notably, Lilly has accepted the first clinical candidate under that collaboration, and we are targeting clinical entry for the program by the end of 2020. In addition, Lilly has nominated a fourth target for the cardio-metabolic aspect of that collaboration. They have 2 cardio-metabolic nominations remaining.

We have made good progress in our Alexion and Boehringer Ingelheim collaborations as well, and I look forward to providing news as we hit milestones in those collaborations. However, Boehringer has informed us that they will not be advancing the first clinical candidate in that collaboration, which has been denoted as DCR- LIV1 on our pipeline. This is not due to performance of the candidate but rather based on the biology of inhibiting that target for the treatment of NASH.

As I mentioned in the beginning of the call, these collaborations make us a stronger company. We see strong potential for additional collaborative activity. The liver is deeply enmeshed in a wide variety of biological processes, and consequently, our liver-targeted GalXC technology is broadly applicable in multiple therapeutic areas, which is not exhausted by our current programs and collaborations. In future collaborations, we are seeking to replicate the opt-in feature that is present in the Roche collaboration, specifically, the ability for Dicerna to opt-in after clinical proof-of-concept for co-commercialization rights in the U.S.

Finally, I'd like to mention our efforts in expanding GalXC to other tissues. We are very pleased with results to date in the nervous system as well as other tissues. We expect to present data on our delivery outside the liver during 2020.

On that note, I will turn the call over to Jack to discuss our financials before we open the line up for Q&A.

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John B. Green, Dicerna Pharmaceuticals, Inc. - CFO [4]

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Thank you, Doug. I'd like to briefly walk through the key financial results and direct you to our 10-Q filing for additional details.

Net loss for the third quarter ended September 30, 2019, was $30.8 million or $0.45 per share compared to $19 million or $0.35 per share for 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 increased spending across our clinical programs.

R&D expenses were $30.1 million for the third quarter of 2019 compared to $11.7 million for the same period in 2018. The $18.4 million increase year-over-year was primarily due to increased manufacturing costs, clinical study costs and employee-related expenses due to an increase in our headcount necessary to support our growth. We expect overall research and development expenses to increase throughout 2019 and into 2020 and for the foreseeable future as we ramp our clinical manufacturing activities, continue other activities associated with our 3 proprietary product candidates and increase activities under the Lilly, Alexion and BI agreements, and potentially under the Roche agreement if they choose to select additional targets.

G&A expenses were $10.6 million for the third quarter 2019 compared to $5.4 million for the third quarter 2018. The increase is predominantly due to employee-related expenses as a result of increased stock-based compensation expense and headcount necessary to support our growth, as well as an increase in general and business development consulting expenses. We expect G&A expenses to increase in 2019 as compared to 2018, largely due to investments in staffing and market readiness activities.

During the third quarter 2019, we recognized $8 million in revenue from our collaborative agreements with Lilly, Alexion and BI compared to $1.5 million from the BI collaboration in the third quarter of 2018. As of September 30, 2019, we had $312.7 million in cash, cash equivalents and held-to-maturity investments compared to $302.6 million at December 31, 2018.

In addition to that, we will receive $200 million from the upfront payment upon closing of the Roche agreement. We believe that our cash, cash equivalents and held-to-maturity investments, along with the upfront payment from Roche, which together totals approximately $0.5 billion, will be sufficient to fund our operating plan beyond 2021, which includes advancing DCR-PHXC through pivotal development, regulatory filing and potential commercial launch, completing proof-of-concept studies for DCR-HBVS and participants with HBV and advancing our DCR-A1AT program through the initial Phase I/II clinical study.

With that, I will turn the call back over to Doug.

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [5]

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Thanks, Jack. We're fortunate in the strength of our balance sheet. With these resources, we will continue to drive our rare disease programs, work with our collaborators and advance our early-stage opportunities as we also prepare to commercialize DCR-PHXC. It has been an eventful year-to-date for Dicerna, and we look forward to hitting some substantial milestones in coming quarters.

