Nisha Hirani, M.D., Zacks Small-Cap Research (8 clicks)
Research analyst, biotech, small-cap, micro-cap
Profile| Send Message| Follow (28 followers)
Performance
Tenax Therapeutics: Evaluating Levosimendan In Septic Shock
Oct. 13, 2015 11:37 AM ET | About: Tenax Therapeutics, Inc. (TENX)
Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. (More...)
Summary
In addition to evaluating levosimendan in a Phase 3 trial in cardiac surgery patients, Tenax is also studying levosimendan in septic shock.
The Phase 2 LeoPARDS trial is designed to determine if levosimendan reduces the incidence and severity of acute organ dysfunction in adult patients with septic shock.
Septic shock is a life-threatening condition that causes blood pressure to fall to dangerously low levels, resulting in compromised blood flow to vital organs.
Septic shock represents an area of high unmet medical need, as it is associated with high mortality, morbidity and critical care costs.
Tenax Therapeutics, Inc. (NASDAQ:TENX) is a development-stage specialty pharmaceutical company focused on the identification, development, and commercialization of products for critical care patients. In our opinion, the Tenax development portfolio includes a novel product candidate, levosimendan, that has the potential to address various critical care conditions with high unmet medical need.
As a reminder, our article from September 25, 2015 provides a background on Tenax's lead candidate, levosimendan, for the treatment of low cardiac output syndrome (LCOS). We view levosimendan as a relatively de-risked clinical development opportunity for LCOS due to the usage of the drug in over 1 million patients outside of the North America.
For the purpose of this article, we would like to offer some background on sepsis and an overview of levosimendan in septic shock as Tenax is currently evaluating the drug candidate in a Phase 2 trial for this indication.
Background on Sepsis
Septic shock is a life-threatening condition that causes blood pressure to fall to dangerously low levels, resulting in compromised blood flow to vital organs, such as the liver and kidney. It is an overwhelming immune response to an infection, typically bacterial, but also to those caused by fungi, parasites, or viruses. The infection itself is not the cause of the symptoms associated with sepsis. Instead, it is the vast amounts of pro-inflammatory cytokines released by the immune system that causes symptoms such as fever, elevated heart rate, hyperventilation, altered mental state, and low blood pressure.
During the course of an infection, the immune system is responsible for recognizing invading pathogens. Part of this process involves the release of cytokines to stimulate inflammation and other immune system cells to aid in the fight against the invading pathogen. For reasons that are not well understood, these immune cells sometimes release more cytokines than are necessary. This results in making blood vessels slack and permeable, thereby reducing blood pressure and allowing the fluid component of blood to seep into surrounding tissues. The blood component is left behind and forms small clots in tiny blood vessels, which decreases the amount of oxygen that can reach major organs. This is the danger point, as patients who have progressed this far have reached the later stages of the disease. At this point, confusion sets in, the heart begins beating erratically, the kidneys and other major organs begin to fail, and the patient's blood pressure cannot be raised. Thus far, there is no cure for sepsis, other than palliative care, typically in an intensive care unit. Patients meet the criteria for septic shock if they have sepsis with persistent hypotension and perfusion abnormalities despite adequate fluid resuscitation.
(click to enlarge)
The condition of sepsis has been known for an extremely long time; however, it has always been difficult to define and diagnose. For the past century, sepsis has been defined as the systemic host response to an infection (Riedemann et al., 2003). Sepsis was originally thought to be associated with the presence of bacteria in the bloodstream (bacteremia). However, many patients present with symptoms of sepsis and do not have an active bacterial infection in their blood. Based on the lack of a consensus definition, in 1991, a conference was convened to focus on a way to clinically define sepsis. The outcome of this meeting was a joint publication by the American College of Chest Physicians and the Society of Critical Care Medicine with consensus definitions of sepsis (ACCP/SCCM, 1992). Importantly, this publication introduced the term systemic inflammatory response syndrome (SIRS), for which no definable presence of bacterial infection is required. In addition, the terms "severe sepsis" and "septic shock" were introduced to differentiate the different stages of sepsis.
(click to enlarge)
Incidence of Sepsis
The consensus definitions of sepsis (above) have allowed for epidemiological studies to be conducted on the incidence of sepsis, which occurs in approximately 2% of all hospitalizations in developed countries. There has been more attention paid to the incidence of severe sepsis and septic shock, with published reports showing an incidence of severe sepsis of 50 to 100 cases per 100,000 people in the population (Danai et al., 2005). Trends indicate that there is a growing incidence of severe sepsis in the United States and there are over 1.5 million U.S. inpatient hospital stays associated with a primary or secondary diagnosis for septicemia annually (below) (AHRQ, 1993-2009).
