Reata's Bits and Pieces

Reata is attempting to develop two plant triterpenoid derivatives, bardoxolone (RTA-402, CDDO-Me) and omaveloxone (RTA-408), for a broad variety of diseases. These two derivatives are follow-on candidates from an earlier failed candidate, RTA-401, also referred to as CDDO. These derivatives tend to be worked on in an effort to improve the weak anti-inflammatory properties of the parent triterpenoids. The general consensus is these triterpenoids disrupt the interaction between Keap1 and Nrf2, releasing Nrf2 to upregulate a variety of anti-inflammatory / anti-oxidant genes including thioredoxin, glutathione reductase and superoxide dismutase.

The interaction of CDDO and its derivatives with its target proteins is mediated by relatively nonspecific targeting of exposed thiol groups on proteins. In effect, this isn’t a specific targeting mechanism, and there is even data to suggest that thiol-containing antioxidants (such as glutathione) can alter the binding selectivity of CDDO and its derivatives. Further underlying this poor selectivity is the relatively long list of “target” proteins for CDDO and its derivatives. In addition to Keap1/Nrf2, there are data demonstrating effects on the NF-kB regulatory mechanism (via interference with IK-kB), PPAR, JAK/STAT, TGF, PTEN and mTOR. Rather than providing confidence these derivatives will have an effect, the large number of targets lessens enthusiasm that the drugs have a concerted impact on disease.


2. Clinical Trials

2.1. Phase I Trials

RTA-401 (CDDO)

This parent compound was tried in two phase 1 trials, one aimed at AML and the other enrolling those with solid tumours. In the AML trial, there were no responses. This was no different in the solid tumour trial, as no anti-tumour activity was observed. However, the trial was closed at 7 accrued patients when the 6th and 7th enrollees both developed pulmonary emboli. These two events were in addition to a pulmonary embolism in patient 5 and a deep vein thrombosis event in patient 4. In the publication, all events were deemed related to the study drug. In effect, RT-401 could not be safely dosed in an oncology indication and was abandoned.


RTA-402 (Bardoxolone, CDDO-Me)

This compound is a methylated version of the parent CDDO triterpenoid. This drug was used in a 44 patient phase I trial enrolling patients with solid tumours or lymphomas. Unsurprisingly, and similar to the parent compound, the drug had little to no meaningful efficacy. Two responses were observed, one complete response in a mantle cell lymphoma patient and a partial response in an anaplastic thyroid tumour patient. Despite these two responses, it should be noted there is no follow-up trial in either patient population, suggesting that the company was unimpressed with the trial outcome.

Nonetheless, this trial has the fortuitous observation that patients on drug had an increase in estimated glomerular filtration rate via measurements of serum creatinine. This, along with the disappointing anti-tumour activity, appears to have led to Reata moving the drug to a chronic kidney disease (CKD) population.


RTA-408 (Omaveloxone)

There was a phase I in melanoma called REVEAL. The trial enrolled 11 patients, but no data have been disclosed.


2.2. Phase II Trials

2.2.1. RTA - 402 / Bardoxolone


RTA-402 - CKD / Type 2 Diabetes

The phase II trials of RTA-402 were focused on Stage 3/4 CKD and type 2 diabetes patients. The results of these are not relevant given the results from the Phase III Beacon trial described later. However, the important point to remember is that these trials did not reveal the safety signal observed in the phase 3 Beacon trial.

RTA-402 - Pulmonary Hypertension

Arguably this is the most well developed, active program at this time. They believe the myriad of preclinical mechanisms on display by bardoxolone, including anti-reactive oxygen species (ROS), anti-inflammation and anti-fibrotic, will all contribute to improving performance in pulmonary hypertension (PH) patients. To this end, they’re presenting data mostly pertaining to the connective tissue disease (CTD) classification of pulmonary arterial hypertension (PAH), which is part of WHO group I of PH patients. The various cohorts of the LARIAT trial are as described below, and particular emphasis is on the CTD-PAH group that forms the basis of the now enrolling CATALYST phase 2/3 trial.


The cohorts from the LARIAT trial are generally as below:

Cohorts 1 and 2

These two cohorts are basically identical expect that Cohort 1 is enrolling PAH patients (encompassing both idiopathic or CTD subgroups of PAH) that have pre-entry 6 meter walk distance (6MWD) of 150m>x>450 and a less sick cohort that enrolled those with entry 6 MWD of >450m (Cohort 2).