These milestones include enrollment of the first healthy volunteers in the Phase I/II trial of DCR-A1AT for the treatment of patients with alpha-1 antitrypsin deficiency-associated liver disease expected in the fourth quarter of 2019; multi-dose data from PHYOX3, our long-term, multi-dose, open-label rollover extension study for the treatment of PH expected in the first half of 2020; completion of enrollment of our PHYOX2 pivotal clinical trial by the end of the first half of 2020; proof-of-concept data from all planned cohorts of our DCR-HBVS Phase I clinical trial in mid-2020.

I'd like to thank you all for listening today. And now I'll turn the call over to the operator to take your questions.

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Questions and Answers

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Operator [1]

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(Operator Instructions) Your first question will come from Mani Foroohar of SVB Leerink.

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Mani Foroohar, SVB Leerink LLC, Research Division - MD of Genetic Medicines & Senior Research Analyst [2]

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Congratulations on the progress over the last quarter. A couple of quick ones. First, sort of a relatively sort of boring modeling question. When we think about potential announcement of first targets from Alexion, Lilly, et cetera, potentially next year or year after, about what scale should those -- when we expect those milestones to be in the early years, just directionally?

And then more of a development question. When we think about the R&D Day around mid next year, is that about the same time that we should expect the OLE data for DCR-PHXC PHYOX3? Or should we expect that OLE data before the Analyst Day?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [3]

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Okay. So on the milestone question, in general, the first milestone is an IND filing or first patient dosed milestone. And I think low double-digit million is the right descriptor. Those payments have -- those milestones can't be disclosed quantitatively, I don't believe.

For the R&D Day, certainly a fair question when we're going to talk about open-label data. To be perfectly honest, we have not fully planned our first half calendar. It's -- as an open-label trial, we could take a data cut at any time, but we are interested in sharing data when we think it's meaningful, which means getting a substantial number of patients through at least a good handful of doses. So we have a fair read on the multi-dose effect.

So that's not -- that's before midyear. And then the question is, is there a forum. And frankly, I just haven't looked at that closely enough to know if there is particular conference. So we'll try and provide better guidance by JPMorgan and work that out. But it would certainly be no later than the R&D Day.

We had originally talked about an R&D Day for December with the primary purpose of which was to share an interim read from the Phase I trial in HBV. With this collaboration and in consultation with Roche, we thought it was -- with that collaboration now signed, better to wait until data from all the cohorts is available. And so we reset the timing of the R&D Day based on that.

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Mani Foroohar, SVB Leerink LLC, Research Division - MD of Genetic Medicines & Senior Research Analyst [4]

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All right. That's really helpful. I know we've got a lot of people on the queue, so I'll step back in.

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Operator [5]

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Your next question will come from Jonathan Miller of Evercore.

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Jonathan Miller, Evercore ISI Institutional Equities, Research Division - Associate [6]

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And congratulations again on all the progress during the quarter. I guess one thing I'm very curious about with the Roche HBV collaboration is that they've got several mechanisms in development, but they don't seem to have versions of some common approaches, most notably a NUC but also a capsid inhibitor, which of their combination agents are most promising to you? And do you think that NUC is not a necessary element to a potential combo in HBV?

And then secondly, just a clarification on PH2 endpoint alignment that you got with the FDA. Am I right in assuming that, that endpoint will be parallel to the PH1 endpoint where urinary oxalate reduction will be an average of several months' worth of 24-hour measurements?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [7]

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Yes. So let me handle those questions. First, with respect to Roche's portfolio of combination elements. I'm going to respectfully decline to pick favorites from the Roche portfolio. And I know that there are elements in that portfolio that have not been publicly disclosed. So apologies for not being forthcoming there.

With respect to NUC, it is certainly our expectation that all combinations will include a NUC as a foundation. NUCs are effective in reducing viral agents. And I don't see in the near-term efforts to build combinations that lack NUCs. That said, I'm not fully privy to Roche's long-term thinking on the -- what will be in combos.

And the next -- what was the next question?

