11. Subsequent Events
On May 6, 2022, an alleged stockholder of the Company filed a derivative action in the Court of Chancery of the State of Delaware against all of the directors of the Company and naming the Company as a nominal defendant. See Note 10, Commitments and Contingencies of Notes to Unaudited Consolidated Financial Statements for a description of the litigation.
15
Item 2. Management’s Discussion and Analysis of Financial Condition and Results of Operations
You should read the following discussion and analysis of our financial condition and results of operations together with our consolidated financial statements and related notes and other financial information appearing in this Quarterly Report on Form 10-Q. Some of the information contained in this discussion and analysis or set forth elsewhere in this Quarterly Report on Form 10-Q, including information with respect to our plans and strategy for our business, operations, and product candidates, includes forward-looking statements that involve risks and uncertainties. Factors that may cause actual results to differ materially from current expectations include, among other things, those described under the headings “Risk Factors” and “Cautionary Note Regarding Forward-Looking Statements” and discussed elsewhere in this Quarterly Report on Form 10-Q.
Overview
We are a clinical-stage biopharmaceutical company focused on identifying, developing, and commercializing innovative therapies that change patients’ lives for the better. We concentrate on small-molecule therapeutics with novel mechanisms of action for the treatment of severe, life-threatening diseases with few or no approved therapies. Our lead programs are omaveloxolone in FA and bardoxolone in rare forms of CKD and a rare neurological disease. We have an NDA under review with the FDA for bardoxolone in patients with CKD caused by Alport syndrome and plan to file an NDA for omaveloxolone in patients with a neurological disorder called Friedreich’s ataxia (FA).CKD. Both bardoxolone and omaveloxoloneof our lead product candidates activate the transcription factor Nrf2 to normalize mitochondrial function, restore redox balance, and resolve inflammation. Because mitochondrial dysfunction, oxidative stress, and inflammation are features of many diseases, we believe omaveloxolone, bardoxolone, and omaveloxoloneour next-generation Nrf2 activators have many potential clinical applications. We possess exclusive, worldwide rights to develop, manufacture, and commercialize omaveloxolone, bardoxolone, omaveloxolone, and our next-generation Nrf2 activators, excluding certain Asian markets for bardoxolone in certain indications, which are licensed to Kyowa Kirin. In addition, we are developing RTA 901, the lead product candidate from our Hsp90 modulator program, in neurological indications. We are the exclusive licensee of RTA 901 and have worldwide commercial rights.
Recent Key Developments
Omaveloxolone for Friedreich’s Ataxia
The FDA has granted Fast Track Designation, Orphan Drug Designation, and Rare Pediatric Disease Designation to omaveloxolone for the treatment of FA. In March 2022, we completed rolling submission of an NDA to the FDA for omaveloxolone for the treatment of patients with FA. This NDA is supported by the efficacy and safety data from the MOXIe Part 2 trial and additional supporting data from the MOXIe Part 1 and MOXIe Extension trials.
We are continuing to complete the regulatory procedures and submissions required prior to filing a Marketing Authorization Application (MAA) in Europe for approval of omaveloxolone for the treatment of patients with FA. We have secured agreement on our Pediatric Investigation Plan with the Pediatric Committee, and we also received European Medicines Agency (EMA) Follow-Up Protocol Assistance feedback regarding our nonclinical and chemistry manufacturing controls (CMC) programs. The EMA feedback indicated that there were no identified impediments to our planned MAA submission and included agreement that certain nonclinical studies, including 2- year carcinogenicity study data, may be submitted after approval. We plan to submit an MAA to the European Medicines Agency for omaveloxolone in the fourth quarter of 2022.
RTA 901 for Neurological Indications, Including Diabetic Peripheral Neuropathic Pain
In the first quarter of 2022 we initiated additional Phase 1 clinical pharmacology studies of RTA 901, including a drug-drug interaction study. Following completion of these Phase 1 studies, we plan to initiate a randomized, double-blind placebo-controlled Phase 2 trial of RTA 901 in diabetic patients with peripheral neuropathic pain in the fourth quarter of 2022.
Bardoxolone in Patients with CKD Caused by Alport Syndrome
In April 2021,We received a Complete Response Letter (CRL) from the FDA accepted for filing thein February 2022 with respect to its review of our NDA for bardoxolone forin the treatment of patients with CKD caused by Alport syndrome, which is currently under review bysyndrome. The CRL indicated the FDA. The FDA completed a bioresearch monitoring inspection of Reata.cannot approve the NDA in its present form. We did not receive any observations.
We also completed a mid-cycle communication meetingwill continue to work with the FDA to confirm our next steps on our Alport syndrome program.
16
and were advised that an Advisory Committee meeting is scheduled for December 8, 2021. The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for the application, is scheduled for February 25, 2022.
We are pursuing marketing approvals outside of the United States. OnIn October 28, 2021, we announced our submission of our Marketing Authorization Application (MAA) withsubmitted an MAA to the European Medicines Agency (EMA)EMA for marketing approval of bardoxolone forin the treatment of patients with CKD caused by Alport syndromesyndrome. In the first quarter of 2022, we received the 120-day list of questions from the EMA. We are in the European Union. On July 27, 2021, Kyowa Kirin,process of preparing our strategic collaborator in CKD in Japan, submitted an NDA in Japan toresponses. We requested a 90-day extension for our responses which was granted by the Ministry of Health, Labour and Welfare (MHLW)EMA. The timeline for bardoxolone for improvement of renal function in patients with Alport syndrome, which is currently under review.the EMA’s review cycle was therefore extended.
Bardoxolone in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)
We are currently enrolling patients in FALCON, ana Phase 3, international, multi-center, randomized, double-blind, placebo-controlled Phase 3 trial studying the safety and efficacy of bardoxolone in patients with ADPKD, randomized one-to-one to active drug or placebo. The studyFALCON is enrolling patients in a broad range of ages 18 to 70 years old, with an estimated glomerular filtration rate (eGFR) between 30 toand 90 mL/min/1.73 m2. We are preparing a protocol amendment for FALCON following the Type B meeting with the FDA regarding the ADPKD development program as outlined in our Quarterly Report on Form 10-Q for the second quarter of 2021 and as follows. The primary endpoint is the off-treatment eGFR change from baseline versus placebo at Week 104. We increased the sample size fromMorethan 550 to 700 patients to account for this dilution in the treatment effect.
Patients will be treated with bardoxolone or placebo for 100 weeks followed by a four-week withdrawal period. There will be no off-treatment period from Week 48 to Week 52. The trial will remain blinded until study completion. The key secondary endpoint is the eGFR change from baseline versus placebo at Week 100.
More than 450 patients are currently enrolled in the study, andtrial.
In the first quarter of 2022, we expectsubmitted a protocol amendment to complete enrollment by the middle of 2022.
Bardoxolone in Patients with CKD at Risk of Rapid Progression
MERLIN is a multi-center, double-blind, placebo-controlled,FALCON Phase 23 trial to evaluate the safety and efficacy of bardoxolone in patients at riskwith ADPKD with the FDA and other relevant health authorities. As agreedwith the FDA prior to submission of rapidly progressing CKD duethe amendment, we recently had a Type A meeting to multiple etiologies including IgA Nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), type 1 diabetic CKD (T1D CKD), type 2 diabetic CKD (T2D CKD), hypertensive CKD,discuss key changes made to the FALCON protocol. Based on the discussion during the meeting and others. Thethe meeting minutes, the Division stated that the proposed primary endpoint of the trial iseGFR change in eGFR from baseline toat Week 12. We108 (8 weeks after planned drug discontinuation at Week 100) was reasonable since the available data suggest that bardoxolone’s acute pharmacodynamic effect on eGFR should be largely resolved. The Division provided guidance on handling of data from patients who completed Year 2 of the study before the protocol amendment and so did not have completed enrollmentan eGFR assessment at Week 108. This included direction on imputing missing data for these patients in the MERLIN trialprimary analysis. The Division stated that, in addition to the primary endpoint, it will be important to demonstrate that the treatment effect accrues over time to support a claim that bardoxolone slows the loss of kidney function in patients with ADPKD and expect to have top-line data inprovided guidance on the first quarter of 2022. If the results of this study are positive, we would potentially proceed to a larger Phase 3 trial with similar eligibility criteria. Patients at risk for rapid progression experience a significant risk of progressing to end-stage kidney disease (ESKD) and are a population with high unmet need across multiple forms of CKD.
Omaveloxolone in Patients with Friedreich’s Ataxia (FA)
On September 30, 2021, we announced that we completed our pre-NDA meeting with the FDA for omaveloxolonestatistical methodologies for the treatmentexploratory eGFR slope analyses. The FDA also confirmed that if FALCON is positive, it could support registration of patients with FA. The purpose of the pre-NDA meeting was to discuss the content of Reata’s planned NDA submission for full approval for omaveloxolone for the treatment of FA. We are not planning to conduct a second pre-approval clinical study prior to the NDA submission. In response to our questions about the contents of the filing, and because of the seriousness of the indication, the FDA exercised its discretion, subject to review, to permit us to submit the results of certain clinical pharmacology and nonclinical studies after approval. We continue to work with the FDA as we finalize the NDA package for submission during the first quarter of 2022.bardoxolone in ADPKD.
Update on Adjustments to Operations Due to COVID-19
We continueWhen COVID-19 emerged as a global pandemic in the first quarter of 2020, Reata was quick to closely monitorrespond and adherewas an early adopter of a work-from-home policy, with the exception of the laboratory that continued to COVID-19 guidance issued by local, state,operate throughout under strict safety protocols. For all remote employees, we provided appropriate workstation equipment as well as training and national authorities. Since Mayresources to support employees’ mental and emotional wellbeing. In the second quarter of 2021, we haveReata relaxed its policy and permitted employees to voluntarily return to the office on flexibleas required. Although the Omicron variant temporarily caused us to again restrict office attendance, in February 2022 we permitted modified work schedules. Dueschedules to the current Covid-19 pandemic situation, we have not committed to a formal return to the office datemeet business and are asking employees to continue to work with management on schedules that meet both Reata’s and the employee’spersonal needs. Pandemic management protocols remain in place for those who do attend either campus.
Background: Our Programs
The following chart outlines each of our programs by indication and phase of development:
In addition, Kyowa Kirin,1Rolling NDA submission completed in March 2022.
2DPNP: Diabetic peripheral neuropathic pain.
17
3On February 25, 2022, we received a CRL from the FDA. We will continue to work with the FDA to confirm our next steps on our Alport syndrome program. MAA in EU is under review.
4AYAME trial conducted in Japan by our strategic collaborator in CKD, is currently conducting its registrational trial of bardoxolone in diabetic (type 1 and 2) CKD in Japan.Kyowa Kirin. Kyowa Kirin completedexpects the last patient enrollmentvisit in this trial in June 2019.the second half of 2022.
*NDA under review. NDA accepted for filing on April 26, 2021, with a PDUFA date of February 25, 2022.
**NDA submission planned for 1Q 2022.
***DPNP: Diabetic peripheral neuropathic pain
Programs in Chronic Kidney Disease
We are developing bardoxolone for the treatment of patients with CKD caused by Alport syndrome, ADPKD, and certain other forms of CKD that, in the aggregate, affect more than 700,000 patients in the United States. CKD is characterized by a progressive worsening in glomerular filtration rate (GFR), which is the rate at which the kidney filters waste products from the blood. When GFR drops below approximately 15 mL/min/1.73 m2, patients develop ESKD and require dialysis or a kidney transplant to survive. Dialysis leads to a reduced quality of life and increases the likelihood of serious and life-threatening complications. The five-year survival rate for hemodialysis patients is approximately 42%.
eGFR is an estimate of GFR that nephrologists use to track the decline in kidney function and progression of CKD. In 11 separate CKD clinical trials, bardoxolone has been shown to improve eGFR in patients with diverse etiologies of CKD. We believe that bardoxolone treatment has the potential to delay or prevent GFR declines that cause the need for dialysis or a transplant in patients with Alport syndrome, ADPKD, and other rare forms of CKD.
Bardoxolone in Patients with CKD Caused by Alport Syndrome
Alport syndrome is a rare, genetic form of CKD caused by mutations in the genes encoding type IV collagen, which is a major structural component of the glomerular basement membrane in the kidney. The kidneys of patients with Alport syndrome progressively lose the capacity to filter waste products out of the blood, which can lead to ESKD and the need for chronic dialysis treatment or a kidney transplant. Alport syndrome affects both children and adults. In patients with the most severe forms of the disease, approximately 50% progress to dialysis by age 25, 90% by age 40, and nearly 100% by age 60.