(click to enlarge)
It is estimated that there are 1 million cases of sepsis in the United States each year (Martin, 2012; NCHS/CDC, 2011). Interestingly, significant longitudinal changes in the incidence of sepsis have been noted over the past few decades, with the incidence of sepsis in hospitalized patients growing by 8.7% per year (Martin et al., 2003). This increase in the incidence of sepsis is not just confined to the U.S., but has also been noted in the U.K. and Australia (Harrison et al., 2006; Finfer et al., 2004). Furthermore, management estimates that the annual incidence of septic shock in the U.S. is over 450,000 patients per year based on ICD-9 coding data. Average mortality rates are often reported to be 20-30% range; however, mortality rates can exceed 50% in some high-risk patients (Leligdowicz et al., 2014). Septic shock is not only associated with high mortality, but also high morbidity and hospital and critical care costs.
There are a number of patient-specific factors that affect the incidence of sepsis and risk factors that predispose certain individuals to developing sepsis. A variety of comorbid conditions will significantly increase an individual's risk of developing sepsis, including HIV, cancer, and diabetes (Danai et al., 2006). Race, ethnicity, and gender have also been shown to result in differential risks for developing sepsis, with males and non-Caucasians having the highest risk (Martin et al., 2003).
Treatment and Management of Sepsis
Prompt diagnosis of sepsis is critical for a positive outcome. A 2006 study reported that for a septic patient, the chance of dying goes up by 7.6% for every hour that goes by without treatment (Kumar et al., 2006). Effective sepsis treatment relies on the use of intravenous fluids, antibiotics, drainage of infected sites, and proper support for organ dysfunction.
Early goal-directed therapy is an approach to the management of severe sepsis during the first six hours after diagnosis. This method was first introduced by Dr. Emanuel Rivers in 2001 and relies on intensive monitoring and aggressive management of perioperative hemodynamics (Rivers et al., 2001). When applied to the treatment of sepsis, the approach involves adjustments in cardiac preload, afterload, and contractility. What this means is that intravenous fluids are titrated in response to heart rate, blood pressure, and urine output. Different types of fluids have been shown to be more advantageous than others, with crystalloid solutions and albumin performing better at reducing mortality in comparison to hydroxyethyl starch (Rochwerg et al., 2014).
In 2013, revised international guidelines for the treatment of sepsis were published (Dellinger et al., 2013). The guidelines call for diagnostic tests to be performed within the first three hours of diagnosis, including measurement of serum lactate and blood cultures, before initiating antibacterial treatment, so long as it does not delay antimicrobial treatment for more than one hour. For every one hour delay in the use of antibiotics, a patient's risk of dying increases by 6% (Soong et al., 2012). Additional means of treatment include the use of antihypotensive agents to raise the patient's blood pressure and tracheal intubation if the patient's oxygen level remains low.
Sepsis patients are typically considered to be high risk for morbid complications and death. A rough percentage of patients who ultimately die from sepsis are as follows, broken down by the consensus definitions:
Sepsis: 10-20%
Severe sepsis: 20-50%
Septic shock: 40-80%
Thankfully, the overall mortality rate for those with sepsis has been declining, with the rate falling from 30% of sepsis patients in the 1980s and 1990s to 20% of patients within the past decade (Martin et al., 2003). Regardless, the number of individuals who die each year from sepsis (~200,000 in 2007) is similar to the number who die from acute myocardial infarction. Sepsis is the 10th leading cause of death in the United States. In the United States, sepsis accounts for more deaths than the number of deaths from AIDS, breast cancer, and prostate cancer, combined. We view septic shock as an area of high unmet medical need and believe that if Tenax can demonstrate a clinical improvement in mortality, morbidity, and length of hospital/ICU stay, levosimendan could be adopted as a standard of care therapy for treating life-threatening septic shock.
Scientific Evidence that Supports Levosimendan in Septic Shock
A recent meta-analysis (Zangrillo et al., 2015) examined levosimendan in regards to the reduction of mortality in severe sepsis and septic shock patients as compared to standard inotropic drugs, such as dobutamine. The meta-analysis examined randomized trials in sepsis and septic shock, and analyzed seven studies that included a total of 246 patients. It was found that levosimendan was associated with significantly reduced mortality (59/125 or 47%) vs. standard inotropic therapy (74/121 or 61%).
Levosimendan's proposed mechanism of action suggests the potential of the drug to be evaluated in cases of septic shock. The observed vasodilatory effects of levosimendan could lead to potential cardiac and hemodynamic improvements in these cases with a potential positive impact on microvascular blood flow and protection of mitochondria from oxidative injury and broader organ protection effects by the opening of potassium channels.
Levosimendan in Septic Shock: Phase 2b LeoPARDS trial
In August 2014, Tenax announced a collaboration with the Imperial College London to provide an additional $0.5 million funding for the ongoing Phase 2 LeoPARDS trial ("Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis") in the UK evaluating levosimendan in sepsis. The trial is being managed by NIHR, and led by the Imperial College London, with Tenax helping to accelerate the enrollment process. The trial is designed to evaluate if levosimendan reduces the incidence and severity of acute organ dysfunction in adult patients with septic shock, the effect of the drug on organ function, in addition to evaluation of the drug's safety profile in sepsis. The trial was initiated in the first quarter 2014, and as of October 8, 2015, 445 out of 516 patients are enrolled. Management believes that enrollment will be complete before the end of calendar year 2015 with data expected in calendar year 2016.
LeoPARDS is a randomized, double-blind, placebo-controlled multi-center trial based on previous smaller studies that have evaluated levosimendan as it pertains to sepsis. Adult patients with suspected or confirmed infection and 2 or more SIRS (systemic inflammatory response syndrome) criteria [fever or hypothermia: temp >38°C/100.4°F or <36°C/96.8°F; tachycardia: heart rate >90bpm; tachypnea or need for mechanical ventilation: respiratory rate >20 or PaCO2 <32mmHg; leukocyte count (>12,000cells/mm3, <4000cells/mm3, or >10% immature band forms)] who are dependent on vasopressors to maintain their blood pressure are eligible for LeoPARDS enrollment. Once eligibility criteria are met there is a 24-hour window for recruitment to the trial, and enrolled patients are randomized to receive either levosimendan (0.05 to 0.20μg/kg/min) or placebo for 24 hours in addition to the standard of care.
The primary outcome measure will be the mean SOFA (sequential organ failure assessment) score on ICU after randomization between treatment groups. Secondary outcomes that are also being evaluated include oxygen delivery (ScvO2) and cardiac output; incidence and duration of renal failure (AKIN criteria); serum bilirubin; time to extubation; 28-day, hospital and three- and six-month survival; ICU and hospital length of stay, and ICU-free days; duration of renal replacement therapy; and days free from catecholamine therapy.
LeoPARDS data are expected in early calendar year 2016. The data collected from the LeoPards trial will help guide Tenax regarding the future plans for U.S. development. We believe that positive LeoPARDs data could support an NDA filing. As an aside, in November 2014, Tenax had a meeting with the FDA regarding the development of levosimendan in septic shock and received guidance on how LeoPARDS data might be analyzed to support regulatory filing. As per management, the Imperial College London recently submitted the statistical analysis plan (SAP), with an addendum from Tenax, to the FDA. The SAP included additional secondary endpoints around clinically meaningful measurements. We believed that this submission was going to occur by the end of the third quarter 2015, and so it is nice to see that its submission earlier than expected. We look forward to receiving more updates on the clinical and regulatory path forward in the near future.
On September 10, 2015, Tenax announced a partnership with Sepsis Alliance, a North American nonprofit patient advocacy organization that promotes sepsis awareness and treatment. As part of the partnership, Tenax will be the second Lead Sponsor of Sepsis Alliance's Sepsis Challenge National Events program during the remainder of 2015 and 2016, and was a sponsor at the Sepsis Heroes event on September 17, 2015 in New York City.
Conclusion
We believe the primary driver of value for Tenax is levosimendan in the cardiac surgical/LCOS setting. That being said, we are interested in seeing if levosimendan will prove to have efficacy as it relates to septic shock.
As mentioned in our previous article from September 2015, we continue to believe that levosimendan is a relatively de-risked clinical development opportunity for the indication of Low Cardiac Output Syndrome (LCOS). If levosimendan proves to be successful in the cardiac surgery market, and if the company makes further progress with additional indications, such as septic shock, we believe there is the possibility for significant upside to the Tenax story. Currently, we believe Tenax is worth $10 per share which is solely based on levosimendan in LCOS and cardiac surgery. Our model has yet to include any contribution from levosimendan in septic shock.
We view septic shock as an area of unmet clinical need, as the condition is often associated with high mortality, morbidity, and critical care costs. If all goes according to the timeline, the Phase 2 LeoPARDS trial should be fully enrolled by the end of calendar year 2015. As of now, data are expected in early calendar year 2016, and we look forward to reviewing the data once available. If the data are positive, we believe that it could support an NDA regulatory filing. Tenax plans to file an NDA in late 2017, and management believes that it may not be required to conduct a Phase 3 trial if the LeoPARDS data are positive. At this point, we are taking a wait and see approach in regards to levosimendan in septic shock. We look forward to learning more about levosimendan in septic shock in the near future.
Co-authored by: David Bautz, PhD
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Editor's Note: This article covers one or more stocks trading at less than $1 per share and/or with less than a $100 million market cap. Please be aware of the risks associated with these stocks.