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Jonathan Miller, Evercore ISI Institutional Equities, Research Division - Associate [8]

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On the PH2 endpoint, are you taking an average -- is it parallel to PH1?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [9]

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Yes, it's exactly parallel to the PH1, and it involves an area under the curve measurement for the month 3, 4, 5 and 6 and comparing that to baseline oxalate. There's formula associated with that and is the exact same analysis applied to PH1 and PH2 for judging whether full approval will be granted.

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Operator [10]

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The next question is from Yaron Werber of Cowen.

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Brendan Smith, Cowen and Company, LLC, Research Division - Research Analyst [11]

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This is Brendan on for Yaron. Congrats on a great quarter. My question actually is just in reference to the HBV program. I'm wondering if you could give us just a little bit of color on what you're expecting in terms of the S antigen reduction in the single dose versus the multiple dose cohorts. And conversely also, would you -- what levels of reduction would you expect to correlate with the antigen seroclearance and seroconversion?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [12]

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Yes. So I'll say a few comments and then perhaps, Ralf, you want to add something to it. The function of the Group B, which is the single-dose study in NUC-naive patients, part of the motivation there is just to get the pharmacodynamic curve associated with a single dose that will facilitate our modeling and simulation efforts in setting dose regimens later. Most of our studies in animal models are done with multiple dose. Most of the comparative human clinical data from other approaches is multiple dose. And that means that we have less to base a speculation about what we'd see in a single dose in terms of S antigen reduction. But I would note that 3 milligrams per kilogram in the PH trial appears to be near saturating dose for response, and so we would expect to be fairly high up the dose response curve even with a single dose.

As for expectations from the multiple dose study, based on our preclinical work, we think we would be at least as good as comparable RNAi approaches from others with the potential based on our 3 gene hypothesis to perhaps be a little better and have a longer duration. But, of course, remains to be seen from the data.

Ralf, do you want to add anything?

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Ralf H. Rosskamp, Dicerna Pharmaceuticals, Inc. - Chief Medical Officer [13]

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Thank you, Doug. I think you captured it very well. Maybe I want to point out in the NUC-naive group, to my knowledge, that's the first time that an RNAi drug is going into a NUC-naive group and actually keep them off NUCs. So our protocol stipulates that NUCs will only be given to those patients after 3 months observation period. In other trials, they took NUC-naive patients, but combined them with the first dosing of the RNAi. I think that's really a difference and this will give us really an insight how the RNAi therapy works in patients who, at least for 3 months, are not on NUCs. And this goes back to the question, is it always in combination with NUCs. So we're able to compare here that Group B, the NUC-naive patients with those with a background on NUCs. And I think it's a very interesting scientific conclusions can be drawn from this data.

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Operator [14]

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Your next question will come from Stephen Willey of Stifel.

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Stephen Douglas Willey, Stifel, Nicolaus & Company, Incorporated, Research Division - Director [15]

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And congratulations on the Roche collaboration. Just I guess a quick question of clarification regarding the feedback you received from FDA regarding endpoint alignment with PH2. So did the data that the agency see then was that data from the PHYOX2 pivotal trial?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [16]

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No. They have seen data from PHYOX1, of course, including the PH2 patients enrolled in PHYOX1. They also reviewed the latest natural history data. I believe there is a publication with that data in press. And some of that data was presented at the hyperoxaluria workshop in Boston back in June and some was presented by Sally Hulton at our 2018 R&D Day.

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Stephen Douglas Willey, Stifel, Nicolaus & Company, Incorporated, Research Division - Director [17]

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Okay. I just -- I think the press release is maybe worded a little bit tricky there. With respect to...

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [18]

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Apologies for that.

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Stephen Douglas Willey, Stifel, Nicolaus & Company, Incorporated, Research Division - Director [19]

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Yes, no worries. My reading skills are also quite elementary. With respect to non-hepatic delivery, I know that this is something that you're working through with Lilly right now, but I guess to what extent would Dicerna independently pursue programs that involve targeting an RNAi payload to a non-hepatic tissue?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [20]

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Steve, I absolutely expect that we are going to have non-hepatic programs. We are not at a point today where we feel that we have maximized or fully optimized any of the extrahepatic tissues, and we continue to develop the platform. Having said that, in certain tissue types, we have achieved a level of knockdown where if that's as good as we can get, we would declare clinical candidates at that level of activity.