The Alport Syndrome Foundation estimates that Alport syndrome affects approximately 30,000 to 60,000 people in the United States. According to data provided by IQVIA in April 2020, there are approximately 14,000 projected patients diagnosed with Alport syndrome in all stages of CKD in the United States. However, recent literature suggests that a large number of patients with Alport syndrome are either undiagnosed or misdiagnosed with other forms of CKD. To help nephrologists identify the genetic basis of various forms of CKD, including Alport syndrome, Reata and Invitae Corporation are sponsoring the KIDNEYCODE® genetic testing program.
In November 2020, we announced that the Phase 3 CARDINAL study met its primary and key secondary endpoints at the end of Year 2. The Phase 3 portion of CARDINAL was an international, multi-center, double-blind, placebo-controlled, randomized registrational trial that enrolled 157 patients with CKD caused by Alport syndrome at approximately 50 study sites in the United States, Europe, Japan, and Australia. Patients were randomized one-to-one to bardoxolone or placebo.
At Week 100, in the intent to treat (ITT) population, which included eGFR values for patients who either remained on or discontinued study drug, patients treated with bardoxolone had a statistically significant improvement compared to placebo in mean change from baseline in eGFR of 7.7 mL/min/1.73 m2 (p=0.0005). Patients treated with bardoxolone experienced a mean change from baseline in eGFR of -0.8 mL/min/1.73 m2, while patients treated with placebo experienced a mean change from baseline in eGFR of -8.5 mL/min/1.73 m2.
In the modified ITT (mITT) analysis, which assessed the effect of receiving treatment by excluding values after patients discontinued treatment, patients treated with bardoxolone had a statistically significant improvement compared to placebo in mean change from baseline in eGFR at Week 100 of 11.3 mL/min/1.73 m2 (p<0.0001). In the mITT analysis, patients treated with bardoxolone experienced a mean increase from baseline in eGFR of 1.7 mL/min/1.73 m2, while patients treated with placebo experienced a mean decline from baseline in eGFR of -9.6 mL/min/1.73 m2.
At Week 104 (four weeks after last dose in second year of treatment), patients in the ITT population treated with bardoxolone had a statistically significant improvement compared to placebo in mean change from baseline in eGFR of 4.3 mL/min/1.73 m2 (p=0.023). Patients treated with bardoxolone experienced a mean change from baseline in eGFR of -4.5 mL/min/1.73 m2, while patients treated with placebo experienced a mean change from baseline in eGFR of -8.8 mL/min/1.73 m2. The primary endpoint was analyzed using mixed-model repeated measures with no imputation, and the key secondary endpoint was analyzed using analysis of covariance with treatment-based multiple imputation for missing data.
Bardoxolone was generally reported to be well tolerated in this study, and the safety profile was similar to that observed in prior trials. Eight patients (10%) receiving bardoxolone and 15 patients (19%) receiving placebo experienced a treatment-emergent serious adverse event (SAE). No SAEs were reported in pediatric patients treated with bardoxolone. No fluid overload SAEs or major adverse cardiac events were reported in patients treated with bardoxolone. Blood pressure, a sensitive measure of fluid status, was not significantly different between the two groups. Weight loss was more pronounced in patients with a higher body mass index, and mean decreases in weight were not observed in pediatric patients. The urinary albumin-to-creatinine ratio (UACR) was not significantly different between treatment groups at Week 100 or Week 104.
The reported adverse events (AEs) were generally mild to moderate in intensity, and the most common AEs observed more frequently in patients treated with bardoxolone compared to patients treated with placebo were muscle spasms and increases in aminotransferases which are thought to be associated with the pharmacology of the drug. Muscle spasms were generally transient and were associated with reductions of creatine kinase, which is evidence of improved energy metabolism and inconsistent with muscle injury.
Additionally, an update on results from EAGLE was provided during ASN Kidney Week 2021, which was held virtually from November 4 - 7, 2021. EAGLE is an ongoing, international, multi-center, open-label, extended access trial evaluating the longer-term safety and tolerability of bardoxolone in patients with CKD caused by Alport syndrome who participated in the CARDINAL trial or patients with ADPKD who participated in the FALCON trial.
The change from baseline eGFR was evaluated for the patients with Alport syndrome who were treated with bardoxolone for up to three years (two years in CARDINAL and one year in EAGLE), with four-week off-treatment periods occurring at Weeks 48 and 100. Mean increases in eGFR were observed in patients who previously received placebo and initiated treatment with bardoxolone in EAGLE. Patients who previously received bardoxolone for two years in CARDINAL also continued to experience mean increases in eGFR in their third year of treatment.
For the 19 patients randomized to bardoxolone in CARDINAL who completed 48 weeks in EAGLE (bardoxolone-to-bardoxolone group), bardoxolone treatment resulted in a mean change from baseline in eGFR (relative to original CARDINAL Phase 3 baseline) of 7.8 mL/min/1.73 m52 at Year 1, 8.6 mL/min/1.73 m2 at Year 2, and 6.2 mL/min/1.73 m2 at Year 3. This sustained improvement of kidney function is notable when compared to the CARDINAL study population’s expected yearly eGFR decline of 5.1 mL/min/1.73 m2, which was calculated based on five-year historical eGFR data collected before patients entered the study.
The change from baseline eGFR was also evaluated at Week 12, Week 24, and Week 48 relative to Day 0 (before treatment) in EAGLE. The bardoxolone-to-bardoxolone and placebo-to-bardoxolone groups experienced similar increases in eGFR at all time points.
|
|
|
|
|
|
|
|
|
|
|
|
In April 2021, the FDA accepted for filing the NDA for bardoxolone for the treatment of patients with CKD caused by Alport syndrome, which is currently under review by the FDA. The FDA completed a bioresearch monitoring inspection of Reata. We did not receive any observations.
We also completed a mid-cycle communication meeting with the FDA and were advised that an Advisory Committee meeting is scheduled for December 8, 2021. The PDUFA date, the FDA action date for the application, is scheduled for February 25, 2022.
Ex-U.S. Updates for Bardoxolone in Patients with CKD Caused by Alport Syndrome
We are pursuing marketing approvals outside of the United States. On October 28, 2021, we announced our submission of our MAA with the EMA for marketing approval of bardoxolone for the treatment of CKD caused by Alport syndrome in the European Union.
On July 27, 2021, Kyowa Kirin, our partner in Japan, submitted an NDA in Japan to the MHLW for bardoxolone for improvement of renal function in patients with Alport syndrome. Based on this submission, we earned a $5 million milestone payment under the Kyowa Kirin Agreement related to this event, which we receivedoutcome of AYAME and recognized in the third quarter of 2021. If approved for commercial sales, Kyowa Kirin is required to pay us royalties on net sales of bardoxolone in its territory ranging from the low teens to the low 20% range depending on the country of saleFALCON trials, and the amount of annual net sales.
Bardoxolone in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)
ADPKD is a rare and serious hereditary form of CKD caused by a genetic defect in PKD1 or PKD2 genes leading to the formation of fluid-filled cysts in the kidneys and other organs. Cyst growth can cause the kidneys to expand up to five to seven times their normal volume, leading to pain and progressive loss of kidney function. ADPKD affects both men and women of all racial and ethnic groups and is the leading inheritable cause of kidney failure with an estimated diagnosed population of 140,000 patients in the United States. Despite current standard of care treatment, an estimated 50% of ADPKD patients progress to ESKD and require dialysis or a kidney transplant by 60 years of age.
We are currently enrolling patients in FALCON, an international, multi-center, randomized, double-blind, placebo-controlled Phase 3 trial studying the safety and efficacy of bardoxolone in patients with ADPKD randomized one-to-one to active drug or placebo. The study is enrolling patients in a broad range of ages, 18 to 70 years old, with an eGFR between 30 to 90 mL/min/1.73 m2. We are preparing a protocol amendment for FALCON following the Type B meetingour discussions with the FDA regarding the ADPKDbardoxolone program, we will decide future development program as outlined in our Quarterly Report on Form 10-Qplans for the second quarter of 2021 and as follows. The primary endpoint is the off-treatment eGFR change from baseline versus placebo at Week 104. The changed primary endpoint includes data at Week 104 for all patients irrespective of time off-treatment, instead of the off-treatment value four weeks after last dose. Patients who discontinue treatment early will have shortened treatment exposure and longer off-treatment duration, which, therefore is expected to dilute the treatment effect. We increased the sample size from 550 to 700 patients to account for this dilution in the treatment effect.
Patients will be treated with bardoxolone or placebo for 100 weeks followed by a four-week withdrawal period. There will be no off-treatment period from Week 48 to Week 52. The trial will remain blinded until study completion. The key secondary endpoint is the eGFR change from baseline versus placebo at Week 100. We will also add a Week 108 off-treatment eGFR analysis to the study.
More than 450 patients are currently enrolled in the study, and we expect to complete enrollment by the middle of 2022.
Bardoxolone in Patients with CKD at Risk of Rapid Progression
MERLIN is a multi-center, double-blind, placebo-controlled, Phase 2 trial to evaluate the safety and efficacy of bardoxolone in patients at risk of rapidly progressing CKD due to multiple etiologies including IgAN, FSGS, T1D CKD, T2D CKD, hypertensive CKD, and others. The study includes patients with eGFR between 20 and 60 mL/min/1.73 m2, and patients must meet at least one of the following criteria: UACR ≥ 300 mg/g; eGFR decline at a rate of ≥ 4 mL/min/1.73 m2 in prior year; or hematuria defined as > 5-10 red blood cells per high power field (manual method), documented history of positive urinary dipstick for blood in prior year, or macroscopic hematuria in prior 3 years. The primary endpoint of the trial is change in eGFR from baseline to Week 12.
We have completed enrollment in the MERLIN trial. We expect to have top-line data in the first quarter of 2022. If the results of this study are positive, we would potentially proceed to a larger Phase 3 trial with similar eligibility criteria. Patients at risk for rapid progression experience a significant risk of progressing to ESKD and are a population with high unmet need across multipleadditional forms of CKD.
Both the FALCON and MERLIN trials draw from the results of our Phase 2 study called PHOENIX, an open-label, multi-center Phase 2 trial evaluating the safety and efficacy of bardoxolone in patients with ADPKD, IgAN, T1D CKD, or FSGS completed in 2019. In each of these cohorts, patients treated with bardoxolone experienced a statistically significant mean increase from baseline in eGFR after 12 weeks of treatment. The most commonly reported AE across all cohorts was muscle spasms, which were not associated with clinical signs or symptoms of muscle injury. The overall rate of SAEs was low, with three patients reporting treatment-emergent SAEs, none of which were reported as related to bardoxolone. We plan to pursue development opportunities in each of these rare and serious forms of CKD, maintaining our intent to expand the commercial indications for bardoxolone.
Programs in Neurological Diseases
Omaveloxolone in Patients with Friedreich’s Ataxia (FA)
We are developing omaveloxolone for the treatment of patients with FA, an inherited, debilitating, and degenerative neuromuscular disorder that is normallyusually diagnosed during adolescence and can ultimately lead to premature death. In March 2022, we completed rolling submission of our NDA for omaveloxolone for the treatment of patients with FA. Because mitochondrial dysfunction is a key feature of many neuromuscular diseases, we believe omaveloxolone may be broadly applicable to treat neurological diseases by activating Nrf2 to normalize and improve mitochondrial function and adenosine triphosphate (ATP) production. We plan to pursue the development of omaveloxolone and our other Nrf2 activators for one or more additional neurological diseases.
We are also developing RTA 901 for the treatment of neurological diseases. RTA 901 is a highly potent and selective C-terminal modulator of Hsp90, which has a critical role in mitochondrial function, protein folding, and inflammation. RTA 901 has demonstrated profound efficacy in a wide range of animal models of neurological disease, including diabetic neuropathy, neuroinflammation, and neuropathic pain. We plan to initiate a randomized, placebo-controlled Phase 2 trial in DPNP in the fourth quarter of 2022.
Omaveloxolone in Patients with Friedreich’s Ataxia
Patients with FA experience progressive loss of coordination, muscle weakness, and fatigue, which commonly leadsprogress to motor incapacitation and wheelchair reliance. Symptoms generally occur in children, with patients requiring a wheelchair by their teens or early twenties.Based on literature and proprietary research, we believe FA affects approximately 5,000 children and adults in the United States and 22,000 individuals globally. ThereAccording to data provided by IQVIA in 2020, there are currentlyapproximately 4,000 projected patients diagnosed with FA in the United States. The FDA has granted Orphan Drug Designation, Fast Track Designation, and Rare Pediatric Disease Designation to omaveloxolone for the treatment of FA. The European Commission has granted Orphan Drug Designation in Europe to omaveloxolone for the treatment of FA.
