Our investigational drug candidate, veverimer, is a novel, non-absorbed polymer that is designed to treat metabolic acidosis by binding hydrochloric acid in the gastrointestinal tract and removing it from the body through excretion in the feces, thereby decreasing the total amount of acid in the body and increasing serum bicarbonate. Veverimer is administered orally as a suspension in water.
Veverimer is specifically designed to combine high capacity and high selectivity for binding and removing hydrochloric acid. Importantly, veverimer does not deliver sodium or other counterions, potentially allowing for chronic treatment of metabolic acidosis in patients with chronic kidney disease (CKD) and common comorbidities such as hypertension, cardiovascular disease, heart failure or edema, if approved.
Our New Drug Application (NDA) for veverimer is currently under review by the US Food and Drug Administration (FDA) through the Accelerated Approval Program for the treatment of metabolic acidosis and slowing of kidney disease progression in patients with metabolic acidosis associated with CKD. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) goal date of August 22, 2020.* As part of the Accelerated Approval Program, we are currently conducting a confirmatory postmarketing trial, known as the VALOR-CKD trial, or TRCA-303, to evaluate the efficacy and safety of veverimer in delaying CKD progression in subjects with metabolic acidosis.
Our clinical development program, which formed the basis of our NDA submission, included a pivotal Phase 3, double-blind, placebo-controlled, 12-week clinical trial of veverimer (TRCA-301 trial), followed by a 40-week extension trial (TRCA-301E trial). We also conducted a double-blind, randomized, placebo-controlled Phase 1/2 clinical trial (TRCA-101 trial).
We successfully completed a pivotal Phase 3, double-blind, placebo-controlled, 12-week clinical trial of veverimer in 217 patients with CKD and metabolic acidosis (TRCA-301) and a blinded, placebo-controlled, 40-week extension trial (TRCA-301E) that enrolled 196 subjects who completed the 12-week treatment period in the TRCA-301 trial. Results from each of these clinical trials was published in The Lancet in March and June 2019, respectively.
The TRCA-301 trial evaluated the safety, tolerability and efficacy of veverimer. The primary and secondary efficacy endpoints of the TRCA-301 trial were based on the change in serum bicarbonate from baseline to the end of treatment (12 weeks) in veverimer-treated subjects compared to placebo. The trial met these endpoints with high statistical significance (p < 0.0001). The trial also showed significant improvement versus placebo (p = 0.0122) in patient reported physical functioning and a trend towards improvement on an objective measure of muscle function, which were pre-specified exploratory endpoints. veverimer was well-tolerated in the TRCA-301 trial. Both the veverimer and placebo groups had low discontinuation rates and low rates of treatment-related adverse events. Results from this trial were published in The Lancet in March 2019 in an article titled “Veverimer versus Placebo in Patients with Metabolic Acidosis Associated with Chronic Kidney Disease: A Multicentre, Randomised, Double-blind, Controlled, Phase 3 Trial,” by Wesson et al.”
Eligible subjects that completed the TRCA-301 trial were invited to participate in the TRCA-301E extension trial. One hundred ninety-six of the 208 subjects who completed the 12-week treatment period in our pivotal TRCA-301 trial agreed and were eligible to continue into our TRCA-301E extension trial. Based on the initial topline data analyses, the TRCA-301E extension trial met its primary and all secondary endpoints. We believe the trial provides evidence of long-term safety and tolerability of veverimer and that the sustained increase in serum bicarbonate led to improvements in multiple clinical outcomes that matter to both patients and physicians.
The primary endpoint of the TRCA-301E trial was the assessment of the long-term safety profile of veverimer versus placebo. The results demonstrated that fewer subjects on veverimer than on placebo discontinued the 40-week treatment period prematurely (2.6% versus 9.8%, respectively). The incidence of serious adverse events was 1.8% for subjects in the veverimer group and 4.9% for subjects in the placebo group, and none were assessed to be related to study drug by the trial investigator, Medical Monitor or Drug Safety and Pharmacovigilance Team. The only adverse event with a between-group frequency difference of >5% was headache, which was more common in the placebo group. Gastrointestinal adverse events occurred in 21.4% of subjects in the veverimer group and in 25.9% of subjects in the placebo group.