I am very pleased with the level of knockdown we're getting both in neuronal tissue types as well as some non-neuronal tissue types. It is -- there are a lot of tissue types. There are a lot of ways we can play with the GalXC molecules, particularly given the freedom to practice medicinal chemistry in that extended handle region of the molecule. So it is a very large space to explore, if you will, but it's been quite productive.

You pointed out our collaborative work with Lilly, which is -- involves the nervous system. It also involves some cardio-metabolic tissues. That is only a subset of our work on extrahepatic delivery, and there are purely Dicerna efforts proceeding in parallel.

It's been a pretty active year. I know we didn't get out and present at -- this data at any of the technical conferences, but I'm quite certain that in 2020, we'll show some of that data at technical conferences. Nonetheless, you could probably have picked up my tone about extrahepatic delivery has become quite positive, and that is based on results that we've been achieving in the labs.

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Stephen Douglas Willey, Stifel, Nicolaus & Company, Incorporated, Research Division - Director [21]

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Okay, that's quite helpful. And then maybe just lastly, I guess, with completion of enrollment in PHYOX2, I guess seemingly insight, how are you guys thinking about commercialization, I guess both in the U.S. and maybe the question is a bit more directed towards ex U.S. efforts?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [22]

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We are deep in an analysis of how we're going to deal with ex U.S. As for U.S., we're only contemplating that we would do it ourselves.

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Operator [23]

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The next question will come from Ed Arce of H.C. Wainwright.

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Wing Cheung Yip, H.C. Wainwright & Co, LLC, Research Division - Research Analyst [24]

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This is actually Thomas Yip asking a couple of questions on Ed's behalf as he's tied up. So first, just wondering about the HBV deal with Roche, specifically the timing of the upfront payment. Just want to make sure that is contingent on when Roche formally starts the agreement after seeing your Phase I data and wondering if that amount correlates to the number of targets that are chosen by Roche.

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James B. Weissman, Dicerna Pharmaceuticals, Inc. - Executive VP & COO [25]

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This is Jim. Thanks for your question. Of course, given the deal, its size and scope, it has to go through HSR clearance, as you can imagine, and the payment would be expected soon after HSR is cleared. Regarding the number of targets, that has been explained to be up to 5 additional targets. Those are all research collaboration targets. Work on those targets has not begun. It may begin in the future.

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [26]

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Yes. Just so there's no confusion, the $200 million is committed. And assuming that the deal clears HSR, then it's a -- that's a contractually committed payment, not contingent upon data or target selection or any other condition.

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Wing Cheung Yip, H.C. Wainwright & Co, LLC, Research Division - Research Analyst [27]

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Okay. But specifically, regarding the timing, I suppose that would be available after the Phase I data is reported?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [28]

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Well, at this point, we are not planning on reporting data publicly in that time frame. It really will depend on when we get clearance from HSR, and I'm not certain which would be available first. It's not relevant to the $200 million being owed to us. And generally, HSR is going to be, at a minimum, several weeks, and I think we're all aware of another situation where it's going a lot longer than that. But we don't expect that this particular transaction will receive special scrutiny.

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Wing Cheung Yip, H.C. Wainwright & Co, LLC, Research Division - Research Analyst [29]

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Okay. I understand that. Perhaps I'm going to switch gears and ask about the A1AT program. Can you remind us how the volunteer phase work and when should we expect the trial to move to patient dosing after the healthy volunteers?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [30]

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Ralf, would you like to address that?

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Ralf H. Rosskamp, Dicerna Pharmaceuticals, Inc. - Chief Medical Officer [31]

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Yes. Thank you. It's similar to the healthy volunteer part what we did in our PHXC program. So it's a dose escalation. So you start off with a very low dose of -- which is clinically not -- pharmacology not active. You start with a sentinel pair. After 2 weeks, there is a safety review committee deciding whether the rest of the cohort can be dosed. And then when all patients have been dosed, then again, there is a review to see whether we can go into the next dose cohort. And as Doug said, we'll be up to 6 cohorts with a dose of 12 milligram per kilogram.

