New Drug on horizon: Tedizolid by Trius Therapeutics

-Shruti Desai, PharmD Candidate
Trius Therapeutics (NASDAQ: TSRX) is a biopharmaceutical company focused on the developing innovative antibiotics for life-threatening infections. The current drug named Tedizolid  phosphate is in its late clinical stage.

Tedizolid phosphate is a 2nd generation oxazolidinone being developed for the treatment of serious gram-positive infections, including those caused by MRSA. There is also a strong growth of MRSA treatment days. In the day and age of cost-containment, the lower number of hospital days is highly preferred.

Tedizolid phosphate is a novel prodrug that is cleaved in the blood stream to the active compound from Tedizolid phosphate to Tedizolid.  As a second generation oxazolidinone, tedizolid phosphate is chemically different from, and designed for improved potency, resistance and spectrum of activity over, the first generation oxazolidinones such as linezolid (Zyvox). There is only one approved first generation oxazolidinone, linezolid, which is currently the leading branded antibiotic for serious gram-positive infections, with reported worldwide sales of $1.3 billion in 2011.

A recent journal article has clearly demonstrated that there is an active emergence of linezolid-resistance Staphylococcus aureus. Linezolid remains active against >98% of Staphylococcus, with resistance identified in 0.05% of Staphylococcus aureus and 1.4% of coagulase-negative Staphylococcus (CoNS). The emergence of linezolid resistance in Staphylococcus poses significant challenges to the clinical treatment of infections caused by these organisms, and in particular CoNS (Gu B. J Antimicrob Chemother. 2012).

Tedizolid can be given IV or orally for the treatment of serious gram-positive bacterial infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Tedizolid phosphate has successfully completed a Phase 3 trial in patients with acute bacterial skin and skin structure infections (ABSSSI).

Acute bacterial skin and skin structure infections (ABSSI) infections involve deeper tissue or require surgical intervention or are associated with a significant underlying disease (e.g., diabetes or systemic immunosuppression) that complicates response to therapy. A variety of pathogens may be identified in ABSSSI but the two most common Gram-positive pathogens are Staphylococcus aureus and Streptococcus pyogenes. The significant increase in the incidence of MRSA in community as well as hospital acquired infections has resulted in a need for therapy of ABSSSI that is effective against MRSA.

Tedizolid phosphate offers a number of important potential advantages over linezolid, including greater potency, once daily dosing, predictable drug exposure, a shorter course of therapy, in vivo bactericidal (i.e., bacterial killing) activity, lower frequency of resistance, activity against linezolid-resistant bacterial strains and an improved safety profile. TSRX is planning to develop this drug to treat multiple clinical indications, such as infections of the lung and blood, such as, hospital acquired pneumonia (HAP), ventilator acquired pneumonia (VAP) and bacteremia.

Some Advantages of Tedizolid

Greater Potency

• Shorter Dosing Regimen and Once Daily Dosing.
• Tedizolid Phosphate is administered once daily for six days for the treatment of cSSSI (now termed ABSSSI), as compared to twice daily for 10 to 14 days for linezolid. This tremendously help with patient convenience  

Activity against Key Gram-Positive Drug-Resistant Strains and Select Atypical and Gram-Negative Bacteria.

• Tedizolid phosphate is also active against gram-negative bacterium Legionella and strains of the atypical bacterium Chlamydia, and thus may have utility in treating lower respiratory tract infections involving these bacteria.

Favorable and Predictable Pharmacokinetics

• There is little patient-to-patient variability in the concentration of tedizolid phosphate in blood, as compared to linezolid. As a result, we expect that tedizolid phosphate will have more predictable drug exposure which may lead to a more uniform efficacy and safety profile across different patients when compared to linezolid.

Fewer Drug-Drug Interactions

• Unlike linezolid, tedizolid phosphate has not been shown to inhibit the monoamine oxidase system which mediates the metabolism of tyramine, SSRI's and vasoconstrictors.

Tedizolid phosphate may provide MDs with a safe antibiotic for the treatment of serious gram-positive infections that is more potent and more convenient than linezolid and other currently available alternatives.

1st Pivotal Phase 3 trial (ESTABLISH-1):

Trius has announced positive top-line results from our first Phase 3 clinical trial in acute bacterial skin and skin structure infections, or ABSSSI.  The study was looking at Tedizolid  vs. Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infections. (ABSSSI). This was a randomized, double-blind, double dummy, multicenter Phase 3 study of oral Tedizolid 200 mg once daily for 6 days versus oral Zyvox (linezolid) 600 mg every 12 hours for 10 days for the treatment of ABSSSI in adults.