The secondary endpoints of the TRCA-301E trial assessed the durability of effect of veverimer, both on serum bicarbonate levels and on measures of physical function, over the 52-week treatment period for those subjects who participated in the TRCA-301E trial. All were met with high statistical significance.
The durability of the effect of veverimer was assessed based on differences in the treatment groups, in favor of veverimer, in the change in serum bicarbonate from baseline to Week 52 (p=0.0002) as well as in the proportion of subjects achieving a change from baseline to Week 52 in serum bicarbonate of at least 4 milliequivalents per liter (mEq/L) or a serum bicarbonate level in the normal range of 22 to 29 mEq/L (p=0.0015).
The effect of 1-year of treatment with veverimer on physical function was also significantly greater than with placebo, both as measured using self-reported responses to the physical functioning subpart of the Kidney Disease and Quality of Life Short Form survey (p<0.0001) as well as by using a repeated chair stand test (p<0.0001). This KDQOL-SF survey is a questionnaire for kidney disease patients designed to assess health-related quality of life based on physical function during activities of daily living. Subjects in the trial responded to 10 questions, each with a value of 10 points (100 total points). After 1 year of treatment, there was no improvement in the placebo group, whose mean score remained at their baseline score of 56 points. Patients on veverimer had a more than 11-point improvement, on average, moving from a mean score of 53 points to 64 points. This improvement exceeded the 3 to 5-point change cited in the literature as the minimal clinically important difference for responses to this physical function survey (Clement et al., 2009; Collister et al., 2016, Leaf et al., 2009, Samsa et al., 1999).
In the Repeated Chair Stand Test, subjects were asked to stand up and sit down five times as quickly as possible, and the time for these five repetitions was recorded. At week 52, the placebo group improvement was 1.4 seconds compared to the veverimer-treated group, which experienced a 4.3 second improvement in the test, exceeding the minimal clinically important difference of 1.7 seconds cited in the literature (Jones et al., 2013).
We believe the results from the KDQOL Physical Function Survey and the Repeated Chair Stand Test both provide evidence of improvement in physical function and these effects exceed the minimally clinically important difference thresholds reported in the scientific literature. We also believe these results are consistent with the basic pathophysiology of metabolic acidosis and that amelioration of the deleterious effects of metabolic acidosis on physical function could provide another way to slow progression to renal replacement therapy.
A prespecified analysis included the time to death (all-cause mortality), dialysis/kidney transplant (renal replacement therapy) or a ≥50% decline in estimated glomerular filtration rate (eGFR), taken together DD50. Over the combined (TRCA-301 and TRCA-301E trials) 52-week treatment period, the time to DD50 was prolonged in the veverimer group compared to the placebo group, with an annualized DD50 incidence rate, calculated as 100 times the number of events divided by the total person-years, of 4.2% in the veverimer group vs 12.0% in the placebo group (p = 0.0224). In aggregate, the 52-week treatment data with veverimer provides evidence of clinical benefit beyond the increase in serum bicarbonate. Results from this trial were published in The Lancet in June 2019 in an article titled “A multicentre, randomised, blinded, placebo-controlled, 40-week extension study to assess the long-term safety and efficacy of veverimer for the treatment of metabolic acidosis in chronic kidney disease” by Wesson et al.
Previously, we completed a successful 135-subject, double-blind, randomized, placebo-controlled Phase 1/2 trial (TRCA-101), and the results from this trial were published in an article, titled “Randomized, Controlled Trial of veverimer to Increase Serum Bicarbonate in Patients with CKD,” by Bushinsky et al., in the Clinical Journal of the American Society of Nephrology (CJASN).
*Please review our Forward Looking Statements for information regarding the risks and uncertainties related to these statements.