So we haven't guided especially when we start the healthy -- when we start the patient part, but I think we will look at the amount of knockdown we're able to achieve after a single dose in healthy volunteers. And the first dose cohort in the patient part will be at a dose which will achieve a 50% knockdown of A1AT in the healthy volunteers, and then you can assume that the same level of knockdown will be seen in patients. And I'm sure that we will not have to wait to the highest dose of 12 milligram per kilogram until we see a 50% knockdown of the A1AT enzyme in the plasma.

So it really depends how -- at what time we see the 50% reduction in alpha-1 antitrypsin deficiency and then we do a modeling and simulation to confirm that we see there's also at a multi-dose regimen. And once we have this dose established, we will then start the patient part. So it's a little unknown even to us when this will be the case, and therefore, at this time, we haven't given any guidance when the patient part will start.

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Wing Cheung Yip, H.C. Wainwright & Co, LLC, Research Division - Research Analyst [32]

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Okay, understood. And congratulations again on your latest partnership and a great quarter.

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [33]

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Thanks, Thomas.

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Operator [34]

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The next question will come from Madhu Kumar of R.W. Baird.

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Madhu Sudhan Kumar, Robert W. Baird & Co. Incorporated, Research Division - Senior Research Analyst [35]

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So I guess on a macro basis, my first question is, I mean after the kind of torrid pace of dealmaking over the last 24 months, is deal time over now? Do you kind of view the notion that with your current balance sheet, you're going to push more things forward internally, both on a rare disease and non-rare disease basis?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [36]

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Well, let me first start by responding to what I think was the implicit aspect of the question, which is that we're either doing one or the other. And we are trying and I believe succeeding in organizing our work such that there's the Dicerna part and there's the collaborative part. And so our pace of putting programs in the clinic reflects a very careful analysis that we do about the targets that we choose to commit to. It's a multiyear, high opportunity cost, high-dollar cost commitment, and we tend to be very thoughtful about that. That has led to us to make choices that are different than others, the analysis of where to target in HBV, the gene used to target the reduction in oxalate in PH to expand additional payments -- patients reflects the depth of that analysis.

So I don't see any trade-off or timing impact on our choices for our internal pipeline relative to whether we partner more or not in the liver. And now having said -- having addressed that, I would say that -- repeat what I said on the -- in the script, which is that we see strong potential for additional collaborative activity. And while I'm not going to provide any guidance beyond that, wouldn't be saying that if I thought we were going to enter a long period without new collaborative activity.

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Madhu Sudhan Kumar, Robert W. Baird & Co. Incorporated, Research Division - Senior Research Analyst [37]

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Okay. And then thinking about PHYOX2, so I'll first say I don't think Steve read it wrong. It seems -- I mean the press release is written a little bit strange. But is there a sense of how many PH2 patients in PH -- in PHYOX2 would be necessary for basically this kind of recently announced regulatory alignment?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [38]

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Ralf, would you please address that?

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Ralf H. Rosskamp, Dicerna Pharmaceuticals, Inc. - Chief Medical Officer [39]

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Our protocol, which we have discussed with the FDA and also with the EMA does not specify a minimum number of PH2. And actually the primary analysis will be all patients in this study, so will be a combination of PH1 and PH2 patients. So of course, you will then do a sensitivity analysis, and you will have to demonstrate that these results are not driven by the PH1 patients and that no PH2 patients, for instance, has a response. So for sure, the FDA and the EMA will see this. But we don't specify a minimum number.

So our experience is in PHYOX that we had around 20% of patients with PH2. As you know, the prevalence in the PH population of PH2 is around 10% to 15%. So I would assume that out of the 36 patients, which we're going to close, that we'll have something like 4 to 7 PH2 patients, which reflects the prevalence of the disease and which will enable us to separately show that the positive result in reduction is not only driven by the PH1 but is also seen the same way in the PH2 patients.