The baseline enrollment characteristics of the patients enrolled into Cohorts 1 and 2 are below. Of note, and as detailed in their 2015 annual presentation, the baseline 6MWD in the 2.5 mg group of cohort 1 was significantly higher than in the placebo group (despite not being indicated in this table). Also, patients are allowed to be on background therapies.

The above tables show the enrollment for cohorts 1 and 2 plus the efficacy results from cohort 1. None of the individual dose groups were significant versus placebo, and the only favourable comparison was if the data were pooled. However, two important observations about this pooled comparison:

1. There is absolutely no dose response, and if anything it’s inverted. They note this is likely due to baseline patient BMI, with heavier patients in the 2.5 mg group showing no benefit whereas BMI < 30 mg/m2 showed an ostensible benefit (as shown below). This comparison is high suspect, and likely not even worth seriously considering as the number of patients falls to 3 in most of the groups. More likely, this simply reflects the fact this dose group had higher 6MWD at entry.

2. They’ve omitted data from the bardoxolone 10 mg group. The “Baseline Characteristics” table above describing the dose levels and patients enrolled in Cohorts 1 and 2 clearly show that the bardoxolone 10 mg arm in Cohort 1 had 6 patients. However, when the 6MWD comparisons are being made, two patients are omitted and the arm falls to 4 patients only. It’s reasonable to be suspicious about the reason for this omission. There was no explanation in the 2015 Year end report or any follow up data releases.


The CTD-PAH patients across doses were pooled and demonstrated the below change in 6MWD over baseline. Although the change is statistically significant when compared to each patient’s baseline, the difference is not significant (p=0.13) when placebo-adjusted.


They followed up the analysis of Cohort 1 with a brief look at Cohort 2, which are the patients with >450m 6MWD at baseline. Only 6 patients are available, and only one is classified CTD-PAH. These 6 patients from Cohort 2 all received 5 mg bardoxolone, and were compared to the 6 patients (3 CTD-PAH, 3 idiopathic) receiving 5 mg bardoxolone from Cohort 1. It is unclear what this analysis is meant to show. The problems are:

1. The patients are a mix of CTD-PAH and idiopathic patients. In that regard, disease etiology is mixed and is in different proportions between groups (50% CTD-PAH in Cohort 1 vs 17% in Cohort 2).

2. Importantly, Cohort 2 is the healthier arm (>450m baseline 6MWD) but shows identical change in 6MWD when compared to the sicker cohort. So in addition to a lack of dose response for the drug from Cohort 1, the drug seems to provide a larger % gain in 6MWD over baseline for the sicker patients than the healthier ones. That’s extremely unlikely.


Synopsis of Data from Cohorts 1 and 2:

  • No statistically significant increase in placebo-adjusted 6MWD.
  • No dose-response relationship evident for the drug.
  • There are a total of 7 CTD-PAH patients enrolled in the drug arms of Cohorts 1 and 2, but going forward, only 6 of these patients are used in pooled analyses. The 1 CTD-PAH patient in Cohort 2 is omitted.
  • There was on SAE of pneumonia in Cohort 2. It was judged as possibly drug related by the investigator but the company disagrees.
  • 16 patients were enrolled in Cohort 2, but going forward company has dropped the 20 mg arm of this Cohort due to nausea. Any CTD-PAH patients in this dose group appear to have been excluded from any future analyses, and there is no clear indication of the outcomes for the 8 patients (16 enrolled - 6 bard - 2 placebo = 8).


Cohort 3

This cohort is enrolling PAH patients with baseline 6MWD > 150m. Cohort 3a is focused on CTD-PAH, whereas Cohort 3b is looking at the other PAH etiologies. Eligible patients can be receiving zero to two disease-specific PAH background therapies. Patients in the treatment group are titrated from 5 mg to 10 mg doses based on tolerability. The available data need to be imputed from a recent press release, as the data aren’t explicitly broken down. However, in SEC filings the company has disclosed that 24 total patients have been enrolled in this cohort as of YE2015.

As of October, 2016, the company notes that a total of 22 CTD-PAH patients have been enrolled in Lariat’s Cohorts 1, 2 and 3a, with 15 receiving bardoxolone and 7 on placebo. In the press release, they note 6 of the bardoxolone patients were from Cohort 1, meaning that the 2 placebo patients also carried over. It is therefore unclear where the other 9 bardoxolone patients come from, whether from Cohort 2 or 3a. They’ve only indicated 1 CTD-PAH patient enrolled in Cohort 2, and that person was excluded from the pooled analyses of Cohort 1 and 2. It’s unclear why that patients would be included now but not before. That leaves the balance of the 9 remaining patients to be from Cohort 3a.