Diagnosis of FA typically occurs by genetic testing, and most people in the United States with FA are diagnosed in their teens and early twenties. Patients with FA experience progressive loss of coordination, muscle weakness, and fatigue that commonly results in motor incapacitation, with patients requiring a wheelchair in their twenties. The mean age of death for patients with FA is in the mid-thirties. Childhood-onset FA can occur as early as age five, is more common than later-onset FA, and normally involves more rapid disease progression. Currently, there are no approved therapies to treatfor the treatment of FA.
OurMOXIe Part 2 Trial Results
Part 2 of our Phase 2 trial, called MOXIe (MOXIe Part 2), was a two-part,an international, multi-center, randomized, double-blind, placebo-controlled, registrationalrandomized, Registrational trial that studied the safety and efficacy of omaveloxolone in patients with FA. Additionally, patients who completed the study and met eligibility requirements could participate in the MOXIe Extension during which investigators and patients remained blinded to prior treatment assignments. In October 2019, we announced that Part 2 inenrolled 103 patients with FA met itsat 11 trial sites in the United States, Europe, and Australia. MOXIe Part 2 was one of the largest global, interventional trials ever completed in FA. Patients were randomized one-to-one to omaveloxolone or placebo. MOXIe Part 2 was completed in October 2019. The primary analysis population excluded patients with pes cavus (n=82), a musculoskeletal foot deformity that may interfere with the patient’s ability to perform some components of the neurological exam used to score the primary endpoint of the trial. Safety analyses were evaluated in the all-randomized population (n=103).
The primary endpoint for the trial was the change in the Modified Friedreich’s Ataxia Rating Scale (mFARS) score for omaveloxolone relative to placebo after 48 weeks of treatment. Patients treated with omaveloxolone (150 mg/day)Omaveloxolone treatment demonstrated a statistically significant evidence of efficacy for the primary endpoint of the trial, producing a placebo-corrected 2.40-2.40 point mean improvement (decrease) in mFARS after 48 weeks of treatment (p=(n=82; p=0.014). Patients treated with omaveloxolone demonstratedexperienced a mean improvement relative toin mFARS of -1.55 points from baseline, while patients treated with placebo experienced a mean worsening in every subcategory measured undermFARS of +0.85 points from baseline. Further, the observed placebo-corrected improvements in mFARS were time-dependent, increasing over the course of treatment with the largest improvement observed after 48 weeks of treatment.
18
Additionally, all secondary endpoints either favored the omaveloxolone arm or were neutral. Patients on omaveloxolone experienced a nominal improvement in the Activities of Daily Living (ADL) questionnaire, with all nine questions favoring the omaveloxolone arm. On average, ADL scores for patients on omaveloxolone did not change from baseline, while placebo-treated patients worsened. Both patient global impression of change (PGIC) and clinical global impression of change numerically favored omaveloxolone, and improvement in PGIC correlated with the observed improvement in mFARS.
Omaveloxolone treatment was generally reported to be generally well-tolerated. Four (8%) omaveloxolone patients and two (4%) placebo patients discontinued trial drug due to an adverse event (AE). The reported AEs were generally mild to moderate in intensity, and the most common AEs (i.e., reported in > 10% of omaveloxolone-treated patients) observed more frequently (>5% difference) in omaveloxolone compared to placebo were headache, nausea, increased aminotransferases, fatigue, abdominal pain, diarrhea, oropharyngeal pain, muscle spasms, back pain, and decreased appetite. Increases in aminotransferases are a pharmacological effect of omaveloxolone. In preclinical studies, omaveloxolone has been shown to increase production of aminotransferases in vitro, which we believe are related to restoration of mitochondrial function. In MOXIe Part 2, the aminotransferase increases were associated with improvements (reductions) in total bilirubin and were not associated with any evidence of liver injury.
In MOXIe Part 2, the overall rate of serious adverse events (SAEs) was low, with five patients in the omaveloxolone group and three patients in the placebo group reporting SAEs. No new safety signals were identified, and the reported SAEs were sporadic and generally expected in FA patients. In the patients who reported SAEs while receiving omaveloxolone, none led to discontinuation.
MOXIe Extension Trial
The FDA provided us guidance that, although it did not have concernsopen-label MOXIe Extension trial is ongoing, with the reliabilitya total of the mFARS primary endpoint results149 patients enrolled (57 patients from MOXIe Part 2, it was not convinced that the results1 and 92 patients from MOXIe Part 2, as a single study, were sufficient to support approval. The FDA stated that we would need to conduct a second pivotal trial that confirms the mFARS results of MOXIe Part 2 with a similar magnitude of effect. As an alternative, to increase the persuasiveness of MOXIe Part 2 results, we completed additional analyses, including the Delayed-Start Analyses.
During the first quarter of 2021, we submitted results from the Delayed-Start Analyses to the FDA. These additional exploratory analyses analyzed data from MOXIe Part 2 and the MOXIe Extension. In these analyses, parallel trajectories between the patients randomized to placebo (placebo-to-omaveloxolone group) and those randomized to omaveloxolone (omaveloxolone-to-omaveloxolone group) in the double-blind period from MOXIe Part 2 through 48 weeks in the MOXIe Extension could provide evidence of disease-modifying activity.2). A total of 73 out of 75 (97%) patients without pes cavus who completed MOXIe Part 2 were enrolled in the MOXIe Extension. On September 10,Extension, including 39 patients previously randomized to placebo (the placebo-to-omaveloxolone group) and 34 patients previously randomized to omaveloxolone (the omaveloxolone-to-omaveloxolone group). Due to the COVID-19 pandemic, not all patients had mFARS assessments performed at each time point.
19
Delayed-Start Analysis Results from August 2021 we presentedData Cut-Off
The intent of the post-hoc Delayed-Start Analysis is to evaluate whether omaveloxolone has a posterpersistent effect on FA disease course. Conceptually, this analysis evaluates whether the treatment effect that was observed in the placebo-controlled MOXIe Part 2 trial is maintained in the MOXIe Extension trial when all patients are receiving omaveloxolone. If the treatment effect is maintained between those originally randomized to placebo (the placebo-to-omaveloxolone group) versus those originally randomized to omaveloxolone (the omaveloxolone-to-omaveloxolone group), then it demonstrates evidence of a persistent effect on the course of the disease. If the treatment effect is not maintained, and the patients originally randomized to placebo are able to achieve the same absolute response and “catch up” to the patients initially randomized to omaveloxolone, the results are consistent with a symptomatic treatment that does not affect the underlying course of the disease.
Two timepoints were used in the analysis. The first timepoint was at Week 48, the final week of treatment in the placebo-controlled MOXIe Part 2 trial. The second timepoint was at Week 72 of the open-label MOXIe Extension in which all patients received omaveloxolone. A non-inferiority test was used to evaluate if the difference in mFARS between groups observed at the International Parkinsonfirst timepoint was maintained or non-inferior at the second timepoint. The analysis methods, including the specified non-inferiority margin, were based on literature (Liu-Seifert, 2015a, 2015b). When comparing treatment groups using this methodology, maintaining a negative difference between treatment groups in mFARS is evidence of a persistent treatment effect.
The Delayed-Start Analysis used in clinical modules in our initial NDA rolling submission for omaveloxolone was updated as of August 2021. In this updated analysis 58 of 73 patients from MOXIe Part 2 without pes cavus who enrolled into MOXIe Extension had at least 72 weeks of exposure in MOXIe Extension, and Movement Disorder Society Virtual Congress28 of these patients had at least 120 weeks of exposure in the Moxie Extension.
Results of this analysis demonstrated that the between-group difference in mFARS observed at the end of the placebo-controlled MOXIe Part 2 period (least squares mean difference = -2.25 ± 1.07) was preserved at MOXIe Extension Week 72 in the delayed-start period (LS mean difference = -3.51 ± 1.45). Consistent with an updatea persistent treatment effect on disease, the upper limit of the 90% CI for the difference estimate was less than zero (-0.615), meeting the threshold for demonstrating significant evidence of non-inferiority.
Delayed-Start Analysis Primary Endpoint (Non-Inferiority Test)1
Placebo-Controlled Week 48 (Δ1) | Delayed-Start Week Ex. 72 (Δ2) | ||||
Difference (LS Mean ± SE) | -2.25 ± 1.07 p=0.037 | -3.51 ± 1.45 p=0.016 | |||
Estimate = Δ2 – 0.5 × Δ1 | -2.39 ± 1.38 | ||||
Upper Limit of 1-sided 90% CI for Estimate | -0.615 | ||||
1Non-Inferiority test performed using a MMRM analysis with a Toeplitz covariance structure. | |||||
The graphical representation of changes from baseline in mFARS for omaveloxolone and placebo groups shows the separation at the end of the placebo-controlled period is maintained in the open-label period at Extension Week 72 and beyond.
20
Change from Baseline in mFARS (Patients without Pes Cavus)
Many of the visits at Week 48 and Week 72 of the MOXIe Extension were scheduled during the initial peak of COVID-19 cases during Spring to Fall 2020. The mFARS assessment must be conducted in the Delayed-Start Analyses increasingclinic, and many in-clinic visits did not occur due to COVID-19 related travel restrictions and site closures during this period. Apart from 9 to 13 patientsthe data at MOXIe Extension Week 48, parallel trajectories were seen in LS Mean mFARS change from baseline between the placebo-to-omaveloxolone group and increasing from 11 to 17 patients in the omaveloxolone-to-omaveloxolone group. group in MOXIe Extension.
A longitudinal analysis usedwas also performed to calculate annualized slopes incorporating all available data from the MOXIe Extension, which showed similar mean slopes in mFARS for the placebo-to-omaveloxolone group (0.29(0.45 ± 0.680.38 points per year) when compared to the omaveloxolone-to-omaveloxolone group (0.17(0.27 ± 0.610.59 points per year) with no significant difference between slopes (p=0.85)(difference = -0.18 ± 0.67; p=0.79). The resulting parallel trajectories between bothIn MOXIe Extension, omaveloxolone-treated patients have been progressing at a rate that is >75% less than the approximately two points per year that patients progressed in a recent large natural history study (Patel, 2016).
Results from the Delayed-Start Analysis indicate a persistent omaveloxolone treatment groups are consistent with disease-modifying activity.effect on the disease course of FA. Patients who received omaveloxolone during the double-blind MOXIe Part 2 had a benefit that could not be achieved by patients initially randomized to placebo who began omaveloxolone one year later in MOXIe Extension. Notably, patients previously randomized to omaveloxolone in MOXIe Part 2 continued to show mean mFARS values that were similar to their original baseline after over three years of treatment.
On September 30,No new safety signals have been identified in the MOXIe Extension trial.
21
Regulatory Interactions
In the third quarter of 2021, we announced that we completed our pre-NDA meeting with the FDA for omaveloxolone for the treatment of patients with FA.FDA. The purpose of the pre-NDA meeting was to discuss the content of Reata’s planned NDA submission forincluding the nonclinical data and CMC packages, data standard plan, and the overall content plan. In the meeting, we stated that we believed that the MOXIe data, along with the Delayed-Start Analysis, would provide sufficient clinical data to support a full approval. The FDA stated that the proposed primary and supportive efficacy data appear reasonable, though the Delayed-Start Analysis was viewed as exploratory. The FDA noted that the ability of the data to support full approval, for omaveloxolone forand the treatmentadequacy of FA. We are not planning to conductthe data and the determination of which data may be supportive of efficacy, would be a second pre-approval clinical study prior to the NDA submission.matter of review. In response to our other questions about the contents of the filing, and because ofNDA, the FDA exercised its discretion based on the seriousness of the indication the FDA exercised its discretion,and unmet medical need, subject to review, to permit us to submit the results of certain clinical pharmacology and nonclinical studies after approval. The additional studies include a thorough QT study with omaveloxolone, nonclinical metabolite toxicity studies, and six-month and two-year nonclinical carcinogenicity studies. The need for a drug-drug interaction study with a moderate CYP3A inducer will be established upon review of the adequacy of our submitted physiological based pharmacokinetic (PK) model.
On November 18, 2021, the FDA granted omaveloxolone Fast Track Designation for the treatment of FA, providing eligibility for FDA programs such as Priority Review and rolling submission of the NDA, if relevant criteria are met. The FDA granted our request for a rolling submission, and in March 2022, we completed submission of the NDA. This NDA is supported by the efficacy and safety data from the MOXIe Part 2 trial and additional supporting data from the MOXIe Part 1 and MOXIe Extension trials.
We continueare continuing to workcomplete the regulatory procedures and submissions required prior to filing a MAA in Europe for approval of omaveloxolone for the treatment of patients with FA. We have secured agreement on our Pediatric Investigation Plan with the FDA asPediatric Committee, and we finalizealso received EMA Follow-Up Protocol Assistance feedback regarding our nonclinical and CMC programs. The EMA feedback indicated that there were no identified impediments to our planned MAA submission and included agreement that certain nonclinical studies, including 2- year carcinogenicity study data, may be submitted after approval. We plan to submit an MAA to the NDA packageEuropean Medicines Agency for submission duringomaveloxolone in the firstfourth quarter of 2022.
Omaveloxolone in Other PotentialNeurological Indications
Omaveloxolone is a promising platform molecule. Because mitochondrial dysfunction is a key feature of many neurological and neuromuscular diseases, we believe omaveloxolone may be broadly applicable to treat such diseases by activating Nrf2 to normalize and improve mitochondrial function and ATP production.
Based on our understanding of the pathophysiology of neurological diseases characterized by mitochondrial dysfunction, inflammation, and oxidative stress, we believe omaveloxolone may be applicable to diseases such as progressive supranuclear palsy, Parkinson’s disease, frontotemporal dementia, Huntington’s disease, Amyotrophicamyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and epilepsy. Consistent with this, we have observed compellingpromising activity of omaveloxolone and our other Nrf2 activators in preclinical models of many of these diseases.
Our Nrf2 activators reduced seizure frequency in refractory, progressive epilepsy models and restored mitochondrial function in patient biopsy samples and preclinical models of FA, ALS, familial and sporadic Parkinson’s disease, and frontotemporal dementia. In clinical trials, improvements in neuromuscular function have been observed in FA patients treated with omaveloxolone as assessed by mFARS, and improvements in mitochondrial function, as measured by reductions in blood lactate and heart rate, have been observed in patients with primary mitochondrial disease. Accordingly, we believe that omaveloxolone has the potential to treat a number of neurological and neuromuscular diseases that currently have few or no effective therapies, and we plan to pursue the development of omaveloxolone and our other Nrf2 activators for one or more of these diseases.
RTA 901 in Neurodegeneration and NeuroprotectionNeurological Diseases
RTA 901 is the lead product candidate from our Hsp90 modulator program, which includes highly potent and selective C-terminal modulators of Hsp90. We have observed favorable activity of RTA 901 in a range of preclinical models of neurological disease, including models of diabetic neuropathy, neuroinflammation, and neuropathic pain.
22
Historically, other companies have explored N-terminal Hsp90 inhibitors for cancer therapeutics; however, this approach has been associated with multiple adverse effectsAEs including peripheral neuropathy and ocular toxicity. Binding at the C-terminus of Hsp90 leads to increased transcription of Hsp70, a cytoprotective and molecular chaperone gene, which facilitates cell survival in response to stress without the deleterious activities of N-terminal inhibition.
In preclinical rodent disease models, we observed that RTA 901 administered orally once-daily rescued existing nerve function, restored thermal and mechanical sensitivity, within four weeks, and improved nerve conductance velocity and mitochondrial function. These effects are dose-dependent, reversible, and Hsp70-dependent.
We completed a Phase 1 single and multiple ascending doseSAD/MAD trial of oral, once-daily RTA 901 in healthy adult volunteers to evaluate the safety, tolerability, and pharmacokinetic (PK)PK profile. The PK was linearapproximately dose-proportional up to the highest doses evaluated with a half-life ranging from two to nine hours, andhours. Human exposures were easily achievable in 10-fold excess of thoseexceeded the exposures necessary for efficacy in multiple animal models. No safety or tolerability concerns were reported. Due toIn the first quarter of 2022, we initiated additional delays inPhase 1 clinical drug supply,pharmacology studies of RTA 901, including a drug-drug interaction study. Following completion of these Phase 1 studies, we now plan to initiate additionala randomized, double-blind placebo-controlled Phase 1 studies to evaluate the PK and drug-drug interaction potential2 trial of RTA 901 in the first half of 2022 and a randomized, placebo-controlled Phase 2 study in diabetic patients with peripheral neuropathic pain (DPNP) in the second halffourth quarter of 2022.
There are about four million patients with moderate to severe DPNP in the United States, and about two million adult patients diagnosed with DPNP seek treatment annually. We are the exclusive licensee of RTA 901 and maintainhave worldwide commercial rights.
U.S. Commercial Readiness
Programs in Chronic Kidney Disease
We and Kyowa Kirin, our strategic collaborator in CKD in Japan, are actively building the necessary commercial infrastructure in the United States to effectively support the commercialization of our product candidates,developing bardoxolone for the treatment of patients withCKD in multiple indications, including CKD caused by Alport syndrome, ADPKD, and omaveloxolone fortype 1 and 2 diabetic CKD. CKD is characterized by a progressive worsening in the treatmentrate at which the kidney filters waste products from the blood, called the glomerular filtration rate (GFR). eGFR is an estimate of GFR that nephrologists use to track the decline in kidney function and progression of CKD. When GFR gets too low, patients develop end-stage kidney disease (ESKD) and require dialysis or a kidney transplant to survive.
We received a CRL from the FDA in February 2022 with FA. Our abilityrespect to launch bardoxolone and omaveloxolone is dependent on the acceptance and successful defenseits review of anour NDA and approval by the FDA.
The FDA has granted a PDUFA date of February 25, 2022 for bardoxolone forin the treatment of patients with CKD caused by Alport syndrome. IfWe will continue to work with the FDA to confirm our next steps on our Alport syndrome program. Kyowa Kirin is currently conducting its registrational AYAME trial of bardoxolone in diabetic (types 1 and 2) CKD in Japan.
Bardoxolone in Patients with CKD Caused by Alport Syndrome
Alport syndrome is a rare, genetic form of CKD caused by mutations in the genes encoding type IV collagen, which is a major structural component of the glomerular basement membrane in the kidney. The kidneys of patients with Alport syndrome progressively lose the capacity to filter waste products out of the blood, which can lead to ESKD and the need for chronic dialysis treatment or a kidney transplant. Alport syndrome affects both children and adults and can manifest as early as the first decade of life and causes average annual declines in eGFR of approximately four to five mL/min/1.73 m2. In patients with the most severe forms of the disease, approximately 50% progress to dialysis by age 25, 90% by age 40, and nearly 100% by age 60. There are currently no approved therapies to treat CKD caused by Alport syndrome.
The Alport Syndrome Foundation has estimated that Alport syndrome affects approximately 30,000 to 60,000 people in the United States. According to data provided by IQVIA in 2020, there are approximately 14,000 projected patients diagnosed with Alport syndrome in all stages of CKD in the United States. However, recent literature suggests that a large number of patients with Alport syndrome are either undiagnosed or misdiagnosed with other forms of CKD.
On November 9, 2020, we anticipatereported interim results from the long-term extension EAGLE trial. EAGLE is an international, multi-center, open-label, extended access trial evaluating the longer-term safety and tolerability of bardoxolone in patients with CKD caused by Alport syndrome who participated in the CARDINAL trial or patients with ADPKD who participated in the FALCON trial. The change from baseline in eGFR was assessed for the 14 patients with Alport syndrome who were treated with bardoxolone for three years (two years in CARDINAL and one year in EAGLE), with four-week off-treatment periods occurring at Weeks 48 and 100. Bardoxolone treatment resulted in a mean on-treatment increase from baseline in eGFR of 11.5 mL/min/1.73 m2 at Year 1, 13.3 mL/min/1.73 m2 at Year 2, and 11.0 mL/min/1.73 m2 at Year 3.
23
In February 2022, we provided the FDA with an update on results from patients with CKD caused by Alport syndrome in the ongoing EAGLE trial. Mean increases in eGFR were observed at Week 12, Week 24, and Week 48 relative to Day 0 (before treatment) in EAGLE in patients who previously received placebo and initiated treatment with bardoxolone in EAGLE. Patients who previously received bardoxolone for two years in CARDINAL experienced similar mean increases in eGFR at all timepoints. For the 37 patients randomized to bardoxolone in CARDINAL who completed 48 weeks in EAGLE, bardoxolone treatment resulted in a mean on-treatment change from baseline in eGFR (relative to original CARDINAL baseline) of 9.2 mL/min/1.73 m2 at Year 1, 7.8 mL/min/1.73 m2 at Year 2, and 6.7 mL/min/1.73 m2 at Year 3.
A subset of patients with Alport syndrome (n=18) completed 96 weeks of treatment in EAGLE, which amounts to approximately four years of total treatment, and had a mean ± standard error change in eGFR from CARDINAL baseline of 5.5 ± 3.5 mL/min/1.73 m2. This sustained improvement of kidney function is notable when compared to the CARDINAL trial population’s expected yearly eGFR decline of 5.1 mL/min/1.73 m2, which was calculated based on five-year historical eGFR data collected before patients entered the trial. No new safety findings have been identified in the EAGLE trial.
On February 25, 2022, we received a CRL from the FDA with respect to its review of our NDA for bardoxolone in the treatment of patients with CKD caused by Alport syndrome. The CRL indicated that the FDA cannot approve the NDA in its present form. Based on its review, the FDA concluded that it does not believe the submitted data demonstrates that bardoxolone willis effective in slowing the loss of kidney function in patients with Alport syndrome and reducing the risk of progression to kidney failure and has requested additional data to support the efficacy and safety of bardoxolone. Their conclusion was based on efficacy and safety concerns primarily set forth in the FDA’s briefing book and discussed at the Cardiovascular and Renal Drugs Advisory Committee meeting held on December 8, 2021.
The FDA stated that the issues could be resolved by providing evidence of effectiveness that includes evidence from an adequate and well-controlled study showing a clinically relevant effect on the rate of loss of kidney function in patients with Alport syndrome or, alternatively, an effect on a clinical outcome (i.e., an endpoint that captures how patients with Alport syndrome feel, function, or survive). In addition, the FDA stated that we would need to address whether bardoxolone has a clinically relevant effect on the QT interval and show that the demonstrated clinical benefits of bardoxolone outweigh its risks. The FDA welcomed continued discussion on the details of a path forward. We plan to work closely with the FDA to achieve our goal of bringing this important medicine to patients in the United States.
In October 2021, we submitted an MAA to the EMA for bardoxolone in the treatment of patients with CKD caused by Alport syndrome. In the first US product launch,quarter of 2022, we received the 120-day list of questions from the EMA. We are in the process of preparing our responses. We requested a 90-day extension for our responses which was granted by the EMA. The timeline for the EMA’s review cycle was therefore extended.
Bardoxolone in Patients with Autosomal Dominant Polycystic Kidney Disease
ADPKD is a rare and our commercial readiness efforts alignserious hereditary form of CKD caused by a genetic defect in PKD1 or PKD2 genes leading to the formation of fluid-filled cysts in the kidneys and other organs. Cyst growth can cause the kidneys to expand up to five to seven times their normal volume, leading to pain and progressive loss of kidney function. Inflammation appears to play a role in cyst growth and is associated with this date. Indisease progression in ADPKD.
ADPKD affects both men and women of all racial and ethnic groups and is the leading inheritable cause of kidney failure with an estimated diagnosed population of 140,000 patients and an estimated prevalent population of 400,000 patients in the United States. Despite current standard-of-care treatment, an estimated 50% of ADPKD patients progress to ESKD and require dialysis or a kidney transplant by 60 years of age. The only therapy currently approved for ADPKD is JYNARQUE® (tolvaptan), developed by Otsuka Pharmaceuticals Co., Ltd., which was approved in the United States ourin 2018 to slow kidney function decline in adults at risk of rapidly progressing ADPKD.
We are currently enrolling patients in FALCON, an international, multi-center, randomized, double-blind, placebo-controlled trial studying the safety and efficacy of bardoxolone in patients with ADPKD randomized one-to-one to active drug or placebo. FALCON is enrolling patients in a broad range of ages, with an eGFR between 30 and 90 mL/min/1.73 m2.
24
In the firstquarter of 2022, we finalized a protocol amendment to FALCON, and we initiated submission of the amendment to the FDA and other relevant health authorities. The major protocol amendment changes include an increase in the sample size from 550 to 850 patients, addition of adolescent (12 to 17 years) patients with ADPKD for a total age range of 12 to 70 years, removal of the off-treatment period (Week 48 – Week 52) during Year 1, change of the primary endpoint of off-treatment eGFR change from baseline at Week 52 (or four weeks after drug discontinuation in Year 1) to eGFR change from baseline at Week 108 (eight weeks after planned drug discontinuation at Week 100). The protocol amendment also includes addition of an exploratory endpoint of eGFR change from baseline at Week 112 (12 weeks after planned drug discontinuation at Week 100), and addition of a sub study with ambulatory blood pressure monitoring.
As agreed with the FDA prior to submission of the amendment, we recently had a Type A meeting to discuss key changes made to the FALCON protocol. Based on the discussion during the meeting and the meeting minutes, the Division stated that the proposed primary endpoint of eGFR change from baseline at Week 108 (8 weeks after planned drug discontinuation at Week 100) was reasonable since the available data suggest that bardoxolone’s acute pharmacodynamic effect on eGFR should be largely resolved. The Division provided guidance on handling of data from patients who completed Year 2 of the study before the protocol amendment and so did not have an eGFR assessment at Week 108. This included direction on imputing missing data for these patients in the primary analysis. The Division stated that, in addition to the primary endpoint, it will be important to demonstrate that the treatment effect accrues over time to support a claim that bardoxolone slows the loss of kidney function in patients with ADPKD and provided guidance on the statistical methodologies for the exploratory eGFR slope analyses. The FDA also confirmed that if FALCON is positive, it could support registration of bardoxolone in ADPKD.
Pursuant to the protocol amendment, patients will be treated with bardoxolone or placebo for 100 weeks followed by a twelve-week withdrawal period. The trial will remain blinded until study completion. All patients will be asked to return at Week 108 independent of the time of study drug discontinuation. The secondary endpoint is the eGFR change from baseline at Week 100. More than 550 patients are currently enrolled in the trial.
AYAME Trial in Diabetic CKD Conducted by Kyowa Kirin
Upon completion of Kyowa Kirin's Phase 2 TSUBAKI trial of bardoxolone in patients with Stage 3 and 4 diabetic CKD in Japan, and after discussions with the Pharmaceuticals and Medical Devices Agency, Kyowa Kirin initiated a Phase 3 outcomes trial called AYAME in patients with Stage 3 or 4 diabetic CKD in Japan. The primary endpoint is time to onset of a ≥ 30% decrease in eGFR from baseline or ESKD. The secondary endpoints are time to onset of a ≥ 40% decrease in eGFR from baseline or ESKD, time to onset of a ≥ 53% decrease in eGFR from baseline or ESKD, time to onset of ESKD, and change in eGFR from baseline at each evaluation time point. Kyowa Kirin completed patient enrollment in AYAME in June 2019 and expects the last patient visit to occur in the second half of 2022.
U.S. Commercial Readiness
With the NDA submission of omaveloxolone complete, we are advancing commercial launch preparations in the United States. We are in the process of building the commercial infrastructure necessary to effectively support the commercialization of omaveloxolone for the treatment of FA, if and when we receive regulatory approval. Commercial launch preparation for omaveloxolone in FA will continue to advance in step with the regulatory progress.
Our ability to launch omaveloxolone is dependent on the successful filing and defense of an NDA and approval by the FDA. We have hired commercial leadership team is in place. We are expanding quality and compliance functionsintend to support commercialization and are buildingbuild the organization,teams, infrastructure, systems, and processes necessary for the launch of bardoxolone, includingomaveloxolone. This will include sales, marketing, market access, patient support, and distribution. We recently hired a team of payer account directors focused on educating privateAdditionally, we are expanding quality and public payers about Alport syndrome, disease severity, and the needcompliance functions to treat diagnosed patients. Their role is to facilitate coverage and reimbursement of bardoxolone for Alport syndrome upon approval. We have hired our regional business directors who will be responsible for hiring our clinical sales specialists and for driving sales at approval.
Launch readiness efforts are underwaysupport commercialization. A trade name for omaveloxolone has been selected.
25
One challenge unique to rare-disease commercialization is patient identification due to the very small and sometimes heterogeneous disease populations. Our management team is experienced in maximizing patient identification for both clinical development and commercialization purposes in rare diseases. Commercial infrastructure for orphan products typically consists of a targeted, specialty sales force that calls on a limited and focused group of physicians and personnel involved in sales management, internal sales support, marketing, patient access, and distribution.
Ex-U.S. Commercial Readiness
Our ability to launch omaveloxolone is dependent on the treatmentsuccessful filing and defense of patientsan MAA and approval by EMA or other regulatory agencies. Outside of the United States, where appropriate and depending on the terms of our contractual arrangements, we plan, either alone, or with FAnew collaboration partners, to commercialize our products. Our strategic collaborator Kyowa Kirin has all rights to commercialize bardoxolone in its territories. We are refining our strategy and market assessments with respect to potential launches in the United States. We are efficiently building core functions for our bardoxolone program to also support the planned launch of omaveloxolone for FA, including shared distribution, access and patient hub services, IT, insights, and analytics functions. Disease awareness efforts to help providers more quickly identify FA patients are underway,EU, and we continue to engageevaluate market opportunities for our products in other global markets. Commercial launch preparation for omaveloxolone in FA outside of the United States will advance in step with the patient community through multiple digital and social platforms.regulatory progress.
If and when we receive regulatory approval for our product candidates, we plan to utilize a specialty pharmacy distribution model to support product availability to patients, with a patient-centered hub to support on-label utilization, ease of access, and patient education and compliance. We also completed preliminary field force sizing and structure for our sales teams and have launched disease awareness campaigns to educate physicians about Alport syndrome and FA. Trade names for bardoxolone and omaveloxolone have been selected.
Corporate Overview
To date, we have focused most of our efforts and resources on developing our product candidates and conducting preclinical studies and clinical trials. We have historically financed our operations primarily through revenue generated from our collaborations with AbbVie and Kyowa Kirin, from sales of our securities, secured loans, and a strategic financing from BXLS. We have not received any payments or revenue from collaborations other than nonrefundable upfront, milestone, and cost sharing payments from our collaborations with AbbVie and Kyowa Kirin, from the Development Agreement with BXLS, and from reimbursements of expenses under the terms of our agreement with Kyowa Kirin. We have incurred losses in each year since our inception, other than in 2014. As of September 30, 2021,March 31, 2022, we had $713.2$532.0 million of cash and cash equivalents and an accumulated deficit of $1,170.2$1,329.5 million. We continue to incur significant research and development and other expenses related to our ongoing operations. Despite contractual product development commitments and the potential to receive future payments from Kyowa Kirin, we anticipate that we will continue to incur losses for the foreseeable future, and we anticipate that our losses will increase as we continue our development of, seek regulatory approval for, and potentially commercialize our product candidates. If we do not successfully develop and obtain regulatory approval of our existing product candidates or any future product candidates and effectively manufacture, market, and sell any products that are approved, we may never generate revenue from product sales. Furthermore, even if we do generate revenue from product sales, we may never again achieve or sustain profitability on a quarterly or annual basis. Our prior losses, combined with expected future losses, have had and will continue to have an adverse effect on our stockholders’ equity and working capital. Our failure to become and remain profitable could depress the market price of our Class A common stock and could impair our ability to raise capital, expand our business, diversify our product offerings, or continue our operations.
The probability of success for each of our product candidates and clinical programs and our ability to generate product revenue and become profitable depend upon a variety of factors, including the quality of the product candidate, clinical results, investment in the program, competition, manufacturing capability, commercial viability, and our collaborators’ ability to successfully execute our development and commercialization plans. We will also require additional capital through equity, debt, or royalty financings or collaboration arrangements in order to fund our operations and execute on our business plans, and there is no assurance that such financing or arrangements will be available to us on commercially reasonable terms or at all. For a description of the numerous risks and uncertainties associated with product development and raising additional capital, see “Risk Factors” included in our Annual Report on Form 10-K for the year ended December 31, 2021.
26
Financial Operations Overview
Revenue
Our revenue to date has been generated primarily from licensing fees received under our collaborative license agreements and reimbursements for expenses. We currently have no approved products and have not generated any revenue from the sale of products to date. In the future, we may generate revenue from product sales, royalties on product sales, reimbursements for collaboration services under our current collaboration agreements, or license fees, milestones, or upfront payments if we enter into any new collaborations or license agreements. We expect that our future revenue will fluctuate from quarter to quarter for many reasons, including the uncertain timing and amount of any such payments and sales.
Our license and milestone revenue has been generated primarily from the Kyowa Kirin Agreement, the AbbVie License Agreement, and the Collaboration Agreement and consists of upfront payments and milestone payments. License revenue recorded with respect to the Kyowa Kirin Agreement, the AbbVie License Agreement, and the Collaboration Agreement consists solely of the recognition of deferred revenue. Under our revenue recognition policy, collaboration revenue associated with upfront, non-refundable license payments received under our license and collaboration agreements are deferred and recognized ratably over the expected term of the performance obligations under each agreement. Under the Reacquisition Agreement, we no longer have performance obligations under the AbbVie License Agreement and the Collaboration Agreement. Under the Kyowa Kirin Agreement, we only expect to recognize the deferred revenue through mid-2022.
On July 27, 2021, Kyowa Kirin submitted an NDA in Japan to the MHLW for bardoxolone for improvement of renal function in patients with Alport syndrome. Based on this submission, we earned a $5.0 million milestone payment, variable consideration previously considered constrained, under the Kyowa Kirin Agreement. As a result, we recorded $4.7 million in collaboration revenue, a cumulative catch-up for the portion of this milestone that was satisfied in prior periods, and $0.3 million in deferred revenue that will be recognized over the remaining performance obligation period, ending in June 2022.
Research and Development Expenses
The largest component of our total operating expenses has historically been our investment in research and development activities, including the clinical development of our product candidates. From our inception through September 30, 2021,March 31, 2022, we have incurred a total of $1,048.3$1,129.7 million in research and development expense, a majority of which relates to the development of bardoxolone and omaveloxolone. We expect our research and development expense to continue to increase in the future as we advance our product candidates through clinical trials and expand our product candidate portfolio. The process of conducting the necessary clinical research to obtain regulatory approval is costly and time-consuming, and we consider the active management and development of our clinical pipeline to be crucial to our long-term success. The actual probability of success for each product candidate and preclinical program may be affected by a variety of factors, including the safety and efficacy data for product candidates, investment in the program, competition, manufacturing capability, and commercial viability.
Research and development expenses include:
| • expenses incurred under agreements with clinical trial sites that conduct research and development activities on our behalf; • expenses incurred under contract research agreements and other agreements with third parties; • employee and consultant-related expenses, which include salaries, benefits, travel, and stock-based compensation; • laboratory and vendor expenses related to the execution of preclinical and non-clinical studies and clinical trials; • the cost of acquiring, developing, manufacturing, and distributing clinical trial materials; • the cost of development, scale up, and process validation activities to support product registration; and • facilities, depreciation, and other expenses, which include direct and allocated expenses for rent and maintenance of facilities, insurance, and other supply costs.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Research and development costs are expensed as incurred. Costs for certain development activities such as clinical trials are highly judgmental and are recognized based on an evaluation of the progress to completion of specific tasks using information and data provided to us by our vendors and our clinical sites.
27
We base our expense accruals related to clinical trials on our estimates of the services received and efforts expended pursuant to contracts with multiple research institutions and CROs that conduct and manage clinical trials on our behalf. The financial terms of these agreements vary from contract to contract and may result in uneven payment flows. Payments under some of these contracts depend on factors such as the successful enrollment of patients and the completion of clinical trial milestones. In accruing costs, we estimate the time period over which services will be performed and the level of effort to be expended in each period. If we do not identify costs that we have begun to incur or if we underestimate or overestimate the level of services performed or the costs of these services, our actual expenses could differ from our estimates.
To date, we have not experienced material changes in our estimates of accrued research and development expenses after a reporting period. However, due to the nature of estimates, we cannot assure you that we will not make changes to our estimates in the future as we become aware of additional information about the status or conduct of our clinical trials and other research activities.
Currently, Kyowa Kirin has allowed us to conduct clinical studies of bardoxolone in certain rare forms of kidney diseases in Japan and has reimbursed us the majority of the costs for our CARDINAL study in Japan. Kyowa Kirin is the in-country caretaker in our FALCON study in Japan and is payingwe are reimbursing Kyowa Kirin for the costs of a certain number of patients asin the in-country caretaker in our FALCON study in Japan.study.