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Madhu Sudhan Kumar, Robert W. Baird & Co. Incorporated, Research Division - Senior Research Analyst [40]

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Okay. And then last question will be on A1AT. So how do you think about the RNAi approach versus the kind of small molecule protein folding approaches that, among others, Vertex is kind of rolling out there into the clinic to go out -- and their aim to go after both lung and liver manifestations of PiZZ alpha-1 antitrypsin?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [41]

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I certainly have some thoughts on that. Ralf, do you want to start? Or would you like me to go?

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Ralf H. Rosskamp, Dicerna Pharmaceuticals, Inc. - Chief Medical Officer [42]

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I can. Yes, I think you're referring I think to the -- to Vertex approach. We know that if from a natural history that now genotype, so the total knockout of alpha-1 antitrypsin deficiency that those patients instead of in the normal ZZ population start to show lung infestations in their early 20s and not why it is the case in the ZZ population in their 40s and 50s.

So clearly, if you maintain some level of alpha-1 antitrypsin in the circulation, this is a benefit to protect the lung. That's the reason why our first cohort only will attempt to have a 50% reduction on an alpha-1 antitrypsin and the second cohort will be the maximal amount, which will be around 94%, 95% reduction. And we want to see whether by preserving some of the alpha-1 in the circulation, whether the effect in the liver is different.

And as you see, there is also augmentation therapy, so -- which has been shown to also raise the alpha-1 antitrypsin levels and to protect the lung. And therefore, I think that the theoretical approach which we are taking is really to explore whether you really need a full knockdown of the alpha-1 antitrypsin therapy or whether this liver disease, the progression can be stopped with a not full knockdown of alpha-1 antitrypsin.

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [43]

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Yes. What I would add to that is that the lung disease and the liver disease are separate and independent manifestations that are each both partially prevalent. They're treated by different positions with a different set of standard of care associated with each. And we believe that whatever therapeutic approach is most effective in addressing the liver manifestation is going to be the therapy that is preferred by hepatologists and patients for treatment of the liver disease. And similarly, a choice will be made on the lung front versus standard of care there, which is augmentation.

So we're -- we don't really see synergy in applying a potential treatment for both aspects as the disease and its 2 modification -- manifestations is actually treated. And so we're very comfortable with the power of RNAi to address the liver disease and believe that it is going to be highly competitive as a modality for the liver aspect -- for the liver manifestation.

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Operator [44]

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The next question will come from Mayank Mamtani of B. Riley FBR.

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Unidentified Analyst, [45]

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This is [Wayne] on for Mayank. So my first question is if you could perhaps comment on the assumption you may have on the placebo response in type 1 and type 2 patients for the PHYOX2 trial?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [46]

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So I would note that patients do not perceive their oxalate levels and we don't anticipate there to be any response in placebo patients other than the standard variation observed when multiple measurements are taken from an individual patient. We did an observational study some time ago, and we have some quantification of that variation. But we don't see this as the type of disorder where knowledge that someone is on treatment leads to a change in the primary endpoint that's being assessed.

Ralf, do you want to add anything?

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Ralf H. Rosskamp, Dicerna Pharmaceuticals, Inc. - Chief Medical Officer [47]

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Yes, I fully agree. So the primary endpoint is urinary oxalate, which will be measured in a central lab. So neither we nor the investigator will see this urinary oxalate value. So we all -- the patients now. So we all remain unblinded and a patient might -- most likely over a period of 6 months, will not be able to know whether they're on placebo or not. Of course, therefore, the longer-term study is open-label because, yes, we would assume that in the long run, patients have a less stone formation, less stone events, stabilization of their renal function. But in the 6-month trial, I don't think that will be really different. Therefore, the FDA has agreed for both PH1 and PH2 to use urinary oxalate as the surrogate endpoint.

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Unidentified Analyst, [48]

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Okay. And then would you able to share the kidney stone outcomes data as part of the multi-dose PHYOX3 study readout in the first quarter or first half of 2020?