Nonetheless, their Cohort 1+2+3 pooled analysis showed a change in 6MWD that was not statistically significant when placebo-adjusted. They subsequently (and retroactively) removed patients with moderate to severe anemia, resulting in 1 bardoxolone and 2 placebo patients being omitted from the analysis, leaving 14 drug and 5 placebo patients. They note that this comparison is statistically significant when placebo corrected. But it’s clear from the table below that these exclusions were motivated with the outcome in mind:


Notably, the exclusions disproportionately decreased the performance of the placebo group while improving the performance of the drug arm. This is especially strange considering these patients with anemia are “excluded… because treatment with iron supplementation or erythropoietin post-randomization can affect 6MWD values independent of study drug effect.” If anything, treatment with iron supplementation or erythropoietin should improve the 6MWD. It is notable that after exclusion, the change from baseline 6MWD for the placebo group decreased, as would be expected if you remove patients that likely improved their 6MWD due to the effects of erythropoietin. Yet, strangely, the drug group’s 6MWD improves when excluding the patient that received iron supplementation or erythropoietin.


Synopsis of Data from Cohort 3:

  • No clear presentation of the Cohort 3 data is made by the company, and rather they opt for a pooled analysis that obscures the data from the cohort. This is historically a bad sign.
  • The post-hoc exclusion of patients with moderate to severe anemia is clearly a ploy to make the data look better than they are.


Cohort 4

The fourth cohort began enrolling in September 2015, consisting of PH-ILD (pulmonary hypertension-interstitial lung disease, WHO group 3) patients. There are no data available from this cohort, although their filings indicate 7 patients enrolled as of YE2015. More concerning, there was one SAE leading to death. The company’s explanation speaks for itself:

We previously reported that a serious adverse event, or SAE, involving a patient death had occurred in cohort 4a and that the investigator had initially reported it as possibly related to study drug. The investigator has since changed his evaluation to unlikely related. In addition, the Protocol Safety Review Committee that oversees safety for the LARIAT trial concluded that the SAE was unlikely treatment-related.


RTA-402 - Chronic Kidney Disease caused by Alpert Syndrome

The company has recently announced a phase 2 trial in patients with Alpert syndrome. These patients are at heavy risk for developing end-stage renal disease, and Reata believes bardoxolone can increase estimate GFR in these patients in order to delay progression. There are no data available, and given their phase 3 experience with bardoxolone, this is a high risk trial.


2.2.2. RTA-408 / Omaveloxone

Omaveloxone is a close structural analog of bardoxolone methyl that was developed to improve tissue distribution. It basically has the same anti-inflammation / anti-oxidant method of action. No solid clinical data are available from this drug, other than these cursory descriptions found in their filings:


RTA-408 in Friedreich’s Ataxia

This is a condition that inflicts progressive nerve damage due to the inheritance of mutations in the frataxin protein. Absence of frataxin can increase reactive oxygen specifies generated by the mitochondria. RTA-408’s putative anti-oxidant method of action is supposedly the draw here. Their filings note that they’ve enrolled 8 patients as of YE2015 in their MOXIe study. No data are provided.

RTA-408 in Mitochondrial Myopathies

These are a series of disorders that compromise mitochondria function and can result in progressive muscle weakness. Their purported method of action is an increase in ATP turnover caused by RTA-408 that will ostensibly cover the deficit from the mitochondria in this condition. Their filings note they’ve enrolled 8 patients as of YE2015 in their MOTOR trial. No efficacy data are provided, but notably one SAE has been observed. As before, the explanations in their filings aren’t fully convincing:

An SAE of tachycardia was submitted by a clinical site and further reviewed by the chair of the DSMB, who is a cardiologist. The DSMB chair concluded that the event should not be filed as an SAE as it was likely a previously undiagnosed and benign tachycardia, which is common in this patient population.

RTA-408 in Melanoma

The company is currently running a phase 1b trial of RTA-408 in combination with nivolumab in melanoma called DISCOVER. There are no data available from this trial. It is a follow-up to a phase I trial of monotherapy RTA-408 in melanoma. Given the high competition in this area, this program is unlikely to be meaningful.

RTA-408 in Cataract Surgery

This drug was also tried in the GUARD trial, testing a topical formulation of omaveloxone in 307 patients undergoing cataract surgery. There was no efficacy demonstrated.