Primary objective: To determine the noninferiority in the early clinical response rate (see the image below)

Patients with systemic signs of infection diagnosed with acute bacterial skin and skin structure infection (ABSSSI) and patient diagnosed with Cellulitis/ erysipelas, major cutaneous abscess, or wound infections were included in the study. Patients with uncomplicated skin infections, severe sepsis or septic shock and ABSSSI solely due to gram-negative pathogens were excluded to clearly assess the primary endpoint. 

Results:

In the Intent to Treat (ITT) analysis set, tedizolid achieved the primary objective of non-inferiority (10% non-inferiority margin) to linezolid in the primary and secondary efficacy endpoints.  The primary endpoint was cessation of lesion spread and resolustion of fever at 48-72hours after initiation of study drug.

Top-Line Data from the TR701-112 Trial

CE = Clinically Evaluable

Both tedizolid and linezolid were generally well tolerated with comparable overall safety profiles, with drug-related treatment emergent adverse events (TEAE) reported in 24.2% of tedizolid patients versus 31.0% of linezolid treated patients.

*Statistically Significant (p=0.004).

In terms of adverse events, they were higher in linezolid group (31.0%) vs tedizolid (24.2%). Tedizolid showed improved GI tolerability and nausea, vomiting, and diarrhea were statistically significantly in favor of tedizolid (16.3%vs 24.4%, p<0.05)

Tedizolid also had less of a detrimental effect on platelet count (-9.2% for tedizolid vs. -14.9% for linezolid), including percent consider abnormally low (<75% LLN) at 2.3% for tedizolid vs. 4.9% for linezolid.

The data suggest that tedizolid also had less of a detrimental effect liver function. ALT above the normal limit was 27.7% for tedizolid at EOT versus 33.0% for linezolid. 

The data from this trial was presented at 52nd Annual Interscience Conference on Antimicrobial agents and Chemotherapy (ICAAC) in September 2012.

2nd Phase 3 trial (ESTABLISH-2)

TSRX is currently running a 2nd Phase 3 trial which expects to report top-line data in early 2013. This is also a randomized, double-blind, double-dummy, multicenter, global Phase 3 study of IV to oral TR-701 FA 200 mg once daily for 6 days versus IV to oral Zyvox® (linezolid) 600 mg every 12 hours for 10 days for the treatment of ABSSSI in adults. Patients are to start treatment with at least 2 IV doses and may receive IV therapy for the entire treatment duration. The 113 study is the first clinical trial conducted in collaboration with Bayer HealthCare and will recruit patients in North and South America, Europe, Australia, New Zealand, and South Africa.

The primary endpoint for the 2nd phase 3 pivotal trial is to determine the noninferiority (NI) in the early clinical response rate of intravenous (IV) to oral 6 day TR-701 free acid (FA) compared with that of IV to oral 10-day linezolid treatment at 48-72 hours after the first infusion of study drug in the intent-to-treat (ITT) analysis set in patients with acute bacterial skin and skin structure infections (ABSSSI). 

In this trial, patients requiring IV antibiotic therapy and with systemic signs of infection diagnosed with ABSSSI and diagnosed with Cellulitis/ erysipelas, major cutaneous abscess, or wound infections were included. Patients with uncomplicated skin infections, severe sepsis or septic shock and ABSSSI solely due to gram-negative pathogens were excluded. As you can the inclusion and exclusion criteria are similar to 1st pivotal phase 3 trial. With this in mind it the chances of this trial being successful are very high. 

Trius reported 3rd quarter which ended on September 30, 2012, with approximately $70.9 million in cash and investments. During the first nine months of the year, Trius burned approximately $46.7 million in cash from operating and investing activities. At the same time, TSRX has offset this by raising proceeds totaling $48.9 million through financing activities. On August 31, 2012, the company participated in a common stock purchase agreement (CSPA) with Terrapin Opportunity, L.P. to sell Terrapin up to $25 million in registered shares of common stock over a 24-month period. On January 17, 2013, TSRX announced a public offering of 6.3M shares of its common stock $4.75 per share. The gross proceeds to Trius from this offering are expected to be approximately $29,925,000 million. The offering is expected to close on or about January 24, 2013. Certainly, no one likes dilution but TSRX is being conservative and keeping enough cash on hand for its potential NDA submission and other clinical development program.

I strongly believe that commercial success for tedizolid in the U.S. to have peak sales in the $350M - $400M range (with positive ESTABLISH-2 results). The current market share is dominated by vancomycin, linezolid and off-label daptomycin. In US the combined market share of linezolid, daptomycin, cefteroline, and vancomycin is estimated to be $2 billion. