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spk12: Ladies and gentlemen, thank you for standing by and welcome to the Riata Pharmaceuticals second quarter 2021 financial results and update on development programs conference call. An audio recording of today's webcast will be available shortly after the call today in the investor section of Riata's website at riatapharma.com. Before the company proceeds with its remarks, please note that the forward-looking statements disclosure in the company's press release. The company will be making forward-looking statements on today's call. There are many factors that could cause results to differ from expectations, including those noted in the company's SEC filings. On today's conference call, non-GAAP financial measures will be used to help investors understand the business performance. These non-GAAP financial measures are reconciled with comparable GAAP financial measures in Reata's earnings release and presentation from today, which can be found on RIADA's website. Today's statements are not guarantees of future outcomes. Please also note that any comments made on today's call apply only as of today, August 9th, 2021, and may no longer be accurate at the time of any webcast replay or transcript rereading. Following the prepared remarks, we will open the call for questions. We ask that you please limit yourself to one question and one follow-up so we can accommodate as many questions as possible. We are joined today by RIADA's Chief Executive Officer Warren Huff, Chief Research and Development Officer Colin Meyer, and Chief Operating and Chief Financial Officer Monmeet Soni. At this time, I would like to turn the conference call over to Warren Huff, Chief Executive Officer of RIADA.
spk11: Thanks. Good afternoon, everyone, and thank you for joining us today. We have several important updates that we'll be sharing with you today. First, we'll provide a regulatory update for ovambaloxone for Friedreich's ataxia. Second, we'll provide a regulatory update and a clinical update for bardoxalone in rare forms of CKD. I'll give a brief overview and then hand the presentation over to Colin for more detail. We'll start with an update on our omaviloxelone program in patients with Friedreich's ataxia on slide four. As you know, FA is a rare disease characterized by a progressive loss of motor function with patients often requiring a wheelchair by their mid-20s and having a median survival of 35 years. There are no approved therapies for FA. We've reported results from the MOXIE Part 2 study, the baseline controlled study, in the delayed start analysis, each of which met their primary endpoint and provide evidence of the effectiveness of OMAD in patients with FA. We've provided this data to the FDA and we're pleased to report that in May of this year, we received a communication from the FDA suggesting that a pre-MDA meeting is the most appropriate format for a discussion of the development program. During the second quarter of this year, we withdrew our request for a type C meeting and requested a pre-NDA meeting with the FDA. The pre-NDA meeting request has been granted, and the meeting has been scheduled during the third quarter of this year. We submitted briefing materials for the meeting, and we recently received a communication from the division requesting the estimated date of our NDA submission for their planning purposes. We're pleased with the FDA's continued engagement with us in determining a path forward for the program, and pending the outcome of the pre-NDA meeting, we're planning to submit the NDA for OMAV for the treatment of patients with FA during the first quarter of 2022. Additionally, as a result of the recent regulatory progress, in the second quarter, we reinitiated our commercial readiness activities for OMAV. Turning to Bardoxalon on slide five, As all of you know, our new drug application for Vardoxelone for the treatment of patients with chronic kidney disease caused by Alport syndrome has been accepted for filing and is currently under review by the FDA. In connection with the review of the NDA, the FDA recently completed a bioresearch monitoring inspection where we did not receive any observations. We've recently completed the mid-cycle communication review meeting with the FDA, and we continue to prepare for the advisory committee meeting, which has been tentatively scheduled for December the 8th, 2021. The PDUFA date for the NDA is February 25th, 2022. Additionally, we're pleased to report that in July of this year, Kaiwa Kiran, our strategic collaborator in CKD in Japan, submitted an NDA in Japan to the Ministry of Health, Labor, and Welfare for bardoxalon for the treatment of patients with CKD caused by Alport syndrome. Based on this submission, we've earned a milestone payment, and if approved for commercial sales, KKC is required to pay us royalties on net sales of bardoxalon and its territory. Next slide. The purpose of the mid-cycle meeting is for the FDA to provide us with an update of the status of the NDA review, including any issues identified. The mid-cycle communication meeting with the FDA was focused on clinical and statistical review issues. While we've not yet received formal minutes from the FDA, in the preliminary agenda for the meeting, the FDA identified four significant clinical and statistical review issues for us to address. We discussed these issues with the FDA during the meeting, and we believe each is addressable. FDA invited us to submit clarifying questions and our responses in follow-up submissions to the NDA, which, of course, we plan to do. I'll briefly review the issues and our planned responses and then hand the presentation over to Colin to provide more detail. Importantly, the FDA did not designate any safety issues as significant issues. Based on its current review, the FDA noted during the meeting that it does not currently believe a risk evaluation and mitigation strategies or RIMS program is needed for bardoxelone. Throughout the history of the development of bardoxelone and because of its novel effects on EGFR and other parameters, questions have been raised about the safety of long-term use of the drug in CKD patients. We and our partners and collaborators have generated a substantial amount of preclinical data delineating the mechanism of action of bardoxaline, and we've collected a large amount of clinical data, including data in patients treated for two to three years, to address these issues. We believe this large data set may be the reason that there were no safety issues listed as significant in the mid-cycle communication. The lack of significant safety issues to date is important in evaluating the benefit-risk assessment for approval. With respect to the clinical and statistical issues, we believe each issue raised by the Division is addressable. First, we've always known that the key question regarding the efficacy of Bardoxelone and Alport syndrome and other forms of CKD is one of the large improvements in EGFR on treatment will translate into a delay in the need for dialysis or transplant. We would have been very surprised if this issue was not being submitted to the ADCOM. We believe that the two-year data in the cardinal trial demonstrate that in the second year of treatment, which we believe is the most predictive of future results, Bardoxelone patients' EGFR declines from its peak at a rate slower than placebo patients. This reduced rate of decline is on top of a large absolute placebo-corrected improvement in EGFR from 7 to 17 EGFR points, depending on the treatment group. Based on the progression rate of these patients, this represents two to four years of delay to kidney failure. Patients on continuous treatment at goal dose did not have a decline in EGFR during this period, suggesting a potential long-term delay in kidney failure. Turning to the second topic, the FDA indicated that it did not appear that a pre-specified covariate for treatment duration was used in the primary analysis, and this would affect the significance of the results. We clarified in the meeting that the covariate was included in the analysis, that the exclusion of it would have improved the significance of the result, and that the primary analysis was performed in accordance with the SAP. Turning to the third topic, the FDA conducted a series of post hoc sensitivity analyses to test the significance of the year two key secondary results under a variety of scenarios. including using off-treatment EGFR values at week 104, irrespective of time off drug, and excluding all off-treatment values collected less than 28 days after the last dose. These are post hoc analyses, and because Alport syndrome is a rare disease, Cardinal had limited power to show effects and sensitivity analyses that might be observed in much larger trials for more prevalent diseases. The week 104 analysis effectively included many patients that had been off treatment for a minimum of 88 weeks. The less than 28-day analysis excludes nearly one-half of the trial participants, violates randomization principles, and results in modeled estimates that meaningly differ from observed week 104 HEFR changes. Despite these issues, the treatment effect in the sensitivity analyses always favored baroxalone. Finally, the FDA raised an issue regarding the effect of COVID-19 pandemic on Cardinal. The FDA acknowledged that COVID-19 did not significantly impact treatment visits, data collection, or study drug dispensation. They noted that there were significant differences between the patients that finished pre and post COVID. The difference between treatment groups pre and post COVID was driven by the enrollment of a larger number of pediatric patients late in the trial so that they ended the trial in the post-COVID subgroup. This group had more rapid disease progression and increased the overall rate of progression in the post-COVID placebo group. As I stated earlier, we believe that each of these issues are addressable, and the FDA invited us to submit clarifying questions and to address each of the issues in a follow-up submissions to the NDA, which of course we plan to do. I'll hand the presentation over to Colin now to provide greater detail on the issues and our planned responses.
spk08: Thanks, Warren. Turning to slide 9, as Warren mentioned, we recently completed the mid-cycle communication meeting with the FDA, and they identified four significant review issues which were discussed in the meeting. Importantly, the FDA did not designate any safety issues as significant issues. As is customary with review of all NDAs, the FDA may identify other issues and it may request additional information as it continues to review the NDA. The issues the FDA identified were clinical and statistical and include four topics, acute pharmacodynamic effects versus slowing of decline in kidney function, treatment duration as a covariate in week 104 analysis, and sensitivity analysis for off-treatment analysis window duration, and the impact of the COVID-19 pandemic. I will provide additional information about each of these issues that were discussed in the next slide. Thank you. Regarding the first topic, the FDA question whether the observed EGFR increases suggests a slower rate of loss of kidney function in the rhodoxone group as compared to the placebo group. During the mid-cycle communication meeting, the FDA clarified that its preliminary analysis was computed using two distinct chronic EGFR slopes, a slope in year one based on EGFR data from week 12 to week 48, and a slope in year two based on week 64 to week 100. The FDA noted that the observed changes in EGFR loss in the baroxone group starting at week 12 and year one after full manifestation of acute EGFR increase, did not suggest a slower rate of loss of kidney function in the placebo group. As I'll explain shortly, the loss of EGFR from weeks 12 to 48 in year one is explained by the loss of EGFR in bardoxaline patients who discontinued early in the study. Importantly, the rate of EGFR loss from week 64 after full manifestation of the acute EGFR increase to week 100, in year two is lower in the bradoxaline patients than the placebo patients. The FDA did not comment specifically on the rate of EGFR decline in year two of treatment. As I just mentioned, the loss of EGFR observed in patients treated with radoxalone from week 12 to week 48 in year 1 is explained by the loss of EGFR in patients randomized to radoxalone who discontinued treatment, and most discontinuations occurred early in the study. As shown in the figure on the top right of slide 10, patients who discontinued treatment experienced an acute increase in EGFR that was maximal at week 12 and returned to placebo levels by week 36. This loss of the initial acute EGFR effect after discontinuation of drug contributed to the apparent EGFR decline during year one in the intent to treat analysis. As shown in the chart on the bottom of slide 10, Data from year two of Cardinal showed that our Oxfam-treated patients that restarted treatment at week 52 experienced a smaller EGFR loss from week 64 to week 100 compared to the patients on placebo. This was observed in patients in the intended treat population, patients in the pre-specified modified ITT or MITT analysis, patients who achieved Goldos, and patients who did not achieve Goldos. Importantly, patients who remained on varoxilone treatment and maintained their goal dose on average did not progress, while patients receiving placebo continued to decline. In addition to the reduced rate of EGFR decline in year two, varoxilone patients experienced large, absolute placebo-corrected improvements in EGFR at week 100 across all analysis subgroups. based on the historical weight of EGFR loss for these patients. This separation would translate to a delay in kidney failure of at least two to four years. For those patients who are maintained on their goal dose and did not progress, kidney failure could be potentially delayed long-term if they continue to not progress. Lastly, data from EGLE demonstrates treated with baroxone and cardinal are sustained above baseline in the third year of treatment and beyond. We believe these analyses demonstrate that in continuously treated patients, EGFR diverges from placebo over time and could delay kidney failure. Next slide. In the FDA's preliminary communication for the meeting, the FDA questioned whether we had followed the pre-specified analysis model for analyzing week 104 off-treatment values. During the meeting, we explained and the FDA acknowledged that our analysis was conducted in accordance with and did not deviate from the pre-specified SAP, which included treatment duration as a covariate. All clinical studies use an analysis model to compute the treatment effect and p-value. The analysis model incorporates observed data as well as data sets that are generated for missing data. The process of generating data sets for missing data is called the imputation step, and it uses available reference data to produce these data sets. The statistical analysis plan or SAT for Cardinal pre-specified that change from baseline and EGFR for patients treated with Vardoxilone would be compared to placebo week 104 using an analysis of covariance or ANCOVA model. Both the imputation step and the analysis model can include covariates or independent variables between patients, such as treatment group or baseline characteristics. During the meeting, we discussed how the imputation step was conducted. The FDA suggested the treatment duration covariate could have been included in the imputation step. We noted that the SAP did not specify covariates for the imputation step, and therefore, a treatment duration covariate was not included in the imputation step of the analysis. We further explained that due to sparse reference data across the full range of treatment durations, Inclusion of the treatment duration covariate in the imputation step would have resulted in over 30% of imputed EGFR values falling outside the range of observed EGFR values. Many of these values would have been extreme and exceeded biological plausibility. For example, the maximum change from baseline in the observed data was an increase of 28 nil per minute. while the maximum change from baseline in the imputed data would have been nearly four times larger with an increase of 105 mL per minute. We therefore explained that while addition of these extreme values would not have affected the overall treatment effect at week 104, it would have artificially more than doubled the standard error and inflated the p-value. Again, importantly, During the meeting, the FDA acknowledged that the primary analysis was conducted in accordance with and did not deviate from the pre-specified SAP. Turning to slide 12. In Cardinal, we pre-specified the year two off treatment analysis window to include EGFR values obtained at least 14 days after last dose. which is supported by pharmacokinetic and extensive off-treatment data demonstrating that the resolution of acute EGFR increases occurs by 14 days after the last dose. As shown in the table on the bottom of slide 12, we observed no association between the magnitude of off-treatment EGFR values in the post-dose period in year two. These results established that values collected in the earlier part of the analysis window did not bias or affect the conclusions of the off-treatment endpoint. Alport syndrome is a rare disease which limited the overall size of the trial. The study, therefore, had limited power to show treatment effects that meet conventional levels of statistical significance in certain sensitivity analyses for more prevalent diseases. Nevertheless, the FDA has conducted a series of post hoc sensitivity analyses to test the significance of the year two key secondary results under a variety of scenarios, including using off-treatment EGFR values at week 104, irrespective of time off drug. Approximately one half, or 12 out of 26, of discontinuations for patients treated with baroxone occurred within the first 16 weeks of treatment. And these patients were therefore off treatment for a minimum of 88 weeks at the time of their week 104 assessment. When patients discontinued baroxalone, their EGFR trajectory was similar to placebo patients. Including these patients that had discontinued for a long period of time inherently dilutes the treatment effect in the sensitivity analysis. Despite this, the treatment effect in the analysis favored baroxalone, even when including these patients in the week 104 analysis. Furthermore, based on the precedent established in the reprise study of Tolvaptin for the treatment of patients with ADPKD, we power Cardinal to assess the off-treatment effect of Baroxone by including EGFR values collected at least 14 days after the last dose, rather than powering the trial to include EGFR values 104 weeks after randomization for all patients, including those that discontinued treatment early. Two of the FDA's other sensitivity analyses only included values collected at least 28 days after the last dose. These analyses excluded nearly one-half the trial participants in violated randomization principles, which resulted in modeled estimates that meaningfully differed from observed week 140 GFR changes. However, the treatment effect in these analyses favored baroxaline. We performed sensitivity analyses similar to those performed by the FDA that included more available off-treatment EGFR data by using a cutoff of at least 21 days after the last dose. The results for these new analyses were similar to the primary week 104 analyses, and we provided to the FDA as a follow-up to this meeting. Moving to slide 13, as COVID-19 emerged as a pandemic with serious public health implications, During the first quarter of 2020, we took steps to protect the health and safety of patients and healthcare workers involved in the ongoing cardinal trial, while also maintaining the conduct of our studies in accordance with guidance provided by the FDA and the EMA. Due to the timing of study conduct, 31% of year two week 104 assessments were conducted pre-COVID or before March 1st, 2020. and 69% of week 104 assessments were conducted after the start of the global pandemic. In our mid-cycle communication meeting, we were pleased that the FDA acknowledged that COVID-19 did not significantly impact treatment visits, data collection, or study drug dispensation. However, the FDA noted that there appeared to be differences for the week 104 endpoint when analyzed according to data collected in patients pre-COVID versus post-COVID, with the study findings driven by the post-COVID subgroup. The difference between treatment groups pre- and post-COVID was driven by the inclusion of a larger number of pediatric patients in the post-COVID subgroup. This group had more rapidly progressive disease, enrolled later in the trial, and therefore had week one of four assessments conducted during the post-COVID period. Importantly, although differences were observed for the pre- and post-COVID results, the point estimate for the change from baseline in EGFR at week 104 is similar across both periods for rhodoxone-treated patients. Next slide. During the mid-cycle communication meeting, the FDA did not communicate significant issues about any safety topics. Prior safety topics that we have disclosed and discussed on previous calls were not mentioned in writing or during the mid-cycle communication review meeting. Additionally, no new safety signals have been identified in the ongoing EGLE extension study. Based on its current review, the FDA stated that it does not believe a risk evaluation and mitigation safety program, or REMS, will be needed for paroxysmin. Moving on to our other programs in CKD on slide 16, we're also evaluating the safety and efficacy of our oxalone for the treatment of patients with ADPKD, the most common hereditary form of CKD, the Phase III Falcon trial. Falcon has a similar trial design to the Cardinal trial, and it's enrolling patients with Stage II to III CKD across approximately 100 sites globally. We recently had a Type B meeting with the FDA regarding the ADPKD development program. We have not received minutes from the meeting yet. However, based on the discussion in the meeting, we are considering amendments to the Falcon protocol. Based on our experience during the cardinal trial in Alport syndrome patients, we requested the FDA's input regarding the feasibility of using year one data to support early submission and accelerated approval. We acknowledged with the FDA that, like our experience in Cardinal, the timing of clinical study milestones at year one and the required regulatory interactions prior to an initial submission may not allow sufficient time, as previously noted by the FDA, to submit the initial application before year two data are available. Thus, while the study uses an efficient study design that is intended to support an early submission, its ability to support an early NDA may not be possible. In response to our inquiry, the FDA indicated that it is unlikely that the results from the first year of the trial would support an application for assorted approval. As such, the FDA recommended against unblinding the trial after the first year in conducting the proposed year one analysis. The FDA instead encouraged us to specify the year two off treatment analysis as the primary endpoint. We plan to modify the protocol so that the primary endpoint will be the year two off treatment analysis. and we will not unblind the trial until after its completion. Our current SAP specifies that patients who do not receive at least one dose of study drug in this second year will be considered missing in the week 104 analysis. The FDA recommended also evaluating the key efficacy endpoint using EGFR values obtained at specified time points, for example, 104 weeks after randomization, regardless of whether a patient discontinued study treatment at an earlier time point. This is similar to one of the sensitivity analyses conducted by the FDA during review of her Alport syndrome NDA. We will be incorporating the FDA's feedback and submitting the revised SAP for the FDA to review. We want to be sure that we power Falcon for the new FDA comment on discontinued patients. As a result, we may or may not need to increase the sample size from the current target of 550 patients. More than 370 patients are currently enrolled in the study. We continue to expect to enroll 550 patients in Falcon by the end of 2021. However, if we decide to increase the target enrollment, we'll provide updated guidance on our enrollment timeline. Moving to slide 17. Merlin is a double-blind, placebo-controlled Phase II trial in patients at risk of rapidly progressing CKD due to multiple etiologies, including common and rare forms of CKD, such as diabetic CKD, hypertensive CKD, IgG nephropathy, FSGS, and others. The primary endpoint of Merlin is the change in EGFR from baseline to Week 12. We have completed enrollment in the Merlin trial and expect to have top-line data in the fourth quarter of 2021. If the results of this study are positive, we would potentially proceed to a larger phase three trial with similar eligibility criteria. Patients at risk for rapid progression experience a significant risk of progressing to end-stage kidney disease in a population with high unmet need across multiple forms of CKD. With that, I would like to turn the presentation over to Nanit to provide a financial and operational update.
spk01: Thanks, Colin, and good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the second quarter of 2021. Let me start with our cash balance on slide 19. As of June 30th, we maintained a solid balance sheet with approximately $755.7 million in cash and cash equivalents. As you would note, we used approximately $22 million in cash during the quarter as compared to $40.5 million in the first quarter of this year. Although our non-GAAP operating expenses increased by approximately $8 million during the second quarter as compared to the first quarter of this year, the reduction in cash used is explained by the receipt of $23 million tax refund related to CARES Act during the second quarter. In keeping with our current guidance, we expect our cash balance to fund our operations through mid-2024. Moving to expenses, our research and development expenses for the quarter were $40.1 million as compared to $36.8 million for the second quarter of 2020. Our non-GAAP R&D expenses were $34.8 million for the second quarter of 2021 as compared to $29.3 million for the same period of the year prior. Higher R&D expenses were primarily due to increased spend related to ongoing clinical study expenses related to clinical programs and medical affairs activities for Bardoc's loan to support disease awareness and education activities. General and administrative expenses for the quarter were $22 million compared to $16.6 million for the second quarter of 2020. Our non-GAAP G&A expenses were $14 million for the second quarter of 2021 as compared to $9.3 million for the same period of the year prior. Higher G&A expenses were primarily due to increased spend related to commercial readiness activities and hiring personnel to support growth in our activities. Our GAAP net loss for the second quarter of 2021 was $72.7 million or $2 per share on both basic and diluted basis as compared to a net loss of $67.6 million or $2.03 per share on both basic and diluted basis for the same period of the prior year. Our non-GAAP net loss for the second quarter of 2021 was $48.3 $48 million or $1.32 per share on both a basic and diluted basis as compared to a non-GAAP net loss of $40.9 million or $1.23 per share on both a basic and diluted basis for the same period of the year prior. The increase in GAAP and non-GAAP net loss is primarily driven by increased clinical study activities, commercial launch readiness activities, and increased personal costs to support the growth of our development activities compared to the same period of the year prior. Moving to slide 20, which is a reconciliation of GAAP to non-GAAP financial measures, non-GAAP R&D, non-GAAP G&A expenses, and non-GAAP operating expenses exclude stock-based compensation expense, while non-GAAP net loss also excludes other income and expense items. To summarize, our non-GAAP operating expenses were $49.1 million during the second quarter of 2021, reflecting investment in clinical and regulatory activities and commercial launch readiness activities for our pipeline. We are actively preparing for the launch of Pardox Sloan for the treatment of Alpert syndrome and recently reinitiated launch readiness efforts for Homoflex Sloan and Friedreich's ataxia. With that, I will turn the call back over to Warren.
spk11: Thanks, Mameet. As our presentation today indicates, we're making significant progress across our broadening set of programs. We remain focused on working with the FDA during their review of our NDA for bardoxalon for the treatment of patients with Alport syndrome and continue to make steady progress in our other programs in CKD. On the back of our recent interaction with the FDA in the mid-cycle communication meeting, we're preparing for an adcom tentatively scheduled for December the 8th, 2021, and a PDUPA date of February 25th, 2022. In addition, we remain on track to file our MAA for marketing authorization in the European Union in the fourth quarter of this year. lastly we remain dedicated to advancing omav nfa and look forward to updating you on the next steps for this program following our pre-nda meeting later this quarter as we prepare to submit the nda by the first quarter of 2022. that concludes our prepared remarks and we'd like to thank everyone who dialed in i'll now turn the call over to the operator for questions
spk12: Ladies and gentlemen, at this time, we'll begin the question and answer session. To ask a question, you may press star and then one using a touch-tone telephone. To withdraw your questions, you may press star and two. If you are using a speakerphone, we do ask that you please pick up the handset before pressing the numbers to ensure the best sound quality. We also ask that you please limit yourselves to one question and one follow-up. At this time, we'll pause momentarily to assemble the roster. Our first question today comes from from Citi. Please go ahead with your question.
spk02: Hi, great. Hi, Warren and Colin and team. Thank you very much for taking the question as well as I really appreciate all the detail on the cardinal review issues, the four significant clinical and statistical review issues. So regarding those four issues, is there more analysis work that you need to do? or is what you've shown us today in the slides essentially how you intend to answer the FDA's questions, and can you confirm that you will not need to conduct any additional clinical work to respond to these four issues? Thanks.
spk11: Sure. Thanks, Yagal. This is Warren. Yeah, we've tried to be very detailed and transparent in the presentation of the issues, and what you see here is our main approach to addressing each one of the four topics that they raised. We'll be preparing additional analyses to help support each one of the questions and to present our position back to the FDA in a very clear, linear fashion. But we do not anticipate having to produce any additional clinical data to respond to any of the questions.
spk02: OK, great. And then just one on OMA. Could you elaborate a little bit more as far as what you believe to be the key issues that you expect the FDA will raise at the pre-NDA meeting?
spk08: This is Colin. We clearly have been in a dialogue with the division for the past year or so about the interpretation of the efficacy data. And so for the pre-NDA meeting, it's primarily me discuss the mechanics of submission of the NDA. And so we do not anticipate there to be any meaningful discussion of interpretation of clinical efficacy or safety data. And so it's more about the submission standards, how we construct our integrated summaries of safety and efficacy, inclusion of the list of studies that need to be included in various non-clinical CMC and other quality topics.
spk11: And so we've actually already received an information request for them that was a routine request so they can understand which patients will be in what data sets. And I think you may recall we commented before that when they asked us to withdraw the Type C meeting and submit for the request for the pre-NDA meeting, they told us to redirect our briefing materials to the topics that would typically be covered in the pre-NDA meeting.
spk02: Great. Thank you.
spk12: Our next question comes from Salveen Richter from Goldman Sachs. Please go ahead with your question.
spk06: Hi, thank you so much for taking our questions. This is Sonia on for Salveen. Just two questions from us. The first on OMAV in FA, what is the risk that the FDA requires either an additional trial or notes the likelihood of conditional approval for the 3Q pre-NDA meeting?
spk08: So the purpose of the pre-NDA meeting is to discuss the package for the NDA and for us to determine if there will be any additional trials required in the post-marketing setting. FDA had previously signaled that we needed additional evidence to support an NDA submission for marking authorization. And so we believe that the data that we provided them and the baseline controlled study as well as the other data sets have allowed us to overcome that hurdle. And so we do not believe at this point that there will be another pre-marketing trial needed, but we'll determine at the meeting if a post-marketing trial may be needed.
spk06: Thank you. And just one quick follow-up. You mentioned that there will be some additional analyses for the issues that came up with Cardinal. Will we get to see those additional analyses, and if so, when?
spk08: Potentially, there's several that we showed here today on our earnings call. We're working on some, obviously, additional ones to supplement the ones that we disclosed today. One other, I think, aspect of the dialogue was that on a few occasions, the FDA asked about data, and we clarified that it was within the NDA, and so part of what we'll be communicating to them is where the actual content can be found.
spk06: Thank you so much.
spk12: Our next question comes from Carter Gould from Barclays. Please go ahead with your question.
spk10: Great. Good afternoon. I'll echo the earlier comments. Thank you for the level of disclosure tonight. I guess just first to start off around the sensitivity analysis, the off-treatment window, it seems like there's been some bit of evolution in sort of how FDA is addressing this or there's stance in that. So, you know, I guess it would be helpful to get some additional color on, in your view, how that position has evolved, or is this just a reflection of the level of discontinuation you saw early in the study? And I guess my brief follow-on, I didn't hear any comments on the call, but in the queue there was some commentary around CMC for Bardoxelone, and there'd be some some commentary forthcoming, if you could put any kind of color around that and your level of confidence that you're all set on the manufacturing side. Thank you.
spk11: Yes, so this is Warren. I'll start and Colin, feel free to supplement this. The FDA has been very consistent in the Alport review. with respect to the window period. We had specified in the protocol in the analysis a window that was 14 to 35 days. And in the year 104 data, the distribution of values was primarily between day 21 out to around day 35 and beyond. We actually opened the 35 day because of the pandemic. to pick up any values that came in late because of rescheduled visits and that kind of thing. But they, early on, expressed some sensitivity about whether the values taken prior to day 28 could bias the results. And we've demonstrated that if you look at the observed results, this is the data that's set forth in the presentation, you simply see no relationship between the off-treatment period beyond day 14 you know, and the magnitude of the results. If they were biased, you would expect them to be high on the left and lower on the right, and that's clearly not the case. Nevertheless, they continue to explore that issue in their sensitivity analyses. I think you asked your second question was about CMC. Yeah, so in the In addition to the written comments that we got and the discussion in the meeting was all around the clinical and statistical topics, they did let us know in the meeting that we would be receiving comments on CMC. They did not indicate what they were. And I also believe they indicated that we would not be receiving any non-clinical comments. So we haven't seen those yet. So I'm not in a position to comment on it.
spk00: Thank you.
spk12: Our next question comes from Maury Raycroft from Jefferies. Please go ahead with your question.
spk07: Hi, thanks for taking my questions. Just to follow up on the post-hoc off-treatment sensitivity analyses that FDA did, can you talk more about preliminary receptivity that FDA had to your rebuttal findings that helped reconcile their findings, or did FDA seem pretty set in viewing their method as the standard or the best way to assess the data?
spk08: So the purpose of the mid-cycle communication meeting is for them to communicate any issues they've identified to us so that we can provide additional data for them to review in the NDA. And so there was more clarification during the call. We did have some discussion, but we will be providing additional data as part of the NDA to address this. And we believe all these issues are addressed by data analysis that we currently have.
spk11: I just add that these were all sensitivity analyses. This is what the FDA does to probe the robustness of your data. They're going to run the data in many different forms as they draw their conclusions about how persuasive it is. So it's not surprising that they did these analyses. It's not surprising some of them are not going to be significant.
spk08: But in all of them, as I said, the treatment effect favors branoxilin. So it's not like it favors placebo. It goes the other way. When you start splicing up the data, as we discussed, you can lose significance because the ink can be much lower. But importantly, like in subgroup analyses, the data favor branoxilin.
spk07: Got it. And that's helpful perspective. And also sort of following up on an earlier question, out of these different four stat issues, you guys provide an overview on how you're going to address each of them. But if there's an area where FDA is not satisfied, you've got a lot of data outside of the L4 phase three, including the chronic kidney disease studies where you've got off-treatment data out to eight weeks. And so I'm wondering if that could be leveraged as a possibility, where your thoughts are there.
spk11: Yeah, some of our responses will definitely include data from the other clinical trials outside of Alport syndrome. Absolutely, no question about it. Got it. Okay, thanks for taking my questions.
spk12: Our next question comes from Annabelle Samini from Stiefel. Please go ahead with your question.
spk13: Hi, thanks for taking my question. I'm sorry if I'm going to belabor this point again, but with the sensitivity analysis that the FDA did, given that, you know, as you said, clearly from a statistical perspective, discontinuations, you know, cause some dilution. There were violations of randomization principles. You know, just that in conjunction with the fact that ADPKD, it looks like they're looking at eight weeks off treatment. Is that an indication that they don't think that four weeks off treatment is sufficient to assess the post-treatment effect of the extreme EGFR increases that you saw during the treatment period? So that's my first question.
spk08: Yeah, so I think that's really two in one. So I'll address the first one. I think that FDA, you know, it's unclear if they completed, obviously, their entire review of the clinical data. And in regards to the patients who discontinued, you know, as we showed here and as we provided the FDA during our meeting while providing follow-up, you know, those patients behave like placebos after, you know, they go off study drug. And so one of the sensitive analyses that we conducted, you know, includes basically the diluted patients. And once again, it shows that there's a smaller treatment effect, but it still favors baroxalone. But regarding your question about the off-treatment duration, and so we've had multiple discussions with this division to demonstrate and to discuss that 28 days is sufficient to wash out the treatment effect. And there has been agreement about this in the prior discussions. And we have a lot of data to support this. We've done extensive exposure response modeling across many of our trials showing that there's a linear effect with EGFR and plasma concentration without lag that basically supports the extensive clinical data and that the effects are resolved within 14 days. One aspect of the data that we identified and discussed in the meeting demonstrates from two short-term studies of approximately 100 patients who had their first off-treatment value collected 28 days after the last dose, that there's complete resolution. And so the change from baseline for those patients was minus 0.7 with a p-value of 0.91 showing complete resolution. Median change was 0.0. FDA noted that they had not completely reviewed that data. And so that already has been one follow-up that we provided to them. But we have data showing that patients reach their maximum effect within 14 days of reaching their final dose. There's a data set of 177 patients that we have that support that. And the modeling shows that the offset, once again, is similar. We have a data set of over 650 patients with over 1,000 data points demonstrating resolution occurs within 14 days. And so we, once again, discussed this multiple times. We discussed that in a Phase II meeting for PKD. They noted in the review of the NDA that in a Japanese study, there's a small subset of 19 bardoxaline patients who received inhuman clearance that had resolution of their acute increase in GFR as assessed by measured GFR, relative to baseline and placebo within four weeks, but in that subset, EGFR did not appear to have been resolved, and we think this is due likely to the effects on infusion of fluids during the immune clearance procedure, which once again demonstrated resolution effects. And so they raised that issue, and they asked about whether or not we could include an additional off-treatment time point for Falcon, which we agreed to do.
spk13: Okay, and if I could just You said you had a lot of data. Is there anything from EGLE that you'll be able to provide additional support for these findings that you have here?
spk08: Not for off-treatment, but I think as you probably noted in the first issue that they raised. They're looking at all data that would support that Viroxilone has an effect on irreversible disease progression. This can come from the off-treatment analyses from within the cardinal trial as well as longer-term on-treatment data. And that's why they asked about the slopes of the on-treatment changes. And so the EGLE data can supplement that analysis because, as we've discussed, this slope in year one is affected by discontinued patients. And then for the Viroxime-treated patients, in all various subgroups, they progress at a slow rate in the second year. And that continues, basically, to be maintained at treatment effective at baseline in EGLE. And so we think all of it's helpful to basically address this question.
spk11: Yeah, this is Warren Huff. If you were asking if there's a way to provide further data along the way if we needed it, we actually, because of the comments that they have made in all of our newly initiated trials, we've started collecting weekly off-treatment data. So, for example, our Merlin study collects weekly off-treatment data, and if we needed it, that data could be used to further buttress our position here.
spk13: Great. Thank you so much.
spk12: Our next question comes from Brian Scorning from Baird. Please go ahead with your question.
spk09: Hey, good afternoon, team. Thanks for taking my question. I was hoping maybe you could just kind of, to some extent, give us sort of how we think about these four issues that were raised in terms of how meaningful you consider them to be when we go into the adcom and the ultimate decision by the FDA. It seems like some of them, maybe three of them, are just areas where some accept that just a post-hoc sensitivity analysis turning up loss of significance, like COVID, not to belittle the impact it would have, but kind of seems like an obvious and explainable issue. where they may be just looking for a defense nonetheless. But on the first one, on the acute PD effects versus the slowing of decline in kidney function, I guess it just seems like a concern that's repeatedly been raised over the years was addressed by you previously, especially in sort of the immediate data release. And I would have expected to be a meaningful part of the NDA discussion in the submission. So I guess the question here is why is the FDA asking a question that seems to like has been previously well addressed. Can you give me insight into that?
spk11: Sure. This is Warren. I'll start. And I said this in the opening comments. I really am not at all surprised that they would want to serve up the question of whether the acute increases in GFR are going to delay dialysis to an ADCOM. These are, you know, Bardoxilone has a highly novel mechanism of action that These improvements have never been observed before, and so it really doesn't surprise me at all, and we've expected this and welcomed it. This is, to me, not a bad question to be served up. They could have completely disregarded the on-treatment effects and only looked at the off-treatment effects. I think that their question acknowledges that if you're slowing their rate of progression, you know, with the on-treatment benefits, that's a clinical benefit that could support their efficacy determination. And I think that the answer to the question that they put, you know, is very clear. To us it's very clear. Let me just say that the design of the trial is a little complex because it collects the off-treatment values at both year one and year two. And this really precludes a classic chronic slope analysis because you just don't have continuous treatment. And they actually recognized that when we asked them how they did the analysis, they stated that they actually did two separate slopes, one for year one and one for year two. That in itself violates the findings of the NKF, FDA, EMA working group, which basically said that you need two to three years of chronic slope data to compute a slope. So I think everybody looking at struggles a little bit with like, what's the appropriate way to do the analysis? But I think it's just very clear that the year one rate of change, the loss of GFR in year one just doesn't predict year two or the future years. We have that data. It's empirical. And the year two data is really, we believe, is very compelling in that the patients, particularly the patients on continuous treatment, just decline at a much lower rate, at a lower rate than the placebo patients. And the patients on gold dose don't decline at all. And it's just fairly obvious. And that's on top of a large placebo-corrected improvement. And I think it's difficult to make the case that this is not likely to delay dialysis. Colin, do you want to comment?
spk08: Yeah, I think that Brian will mention a couple other things. I think that the tone has changed and the type of questioning we're getting from the agency about this is different than before. As you know, We've talked on these calls, as well as with each of the analysts individually, about the mechanism of actinobaroxone, questions about hyperfiltration, proteinuria, and other safety topics, and those did not make the list. And so in this question that they asked was purely a clinical question about efficacy, and it said, well, is this only reversible, or is there an irreversible component to the increase in EGFR? It's not about how do we know this isn't hyperfiltration, So I think the tone is different. As Warren said, you know, we were fully expecting that this would be the main question at ICON.
spk09: Now if I could just ask real quick, I didn't hear you mention pre-specification of covariates for the imputation step being an update to Falcon. Any plans to do that, or is sort of the issue that you said about imputing figures falling so far outside of the range of what would reasonably be expected to be observed just makes a sort of a moot point?
spk08: Probably makes a moot point, but I think that's one thing that was a relatively finer point in the discussion, and so we'll obviously provide an updated analysis plan on Falcon to FDA to address their primary comments to us. We'll ask them if they agree, and if not, we can have further dialogue with them.
spk09: Great. Thank you.
spk12: Our next question comes from Charles Duncan from Cantor Fitzgerald. Please go ahead with your question.
spk03: Yeah, hi, Warren and team. Thanks for all the information on the call. Lots of questions on Bardoxilone, so I'll ask one on OMAV. You know, in terms of the upcoming FDA or meeting with the agency, I guess could we anticipate that, like today's comments, you would be able to provide some information before the minutes, or should we assume that you'll wait until half minutes, or should we just assume that you're going to go forward with an NDA filing in first quarter?
spk11: Normally, we, like most sponsors, want to wait for the minutes unless we're in a position like we are now where you really need to make disclosures before you're going to receive them. So normally we would wait. unless we're compelled for some other reason, legal reason to disclose them.
spk03: Okay. And then it seemed in the press release that FDA asked for a date for submission. And I guess I'm wondering, is that odd to you? It's odd to me. And I'm just kind of wondering what your thinking is for the agency asking you for when you would submit.
spk11: Well, I think it's consistent with the fact that they ask us to request a pre-NDA meeting, and they ask us to ask the questions we needed to ask, typical for a pre-NDA meeting, which basically means questions that you need to have answered to submit your NDA. It's a very mechanical meeting about data sets and that kind of thing. So that's all consistent with that they think they're going to give us a path to filing.
spk08: Correct, and they're doing resource planning likely so they can allocate the additional reviewers to the NDA. Right.
spk03: Okay, good. And last question is, I know lots of people have done lots of work around BARDA and its value, but on OMAV and its value, I guess I'm wondering if there are any key inputs on pharmacoeconomic value that you would point us to provide perspective on OMAV? You know, not asking for pricing, of course, here, but just kind of what is the key, you know, call it clinical value that you see OMAV as providing?
spk08: Sure, Charles. So I think that the data that we've provided to the agency and disclosed publicly demonstrates not only that the drug is disease-modifying, but also it can meaningfully result in a slowing down of disease progression. And some patients actually recover function that's consistent across all subtypes or all sections of the MFAR score, and it's associated with improvements and how patients report that they're feeling and doing. And so we think it's a pretty meaningful data set, and there's not, you know, one aspect, you know, that's driving the results. And so, you know, we hope that that would suggest the drug would have, you know, broad, you know, activity and, you know, improvements for these patients.
spk03: Very helpful, Colin. Last question is, would you anticipate filing for a broad or narrow indication based on some phenotypic observation with OMAP?
spk08: Our plan would be to provide a draft label to FDA that is broad and mirrors eligibility criteria from our trial, which were quite broad. Okay. Very good. Helpful.
spk03: Thanks.
spk12: Our next question comes from Joe Schwartz from SVB Learing. Please go ahead with your question.
spk04: Great. Hi, guys. This is Will on for Joe, and thanks for taking our question today. So one for us, we're hoping we can go back and get a little bit of historical perspective or context on reaching the agreement with the FDA for the retained EGFR benefit. Does this need to be demonstrated in the context of anything, or is this merely just hitting that 2.5 bar? Any context there would be great. Thank you.
spk08: Well, they requested that we include this analysis in the trial, in our pre-IND meeting, which was 2016. And as you know, that same analysis supported approval of Tolvaptin, with a much smaller placebo-corrected difference. And so, you know, in our view, you know, they wanted to see, you know, a difference that was statistically significant, and they didn't have, you know, a specific, you know, delta that they wanted to see, although they mentioned that, you know, it should be greater than one milpermin at the time, but they backtracked on that in the context of our PKD interaction. Yeah, so they would take less than one if the trial was adequately powered. Great. Thank you.
spk12: Once again, if you would like to ask a question, please press star and then 1. Our next question comes from Matt Kaplan from Lattenberg Bauman. Please go ahead with your question.
spk05: All right. Good afternoon, guys. Just going back to Vardoxone, I guess, as you're preparing for the ADCOM meeting in December, with the four issues discussed, identified by the FDA. Are there any other issues that you're preparing to for at that meeting that could derail the adcom being successful?
spk08: We prepared for numerous potential issues, those that have been raised previously or those that they could raise across many different topics, including efficacy and safety. I think what's important to acknowledge with this mid-cycle review meeting is that one purpose is so that they can communicate issues to us so that we can address them. The other is so both sides can be aware of the issues so that they can be thoroughly briefed. for the adcom. And so we'll be prepared for additional issues, but at this time, these are the issues that FDA identified as, quote, significant. And so as we discussed on the call today, you know, A few of these are what we believe are straightforward clarifications. An interpretation of GFR over time, once again, is something that we've prepared to do, and that's extensively briefed in the NDA. It will be in not only the AgCom briefing books, but our presentation. Okay, that's helpful.
spk05: And then just with Omololoxamone, what are your plans following the FAA NDA submission? in the first quarter to continue to develop the product and other indications.
spk08: Yeah, so we've talked for some time about the applicability of OMAP to many other settings of neurological diseases, including other movement disorders like progressive supranuclear palsy, ALS, Huntington's disease, certain types of dementia, as well as other neurodegenerative diseases. Of course, the feature that the drug primarily affects is mitochondrial dysfunction, which we believe is inherent to a wide variety of settings. And so with the recent breakthrough with division for FA, we're now actively planning internally to initiate new studies and following indications in the future. And we'll be discussing that more in detail on future calls. Thanks for taking the question, guys.
spk12: And thank you. And I'm showing no further questions in the queue at this time. Ladies and gentlemen, thanks for your participation on today's conference. As a reminder, an audio recording of the call will be available shortly after the conference call on Riatta's website at riattapharma.com in the investor section. Thank you very much for your participation. You may now disconnect.
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