2.3. Phase III Trial


RTA-402 - CKD / Type 2 Diabetes

Their only phase III trial to data has been for the use of bardoxolone to delay end-stage renal disease or death from cardiovascular disease in stage 4 CKD and type 2 diabetes. This trial by de Zeeuw randomized 2185 people to placebo or 20 mg of bardoxolone. The impetus of this trial was the observation that bardoxolone increased eGFR, and this would presumably benefit patients with CKD. They did a series of phase 2 trials and eventually ran a phase 3 trial, Beacon. The trial was terminated early due to an increase of cardiovascular events in the bardoxolone arm. 

The company states the increase in heart failure events was due to the susceptibility of patients to retain fluid. In effect, the drug was observed to increase sodium retention, increased blood pressure, decreased body weight and also increased estimated GFR as expected. The company completed retrospective studies of the data and concluded patients with a prior history of heart failure and baseline BNP > 200 pg/mL were the “at-risk” group for fluid retention leading to SAEs. In effect, they claim that the drug can be safely administered if such patients are excluded from future trials. There is currently a trial in Japan by collaborator Kyowa Hakko Kirin that may answer this question, but no data are available.


3. Conclusion

This looks like a classic case of a biotech that knows it has difficult drug candidates. Their lead drug, bardoxolone, has significant safety concerns. In the Beacon trial, the company notes they’ve identified the patient population at-risk for bardoxolone’s AEs. However, this explanation is tenuous on multiple counts, and presents additional program risk:


1) They’ve retrospectively determined this “at-risk” population, and it may be related but not capture the root cause of the bardoxolone-induced increase in heart failure. In effect, there is no guarantee that they’ve completely removed future AE risk from their trials. 

2) Their thesis that bardoxolone increases fluid retention is valid, but puts the pulmonary hypertension program in jeopardy. Pulmonary hypertension patients are, almost by definition, susceptible to fluid retention. Therefore, any subsequent program in PH that enrolls large numbers of patients will be heavily at risk of showing increased SAEs.

3) The data analyses from their phase 2 trials in PH are evidently cherry-picked. Omission of patients without explanation, retrospective omission of patients at risk of moderate / severe anemia, lack of disclosure of full data sets, and almost uniform lack of statistical significance despite the cherry-picked datasets suggests there is little efficacy to be seen. In sum, as of YE2015, their Lariat phase 2 trial has enrolled 85 total patients across cohorts, but the company is most recently making claims on a 19 patient subgroup (14 drug, 5 placebo) of this population. Nobody hides efficacy.

4) A role of anti-oxidants in lung diseases is not clear. In the PANTHER trial, the anti-oxidant n-acetylcysteine had no physiological or clinical benefit in combination therapy for idiopathic pulmonary fibrosis. This population is being tested in Cohort 4 of the Lariat trial, and suggests the anti-oxidant method of action of bardoxolone is unlikely to provide meaningful benefit.

5) There is no clear path to approval. Although the company has started their phase 3 “Catalyst” trial in pulmonary hypertension, their SEC filings are notably shifty about what this trial will allow. The company explicitly notes that:

“During our interaction with the FDA in October 2015, the FDA noted that CATALYST, together with the Phase 2 data from our LARIAT trial in PAH patients and prior clinical trials with bardoxolone methyl, would provide adequate data for a New Drug Application, or NDA, review of the safety profile of bardoxolone methyl.”

This language is present in multiple SEC filings, and is clear that these data will not be sufficient to demonstrate efficacy of the drug for NDA purposes. In effect, the path to approval in pulmonary hypertension is unclear.

6) Perhaps the quickest path to approval for bardoxolone is in Alpert syndrome. But this has the concern of once again testing the drug in a patient population that is notably at risk for end-stage renal disease, overlapping the population that prematurely terminated their large phase 3 trial, Beacon. Although the drug does increase eGFR, it is impossible to ignore the AE profile and there is no clear indication that their retrospective identification of patients at risk for volume retention is, in fact, valid prospectively.


As for the follow-on drug omaveloxone / RTA-408, its near-identical method of action suggests that it won’t salvage the pipeline. Further, although the company is more than happy to provide small n data for bardoxolone, they’ve not released any data (other than AEs) for RTA-408. This suggests the drug is having little meaningful effect to date. Further indirect proof of this is from the September, 2016 disclosure that AbbVie has opted out of co-developing omaveloxone. Although AbbVie reserves the right to opt back in at a future date, leaving the drug behind at phase I suggests there is little efficacy to be observed.


Finally, these derivatives have had a long list of adverse events that have caused a drug to be abandoned (RTA-401) and a large phase 3 trial to stop prematurely (RTA-402). It seems clear the class has safety issues.