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Ralf H. Rosskamp, Dicerna Pharmaceuticals, Inc. - Chief Medical Officer [49]

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Yes, we will report any adverse event, and this would be captured as adverse event or serious adverse event in any complication around amount of urinary oxalate lowering. Again, these patients have preexisting stones already. So it might well be that over the first couple of months or in a year, they have stony ones because they have preexisting stones. Therefore, in addition to stone events by ultrasound in adults by computer tomography, we are measuring whether they form new stones. And here you would most likely see a difference. The existing stones there and they get either surgically removed or they spontaneously go away. But I think a measure -- a better measure is really the new stone formation rate. Again, this will not be something which you'll be able to see over 3 to 6 months. This is something where it will take a longer period. And therefore, our long-term extension study will go for 3 years.

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Unidentified Analyst, [50]

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Okay. And my last question is if you could clarify if Roche has looked at any of the clinical patient label data from the ongoing Phase I study? And are you able to comment on how many biopharma companies were part of the process?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [51]

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So Roche did not look at any data from the trial. And we have not looked at any data from the trial as we haven't reached the planned interim read. I think that all I can say is that it was a competitive process involving more companies than Roche, and I should leave it there.

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Unidentified Analyst, [52]

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Okay, great. And...

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Ralf H. Rosskamp, Dicerna Pharmaceuticals, Inc. - Chief Medical Officer [53]

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Maybe, Doug, I want to add. Roche has seen clinical data first from the healthy volunteers. So they have seen our healthy volunteer safety data because there is no reduction, of course, for definition of S antigen. And they've also seen the clinical safety data of the ongoing HBV study. They have not seen any efficacy as we have not seen any efficacy data in terms of S antigen or other viral parameters, but they have looked at clinical data in terms of safety.

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Unidentified Analyst, [54]

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Okay. Okay. And congrats on the progress.

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Operator [55]

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The next question is from Keay Nakae of Chardan.

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Keay Thomas Nakae, Chardan Capital Markets, LLC, Research Division - Senior Research Analyst of Therapeutics, Devices and Diagnostics [56]

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Just 2 questions on HBV. One, with respect to how you'll recognize the $200 million upfront. Should we assume just a straight-line recognition of deferred over, say, 3 years?

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John B. Green, Dicerna Pharmaceuticals, Inc. - CFO [57]

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Yes, we've got -- this is Jack. We haven't specifically worked out the timing of the revenue recognition. That's in process, and we certainly will be more clear on the next call. However, if you look at the way our current collaborations have been recognized, you can tell that on the balance sheet by looking at the amount that's current and the amount that's long-term in the deferred revenue. It's likely going to be very similar to those contracts. And it will be recognized over the term of the research collaboration.

So that -- I think as a placeholder, as a model, it will be something along those lines, and we'll be -- we'll clarify that as we go -- as we complete our analysis.

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Keay Thomas Nakae, Chardan Capital Markets, LLC, Research Division - Senior Research Analyst of Therapeutics, Devices and Diagnostics [58]

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Okay. The point of the opt-in after seeing concept study, is there some defined level of efficacy in terms of being able to effect some sort of -- some degree of a functional tier that's in place? Or how do you -- or how would you know what parameters cause you to go forward with your opt-in or them to go forward with the program itself?

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Douglas M. Fambrough, Dicerna Pharmaceuticals, Inc. - Co-Founder, CEO, President & Director [59]

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So there are no criteria in the contract that constrains our ability to exercise the opt-in when Roche and if Roche advances the program into pivotal development. We have the right to exercise the opt-in. At this point, I think it's impossible to say what level of activity on what parameters we would require, in part because it's comparative to what's going on from others in the field and how competitive we think product will be. Obviously, we're optimistic about our own program. And I think it's likely will be highly competitive. But we need to see the data. And similarly, I'm sure there's a similar calculus within Roche that they'll make about what they'll -- what they need to see to take it forward. But I cannot say what that might be.

Well, I want to thank you all for joining the call today as we reviewed our third quarter 2019 earnings results. We look forward to a successful fourth quarter and providing additional updates as they are appropriate.

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Operator [60]

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Ladies and gentlemen, that concludes today's conference call. Thank you for participating. You may now all disconnect, and have a good day.