The following table summarizes our research and development expenses incurred:incurred during the three months ended March 31:
|
| Three Months Ended |
|
| Nine Months Ended |
| ||||||||||||||||||
|
| September 30 |
|
| September 30 |
| ||||||||||||||||||
|
| 2021 |
|
| 2020 |
|
| 2021 |
|
| 2020 |
|
| 2022 |
|
| 2021 |
| ||||||
|
| (in thousands) |
|
| (in thousands) |
| ||||||||||||||||||
Bardoxolone |
| $ | 13,634 |
|
| $ | 14,113 |
|
| $ | 40,000 |
|
| $ | 37,765 |
|
| $ | 6,462 |
| $ | 11,386 |
| |
Omaveloxolone |
|
| 3,475 |
|
|
| 5,770 |
|
|
| 6,429 |
|
|
| 20,711 |
|
| 7,597 |
| 2,473 |
| |||
RTA 901 |
|
| 1,164 |
|
|
| 1,527 |
|
|
| 4,991 |
|
|
| 3,489 |
|
| 1,407 |
| 706 |
| |||
Other research and development expenses |
|
| 21,157 |
|
|
| 15,773 |
|
|
| 62,957 |
|
|
| 59,655 |
| ||||||||
Other research and development expenses (1) |
|
| 24,338 |
|
|
| 20,315 |
| ||||||||||||||||
Total research and development expenses |
| $ | 39,430 |
|
| $ | 37,183 |
|
| $ | 114,377 |
|
| $ | 121,620 |
|
| $ | 39,804 |
|
| $ | 34,880 |
|
(1) RTA 1701 expenses have been included in other research and development expenses due to development updates in the program.
The program-specific expenses summarized in the table above include costs that we directly allocate to our product candidates. Our other research and development expenses include research and development salaries, benefits, stock-based compensation and preclinical, research, and discovery costs, which we do not allocate on a program-specific basis.
General and Administrative Expenses
General and administrative expenses consist primarily of employee-related expenses for executive, operational, finance, legal, compliance, and human resource functions. Other general and administrative expenses include personnel expense, facility-related costs, professional fees, accounting and legal services, depreciation expense, other external services, and expenses associated with obtaining and maintaining our intellectual property rights.
We anticipate that our general and administrative expenses will increase in the future as we prepare forincrease our headcount to support our continued research and development and potential commercialization of our product candidates. We have also incurred, and anticipate incurring in the future, increased expenses associated with being a public company, including exchange listing and SEC requirements, director and officer insurance premiums, legal, audit and tax fees, compliance with the Sarbanes-Oxley Act, of 2002, regulatory compliance programs, and investor relations costs. Additionally, if and when we believe the first regulatory approval of one of our product candidates appears likely, we anticipate an increase in payroll and related expenses as a result of our preparation for commercial operations, especially for the sales and marketing of our product candidates.
Other Income (Expense), Net
Other income (expense) includes interest and gains earned on our cash and cash equivalents, interest expense on our Term Loans, amortization of debt issuance costs, imputed interest on long term payables, loss on extinguishment of debt, gain on termination of lease, foreign currency exchange gains and losses, gains and losses on sales of assets, and non-cash interest expense on liability related to the sale of future royalties.
28
Benefit from (Provision for) Taxes on Income
Benefit fromProvision for taxes on income consists of net loss, taxed at federal tax rates and adjusted for certain permanent differences. Realization of deferred tax assets is generally dependent upon future earnings by jurisdiction, of which the timing and amount are uncertain for the majority of our deferred tax assets, and valuation allowances are maintained against them. Changes in valuation allowances also affect the tax provision.
Results of Operations
Comparison of the Three Months Ended September 30,March 31, 2022 and 2021 and 2020 (unaudited)
The following table sets forth our results of operations for the three months ended September 30:March 31:
|
| 2021 |
|
| 2020 |
|
| Change $ |
|
| Change % |
|
| 2022 |
|
| 2021 |
|
| Change $ |
|
| Change % |
| ||||||||
|
| (in thousands, except for percentage data) |
|
| (in thousands, except for percentage data) |
| ||||||||||||||||||||||||||
Collaboration revenue |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| |||||||
License and milestone |
| $ | 5,529 |
|
| $ | 1,182 |
|
| $ | 4,347 |
|
|
| 368 |
|
| $ | 893 |
| $ | 795 |
| $ | 98 |
| 12 |
| ||||
Other revenue |
|
| 1,862 |
|
|
| 219 |
|
|
| 1,643 |
|
| ** |
|
|
| 21 |
|
|
| 149 |
|
|
| (128 | ) |
|
| (86 | ) | |
Total collaboration revenue |
|
| 7,391 |
|
|
| 1,401 |
|
|
| 5,990 |
|
|
| 428 |
|
| 914 |
| 944 |
| (30 | ) |
| (3 | ) | ||||||
Expenses |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| |||||||
Research and development |
|
| 39,430 |
|
|
| 37,183 |
|
|
| 2,247 |
|
|
| 6 |
|
| 39,804 |
| 34,880 |
| 4,924 |
| 14 |
| |||||||
General and administrative |
|
| 25,736 |
|
|
| 18,314 |
|
|
| 7,422 |
|
|
| 41 |
|
| 24,841 |
| 20,704 |
| 4,137 |
| 20 |
| |||||||
Depreciation |
|
| 320 |
|
|
| 289 |
|
|
| 31 |
|
|
| 11 |
|
|
| 308 |
|
|
| 274 |
|
|
| 34 |
|
|
| 12 |
|
Total expenses |
|
| 65,486 |
|
|
| 55,786 |
|
|
| 9,700 |
|
|
| 17 |
|
| 64,953 |
| 55,858 |
| 9,095 |
| 16 |
| |||||||
Other income (expense), net |
|
| (13,751 | ) |
|
| (11,164 | ) |
|
| (2,587 | ) |
|
| (23 | ) |
|
| (9,772 | ) |
|
| (12,556 | ) |
|
| 2,784 |
|
|
| 22 |
|
Loss before taxes on income |
|
| (71,846 | ) |
|
| (65,549 | ) |
|
| (6,297 | ) |
|
| (10 | ) |
| (73,811 | ) |
| (67,470 | ) |
| (6,341 | ) |
| (9 | ) | ||||
Benefit from taxes on income |
|
| — |
|
|
| 93 |
|
|
| (93 | ) |
|
| (100 | ) | ||||||||||||||||
Benefit from (provision for) taxes on income |
|
| (31 | ) |
|
| 15 |
|
|
| (46 | ) |
| ** |
| |||||||||||||||||
Net loss |
| $ | (71,846 | ) |
| $ | (65,456 | ) |
| $ | (6,390 | ) |
|
| (10 | ) |
| $ | (73,842 | ) |
| $ | (67,455 | ) |
| $ | (6,387 | ) |
|
| (9 | ) |
** Percentage not meaningful
Revenue
License and milestone revenue represented approximately 75%98% and 84% of total revenue for the three months ended September 30,March 31, 2022 and 2021, and 2020, respectively, and consisted of the recognition of Kyowa Kirin deferred revenue. The increase in licenseLicense and milestone revenue isincreased by 12% during the three months ended March 31, 2022, compared to the three months ended March 31, 2021, primarily due to the achievement of a regulatory milestone in July 2021, variable consideration previously considered constrained, under the Kyowa Kirin Agreement. As a result, we recorded $4.7 million in collaboration revenue, a cumulative catch-up for the portion of this milestone that was satisfied in prior periods.Agreement.
Other revenue increased duringwas immaterial for the three months ended September 30, 2021, compared to the three months ended September 30, 2020, primarily due to an increase in reimbursements of expenses from Kyowa Kirin for manufacturing expenses incurred. March 31, 2022, and 2021.
Expenses
The following table summarizes our expenses, including as a percentage of total expenses, for the three months ended September 30:March 31:
|
| 2021 |
|
| % of Total Expenses |
|
| 2020 |
|
| % of Total Expenses |
|
| 2022 |
|
| % of Total |
|
| 2021 |
|
| % of Total |
| ||||||||
|
| (in thousands, except for percentage data) |
|
| (in thousands, except for percentage data) |
| ||||||||||||||||||||||||||
Research and development |
| $ | 39,430 |
|
|
| 60 | % |
| $ | 37,183 |
|
|
| 66 | % |
| $ | 39,804 |
| 61 | % |
| $ | 34,880 |
| 62 | % | ||||
General and administrative |
|
| 25,736 |
|
|
| 39 | % |
|
| 18,314 |
|
|
| 33 | % |
| 24,841 |
| 38 | % |
| 20,704 |
| 37 | % | ||||||
Depreciation |
|
| 320 |
|
|
| 1 | % |
|
| 289 |
|
|
| 1 | % |
|
| 308 |
|
| 1 | % |
|
| 274 |
|
| 1 | % | ||
Total expenses |
| $ | 65,486 |
|
|
|
|
|
| $ | 55,786 |
|
|
|
|
|
| $ | 64,953 |
|
|
|
|
| $ | 55,858 |
|
|
|
| ||
29
Research and Development Expenses
Research and development expenses increased by $2.2$4.9 million, or 6%14%, for the three months ended September 30, 2021,March 31, 2022, compared to the three months ended September 30, 2020.March 31, 2021. The increase was primarily due to increased personnel and personnel-related costs to support the product development activities, offset by a decrease in spend related to manufacturing activities of omaveloxolone.activities.
Research and development expenses, as a percentage of total expenses, was 60%61% and 66%62% for the three months ended September 30,March 31, 2022 and 2021, and 2020, respectively. The decrease of 6% was due to the proportionately larger increase in general and administrative expenses, which was primarily due to increased commercial readiness activities.
General and Administrative Expenses
General and administrative expenses increased by $7.4 million, or 41%, for the three months ended September 30, 2021, compared to the three months ended September 30, 2020. The increase was primarily due to increased spend related to commercial readiness activities and personnel and personnel-related costs to support growth in our development activities.
General and administrative expenses, as a percentage of total expenses, was 39% and 33%, for the three months ended September 30, 2021 and 2020, respectively. The increase of 6%1% was due to the proportionately larger increase in general and administrative expenses, compared to research and development expenses.
Other Income (Expense), NetGeneral and Administrative Expenses
Other income (expense), netGeneral and administrative expenses increased by $2.6$4.1 million, or 20%, for the three months ended September 30, 2021,March 31, 2022, compared to the three months ended September 30, 2020.March 31, 2021. The increase was primarily due to an increase in non-cash interestrent expense on liability related to the sale of future royalties.
Benefit from Taxes on Income
Benefit from taxes on income was immaterial for the three months ended September 30, 2021 and 2020.
Comparison of the Nine Months Ended September 2021, and 2020 (unaudited)new headquarters building lease that commenced in December 2021.
The following table sets forth our results of operations for the nine months ended September 30:
|
| 2021 |
|
| 2020 |
|
| Change $ |
|
| Change % |
| ||||
|
| (in thousands, except for percentage data) |
| |||||||||||||
Collaboration revenue |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
License and milestone |
| $ | 7,127 |
|
| $ | 3,519 |
|
| $ | 3,608 |
|
|
| 103 |
|
Other revenue |
|
| 3,430 |
|
|
| 2,308 |
|
|
| 1,122 |
|
|
| 49 |
|
Total collaboration revenue |
|
| 10,557 |
|
|
| 5,827 |
|
|
| 4,730 |
|
|
| 81 |
|
Expenses |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Research and development |
|
| 114,377 |
|
|
| 121,620 |
|
|
| (7,243 | ) |
|
| (6 | ) |
General and administrative |
|
| 68,440 |
|
|
| 55,701 |
|
|
| 12,739 |
|
|
| 23 |
|
Depreciation |
|
| 880 |
|
|
| 851 |
|
|
| 29 |
|
|
| 3 |
|
Total expenses |
|
| 183,697 |
|
|
| 178,172 |
|
|
| 5,525 |
|
|
| 3 |
|
Other income (expense), net |
|
| (39,530 | ) |
|
| (31,967 | ) |
|
| (7,563 | ) |
|
| (24 | ) |
Loss before taxes on income |
|
| (212,670 | ) |
|
| (204,312 | ) |
|
| (8,358 | ) |
|
| (4 | ) |
Benefit from taxes on income |
|
| 669 |
|
|
| 22,336 |
|
|
| (21,667 | ) |
|
| (97 | ) |
Net loss |
| $ | (212,001 | ) |
| $ | (181,976 | ) |
| $ | (30,025 | ) |
|
| (16 | ) |
** Percentage not meaningful
Revenue
License and milestone revenue represented approximately 68% and 60% of total revenue for the nine months ended September 30, 2021 and 2020, respectively, and consisted of the recognition of Kyowa Kirin deferred revenue. The increase in license and milestone revenue is primarily due to the achievement of a regulatory milestone, variable consideration previously considered constrained, under the Kyowa Kirin Agreement. As a result, we recorded $4.7 million in collaboration revenue, a cumulative catch-up for the portion of this milestone that was satisfied in prior periods.
Other revenue increased in the nine months ended September 30, 2021, compared to the nine months ended September 30, 2020, primarily due to increase in reimbursements of expenses from Kyowa Kirin for manufacturing expenses incurred.
Expenses
The following table summarizes our expenses, as a percentage of total expenses, for the nine months ended September 30:
|
| 2021 |
|
| % of Total Expenses |
|
| 2020 |
|
| % of Total Expenses |
| ||||
|
| (in thousands, except for percentage data) |
| |||||||||||||
Research and development |
| $ | 114,377 |
|
|
| 62 | % |
| $ | 121,620 |
|
|
| 68 | % |
General and administrative |
|
| 68,440 |
|
|
| 37 | % |
|
| 55,701 |
|
|
| 31 | % |
Depreciation |
|
| 880 |
|
|
| 1 | % |
|
| 851 |
|
|
| 1 | % |
Total expenses |
| $ | 183,697 |
|
|
|
|
|
| $ | 178,172 |
|
|
|
|
|
Research and Development Expenses
Research and development expenses decreased by $7.2 million, or 6%, for the nine months ended September 30, 2021, compared to the nine months ended September 30, 2020. The decrease was primarily due to decreased manufacturing activities related to omaveloxolone, offset by increased clinical activities related to bardoxolone and RTA 901. The remaining changes included decreased stock-based compensation expense due to accelerated expense recognized during 2020, offset by an increase in personnel and personnel-related costs to support our product development activities.
Research and development expenses, as a percentage of total expenses, was 62% and 68% for the nine months ended September 30, 2021 and 2020, respectively. The decrease of 6% was due to the proportionately larger increase in general and administrative expenses, which was primarily due to commercial readiness activities.
General and Administrative Expenses
General and administrative expenses increased by $12.7 million, or 23%, for the nine months ended September 30, 2021, compared to the nine months ended September 30, 2020. The increase was primarily due to increased spend related to commercial readiness activities, personnel and personnel-related costs to support growth in our development activities, and insurance premiums.
General and administrative expenses, as a percentage of total expenses, was 37%38% and 31%37%, for the ninethree months ended September 30,March 31, 2022 and 2021, and 2020, respectively. The increase of 6%1% was due to the proportionately larger increase in general and administrative expenses, compared to research and development expenses.
Other Income (Expense), Net
Other income (expense), net increaseddecreased by $7.6$2.8 million for the ninethree months ended September 30, 2021,March 31, 2022, compared to the ninethree months ended September 30, 2020.March 31, 2021. The increasedecrease was primarily due to increaseda decrease in effective interest rate in non-cash interest expense on liability related to the sale of future royalties.
We periodically reassess the expected royalty payments under the Development Agreement, and to the extent such payment is greater or less than the initial estimate, we adjust the amortization. Based on our review in the current first quarter of 2022, we lowered our previous estimate of future sales for which royalties will be paid. Accordingly, we have prospectively adjusted and decreased interest income earned due torecognized lower market rates, offset by decreasednon-cash interest expense and loss on extinguishment of debt due toduring the payoff on our Term Loans in 2020.quarter ended March 31, 2022.
Benefit from (Provision for) Taxes on Income
Benefit from (Provision for) taxes on income decreased by $21.7 millionwas immaterial for the ninethree months ended September 30, 2021, compared to the nine months ended September 30, 2020, primarily due to a tax benefit recognized in 2020 related to a carryback claim associated with the CARES Act.March 31, 2022 and 2021.
30
Liquidity and Capital Resources
Since our inception, we have funded our operations primarily through collaboration and license agreements, the sale of preferred and common stock, secured loans, and the sale of future royalties.royalty interests, and secured loans. Through September 30, 2021,March 31, 2022, we have raised gross cash proceeds of $476.6 million through the sale of convertible preferred stock and $785.0 million from payments under license and collaboration agreements. We also obtained $1,222.1 million in net proceeds from our initial public offering, follow-on offerings, and the sale of our Class A common stock under the Purchase Agreement, and $299.0 million in net proceeds from the sale of future royalties under the Development Agreement. We have not generated any revenue from the sale of any products. As of September 30, 2021,March 31, 2022, we had available cash and cash equivalents of approximately $713.2$532.0 million. Our cash and cash equivalents are invested in accordance with our investment policy, primarily with a view to liquidity and capital preservation.
Cash Flows
The following table sets forth the primary sources and uses of cash for each of the ninethree months ended September 30:
|
| 2021 |
|
| 2020 |
| ||
|
| (in thousands) |
| |||||
|
|
|
| |||||
Net cash (used in) provided by: |
|
|
|
|
|
|
|
|
Operating activities |
| $ | (112,769 | ) |
| $ | (277,200 | ) |
Investing activities |
|
| (1,136 | ) |
|
| (539 | ) |
Financing activities |
|
| 8,967 |
|
|
| 191,678 |
|
Net change in cash and cash equivalents |
| $ | (104,938 | ) |
| $ | (86,061 | ) |
March 31:
|
| 2022 |
|
| 2021 |
| ||
|
| (in thousands) |
| |||||
|
|
|
| |||||
Net cash (used in) provided by: |
|
|
|
|
|
| ||
Operating activities |
| $ | (58,185 | ) |
| $ | (45,011 | ) |
Investing activities |
|
| (288 | ) |
|
| (193 | ) |
Financing activities |
|
| 194 |
|
|
| 4,678 |
|
Net change in cash and cash equivalents |
| $ | (58,279 | ) |
| $ | (40,526 | ) |
Operating Activities
Net cash used in operating activities was $112.8$58.2 million for the ninethree months ended September 30, 2021,March 31, 2022, consisting primarily of a net loss of $212.0$73.8 million adjusted for non-cash items including stock-based compensation expense of $41.6$15.4 million, non-cash interest expense on liability related to sale of future royalty of $34.3$9.9 million, depreciation, amortization of issuance costs, and imputed interest expense of $6.2 million, and a net decrease in operating assets and liabilities of $17.1 $10.0 million. The significant items in the change in operating assets that impacted our use of cash in operations include a decrease of $4.5 million in accounts payable due to timing of payments, and a decrease of $8.9 million in direct research and other current and long-term liabilities, primarily due to annual bonus payments.
Net cash used in operating activities was $45.0 million for the three months ended March 31, 2021, consisting primarily of a net loss of $67.5 million adjusted for non-cash items including stock-based compensation expense of $14.7 million, non-cash interest expense on liability related to the sale of future royalties of $10.9 million, depreciation, amortization of issuance costs, imputed interest expense of $2.0 million, and a net increase in operating assets and liabilities of $5.1 million. The significant items in the change in operating assets that impacted our use of cash in operations include a decrease of $22.2$9.3 million in income tax receivableaccrued direct research and other current and long-term liabilities primarily due to the receiptchange in timing of a CARES Act refund, a decreasebonus payments from December to March of $3.1 millionthe following year, which began with the December 2020 payments being delayed to March 2021, and to the termination of PAH-related studies and the completion of CARDINAL and MOXIe clinical trials, offset by an increase in accounts payable of $3.6 million due to timing of payments, and a decrease in deferred revenue of $2.1 million.payments.
Net cash used in operating activities was $277.2 million for the nine months ended September 30, 2020, consisting primarily of a net loss of $182.0 million adjusted for non-cash items including stock-based compensation expense of $45.7 million, loss on extinguishment of debt of $11.2 million, non-cash interest expense on liability related to the sale of future royalties of $11.1 million, depreciation and amortization expense of $6.7 million, and a net increase in operating assets and liabilities of $169.1 million. The significant items in the change in operating assets that impacted our use of cash in operations were an increase in income tax receivable of $22.2 million and a decrease in payable to collaborators of $150.0 million for a payment made on June 30, 2020 under the Reacquisition Agreement.
Investing Activities
Net cash used in investing activities consistedwas $0.3 million and $0.2 million for the three months ended March 31, 2022 and 2021, respectively, consisting of purchases of property and equipment. Net cash used in investing activities for the nine months ended September 30, 2021 were primarily related to lab equipment and leasehold improvements under the 2019 Lease Agreement.
Net cash used in investing activities for the nine months ended September 30, 2020, was not significant.Financing Activities
Financing Activities
Net cash provided by financing activities was $9.0$0.2 million and $4.7 million for the ninethree months ended September 30,March 31, 2022 and 2021, primarilyrespectively, consisting of stock options exercises.
Net cash provided by financing activities was $191.7 million for the nine months ended September 30, 2020, primarily due to $55.4 million and $293.6 million in funding received from the Purchase Agreement and Development Agreement with BXLS, respectively, and $9.9 million from options exercised, offset by $167.2 million to pay off our Term Loans.31
Operating Capital Requirements
To date, we have not generated any revenue from product sales. We do not know when or whether we will generate any revenue from product sales. We do not expect to generate significant revenue from product sales unless and until we obtain regulatory approval of and commercialize one or more of our current or future product candidates. We anticipate that we will continue to generate losses for the foreseeable future, and we expect the losses to increase as we continue the development of, and seek regulatory approvals for, our product candidates, and begin to commercialize any approved products. We are subject to all the risks related to the development and commercialization of novel therapeutics, including those described under the heading “Risk Factors” included in our most recent Annual Report on Form 10-K, and we may encounter unforeseen expenses, difficulties, complications, delays, and other unknown factors that may adversely affect our business. We continue to incur additional costs associated with operating as a public company. We anticipate that we will need substantial additional funding in connection with our continuing operations.
In October 2019, we entered into the 2019 Lease Agreement, relating to a new headquarter building lease of approximately 327,400 square feet of office and laboratory space located in Plano, Texas.
In July 2021, Kyowa Kirin announced the submission of an NDA in Japan for bardoxolone for improvement of renal function in patients with Alport syndrome. We earned a $5.0 million milestone related to this event that was received and began to be recognized in the third quarter of 2021.
In December 2020, we closed a follow-on underwritten public offering of 2,000,000 shares of our Class A common stock for gross proceeds of $281.7 million. Net proceeds to us from the offering were approximately $277.5 million, after deducting underwriting discounts and commissions and offering expenses.
In October 2020, we entered into a lease agreement with the owner of our headquarters and offices located in Plano, Texas, with lease terms extending through June 30, 2022 with an option to renew up to three months. We recorded approximately $4.8 million as a right-of-use asset and lease liability in October 2020.
In June 2020, we closed on the Development Agreement and Purchase Agreement, each dated June 10, 2020, under which certain BXLS entities paid us an aggregate of $350.0 million in exchange for future royalties on bardoxolone and an aggregate of 340,793 shares of our Class A common stock at $146.72 per share.
In June 2020, we paid off our Term Loans, which included payments for principal of $155.0 million, prepayment fees of $5.4 million, exit fees of $6.7 million, and accrued and unpaid interest of $1.0 million.
In March 2020, the United States enacted the CARES Act. Under its provisions, we recognized a tax benefit and receivable of $22.2 million associated with the ability to carryback an applicable prior year’s net operating losses to a preceding year to generate a refund.
In October 2019, we entered into the 2019 Lease Agreement, relating to the lease of approximately 327,400 square feet of office and laboratory space located in Plano, Texas.
|
|
|
|
|
|
|
|
In October 2019, we and AbbVie entered into the Reacquisition Agreement pursuant to which we reacquired the development, manufacturing, and commercialization rights concerning our proprietary Nrf2 activator product platform originally licensed to AbbVie in the AbbVie License Agreement and the Collaboration Agreement. In exchange for such rights, we will pay AbbVie $330.0 million, of which total payments of $250.0 million have been made as of September 30, 2021, with the remaining $80.0 million payable on November 30, 2021. We will also pay AbbVie an escalating, low single-digit royalty on worldwide net sales, on a product-by-product basis, of omaveloxolone and an identified list of certain next-generation Nrf2 activators.
Our longer term liquidity requirements will require us to raise additional capital, such as through additional equity, debt, or royalty financings or collaboration arrangements. Our future capital requirements will depend on many factors, including the receipt of milestones under our Kyowa Kirin Agreement and the timing of our expenditures related to clinical trials. We believe our existing cash and cash equivalents will be sufficient to enable us to fund our operations through mid-2024.the fourth quarter of 2024. However, we anticipate opportunistically raising additional capital before that time through equity offerings, collaboration or license agreements, additional debt financings, or royalty financings in order to maintain adequate capital reserves. In addition, we may choose to raise additional capital at any time for the further development of our existing product candidates and may also need to raise additional funds sooner to pursue other development activities related to additional product candidates.
Decisions about the timing or nature of any financing will be based on, among other things, our perception of our liquidity and of the market opportunity to raise equity, debt, or royalty financing. Additional securities may include common stock, preferred stock, or debt securities. We may explore strategic collaborations or license arrangements for any of our product candidates. If we do explore any arrangements, there can be no assurance that any agreement will be reached, and we may determine to cease exploring a potential transaction for any or all of the assets at any time. If an agreement is reached, there can be no assurance that any such transaction would provide us with a material amount of additional capital resources.resources.
32
Until we can generate a sufficient amount of revenue from our product candidates, if ever, we expect to finance future cash needs through public or private equity or debt offerings, loans, royalty financings, and collaboration or license transactions. The outbreak of COVID-19 has caused significant disruption ofRecent and continued volatility in global financial markets which may reduce our ability to access capital, which could negatively affect our liquidity. Additional capital may not be available on reasonable terms, if at all. If we are unable to raise additional capital in sufficient amounts or on terms acceptable to us, we may have to significantly delay, scale back, or discontinue the development or commercialization of one or more of our product candidates. If we raise additional funds through the issuance of additional equity or debt securities, it could result in dilution to our existing stockholders or increased fixed payment obligations, and any such securities may have rights senior to those of our common stock. If we incur indebtedness or obtain royalty financing, we could become subject to covenants that would restrict our operations and potentially impair our competitiveness, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell, or license intellectual property rights, and other operating restrictions that could adversely affect our ability to conduct our business, and any such debt or royalty financing could be secured by some or all of our assets. Any of these events could significantly harm our business, financial condition, and prospects.prospects. For a description of the numerous risks and uncertainties associated with product development and raising additional capital, see “Risk Factors” included in our Annual Report on Form 10-K for the year ended December 31, 2020.2021.
Our forecast of the period through which our financial resources will be adequate to support our operations is a forward-looking statement and involves risks and uncertainties, and actual results could vary as a result of a number of factors. We have based this estimate on assumptions that may prove to be wrong, and we could utilize our available capital resources sooner than we currently expect. Our future funding requirements, both near- and long-term, will depend on many factors, including, but not limited to:
| • the scope, rate of progress, results, and cost of our clinical trials, preclinical testing, and other activities related to the development of our product candidates; • the number and characteristics of product candidates that we pursue; • the costs of development efforts for our product candidates that are not subject to reimbursement from our collaborators; • the costs necessary to obtain regulatory approvals, if any, for our product candidates in the United States and other jurisdictions, and the costs of post-marketing studies that could be required by regulatory authorities in jurisdictions where approval is obtained; • the continuation of our existing collaboration with Kyowa Kirin and entry into new collaborations and the receipt of any collaboration payments; • the time and unreimbursed costs necessary to commercialize products in territories in which our product candidates are approved for sale; • the revenue from any future sales of our products or for which we are entitled to a profit share, royalties, and milestones; • the level of reimbursement or third-party payor pricing available to our products; • the costs of obtaining third-party commercial supplies of our products, if any, manufactured in accordance with regulatory requirements; • the costs associated with any potential loss or corruption of our information or data in a cyberattack on our computer systems or those of our suppliers, vendors, or collaborators who store or transmit our data; • the costs associated with being a public company; • any additional costs we incur, or delays in clinical trials we experience, associated with the COVID-19 pandemic; and • the costs we incur in the filing, prosecution, maintenance, and defense of our patent portfolio and other intellectual property rights.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
If we cannot expand our operations or otherwise capitalize on our business opportunities because we lack sufficient capital, our business, financial condition, and results of operations could be materially adversely affected.
33
Contractual Obligations and Commitments
We have various contractual obligations and other commitments that require payments at certain specified periods. The following table summarizes our contractual obligations and commitments as of September 30, 2021March 31, 2022 (unaudited):
|
| Payments due by period |
| |||||||||||||||||
|
| Less than 1 year |
|
| 1 to 3 years |
|
| 4 to 5 years |
|
| 6 years and beyond |
|
| Total |
| |||||
|
| (unaudited, in thousands) |
| |||||||||||||||||
Operating lease obligations(1) |
| $ | 3,002 |
|
| $ | 16,605 |
|
| $ | 27,563 |
|
| $ | 186,757 |
|
| $ | 233,927 |
|
Payable to collaborators |
|
| 80,000 |
|
|
| — |
|
|
| — |
|
|
| — |
|
|
| 80,000 |
|
Total contractual obligations |
| $ | 83,002 |
|
| $ | 16,605 |
|
| $ | 27,563 |
|
| $ | 186,757 |
|
| $ | 313,927 |
|
(1) Above table assumes one year rent abatement is applied beginning in June 2023 following FDA approval of omaveloxolone.
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The terms of the Development Agreement require us to pay potential future royalty payments based on product development success. The above table excludes such obligations as the amount and timing of such obligations are unknown or uncertain, which are further described in Note 5, 4, Liability Related to Sale of Future Royalties, to Consolidated Financial Statements contained in this Quarterly Report on Form 10-Q.
Clinical Trials
As of September 30, 2021,March 31, 2022, we have several on-going clinical trials in various stages. Under agreements with various CROs and clinical trial sites, we incur expenses related to clinical trials of our product candidates and potential other clinical candidates. The timing and amounts of these disbursements are contingent upon the achievement of certain milestones, patient enrollment, and services rendered or as expenses are incurred by the CROs or clinical trial sites. Therefore, we cannot estimate the potential timing and amount of these payments, and they have been excluded from the table above.
Critical Accounting Policies and Significant Judgments and Estimates
Our management’s discussion and analysis of our financial condition and results of operations are based on our consolidated financial statements, which have been prepared in accordance with U.S. GAAP. The preparation of these financial statements requires us to make estimates and judgments that affect the reported amounts of assets, liabilities, and expenses and the disclosure of contingent assets and liabilities in our financial statements. On an ongoing basis, we evaluate our estimates and judgments, including those related to revenue recognition, accrued research and development expenses, income taxes, and stock-based compensation. We base our estimates on historical experience, known trends and events, and various other factors that we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying
values of assets and liabilities that are not readily apparent from other sources. Actual results may differ from these estimates under different assumptions or conditions.
Our significant accounting policies are described in Note 2 of Part I, Item 1 of this Quarterly Report on Form 10-Q and in Part I, Item 7, “Critical Accounting Policies and Significant Judgments and Estimates” in our Annual Report on Form 10-K. There have been no changes to our critical accounting policies and estimates since our Annual Report on Form 10-K for the year ended December 31, 2020.2021.
Off-Balance Sheet Arrangements
Since our inception, we have not had any relationships with unconsolidated organizations or financial partnerships, such as structured finance or special purpose entities, that would have been established for the purpose of facilitating off-balance sheet arrangements, and we have not engaged in any other off-balance sheet arrangements, as defined in the rules and regulations of the SEC.
Recent Accounting Pronouncements
For a discussion of recent accounting pronouncements, please see Note 2, Summary of Significant Accounting Policies, of Notes to Consolidated Financial Statements contained in this Quarterly Report on Form 10-Q.
34
Item 3. Quantitative and Qualitative Disclosures About Market Risk.
We are exposed to market risks in the ordinary course of our business. These market risks are principally limited to interest rate fluctuations. We had cash and cash equivalents of $713.2$532.0 million at September 30, 2021,March 31, 2022, consisting primarily of funds in operating cash accounts. The primary objective of our investment activities is to preserve principal and liquidity while maximizing income without significantly increasing risk. We do not enter into investments for trading or speculative purposes. Due to the short-term nature of our investment portfolio, we do not believe an immediate increase of 100 basis points in interest rates would have a material effect on the fair market value of our portfolio, and accordingly we do not expect a sudden change in market interest rates to affect materially our operating results or cash flows.
We contract with research, development, and manufacturing organizations and investigational sites globally. Generally, these contracts are denominated in United States dollars. However, we may be subject to fluctuations in foreign currency rates in connection with agreements not denominated in United States dollars. We do not hedge our foreign currency exchange rate risk.
Item 4. Controls and Procedures.
Evaluation of Disclosure Controls and Procedures
Our management, with the participation of our Chief Executive Officer and Chief Financial Officer, evaluated the effectiveness of our disclosure controls and procedures as of September 30, 2021.March 31, 2022. The term “disclosure controls and procedures,” as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934 (Exchange Act), means controls and other procedures of a company that are designed to ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange Act is recorded, processed, summarized, and reported, within the time periods specified in the SEC’s rules and forms. Disclosure controls and procedures include, without limitation, controls and procedures designed to ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange Act is accumulated and communicated to the company’s management, including its principal executive and principal financial officers, or persons performing similar functions, as appropriate to allow timely decisions regarding required disclosure. Management recognizes that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving their objectives, and management necessarily applies its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Based on the evaluation of our disclosure controls and
procedures as of September 30, 2021,March 31, 2022, our Chief Executive Officer and Chief Financial Officer concluded that, as of such date, our disclosure controls and procedures were effective at the reasonable assurance level.
Changes in Internal Control Over Financial Reporting
There have been no changes in our internal control over financial reporting, as such term is defined in Rules 13a-15(f) and 15d-15(f) promulgated under the Exchange Act, during the ninethree months ended September 30, 2021,March 31, 2022, that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.
35
PART II — OTHER INFORMATION
Item 1. Legal Proceedings.
For a discussion of material pending legal proceedings, please read Note 11,10, Commitments and Contingencies – Litigation, to our condensed consolidated financial statements included in Part I, Item I, “Financial Statements (Unaudited),” of this Quarterly Report on Form 10-Q, which is incorporated into this item by reference.
Item 1A. Risk Factors.
In addition to other information set forth in this Quarterly Report on Form 10-Q, you should carefully consider the risk factors and other cautionary statements described under the heading “Risk Factors” included in our Annual Report on Form 10-K for the year ended December 31, 2020,2021, which could materially affect our businesses, financial condition, or future results. Additional risks and uncertainties currently unknown to us, or that we currently deem to be immaterial, also may materially adversely affect our business, financial condition, or future results. There have been no material changes in our risk factors from those described in the Annual Report on Form 10-K for the year ended December 31, 2020.2021.
Item 2. Unregistered Sales of Equity Securities and Use of Proceeds.
None.
Item 3. Defaults Upon Senior Securities.
None.
Item 4. Mine Safety Disclosures.
None.
Item 5. Other Information.
None.
36
Item 6. Exhibits.
Exhibit Number |
| Description |
3.1 | ||
3.2 | ||
| ||
| ||
31.1* |
| |
31.2* |
| |
32.1** |
| |
32.2** |
| |
101.INS* |
| Inline XBRL Instance Document - The cover page interactive data file does not appear in the interactive data file because its XBRL tags are embedded within the inline XBRL document |
101.SCH* | Inline XBRL Taxonomy Extension Schema Document | |
101.CAL* | Inline XBRL Taxonomy Extension Calculation Linkbase Document | |
101.DEF* | Inline XBRL Taxonomy Extension Definition Linkbase Document | |
101.LAB* | Inline XBRL Taxonomy Extension Label Linkbase Document | |
101.PRE* | Inline XBRL Taxonomy Extension Presentation Linkbase Document | |
104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
|
|
|
|
* Filed herewith. ** Furnished herewith. # Information in this exhibit identified by three asterisks [***] is confidential and has been omitted pursuant to Item 601(b)(10)(iv) of Regulation S-K because it is not material and is the type of information that the Company customarily treats as private or confidential. An unredacted copy of this exhibit will be furnished to the Securities and Exchange Commission on a supplemental basis upon request. 37 SIGNATURES
|
|
|
|
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.
Date: | REATA PHARMACEUTICALS, INC. | ||
|
| ||
| By: | /s/ J. Warren Huff | |
| Name: | J. Warren Huff | |
| Title: | Chief Executive Officer | |
| By: | /s/ Manmeet S. Soni | |
| Name: | Manmeet S. Soni | |
| Title: | Chief Operating Officer, Chief Financial Officer, and |
3938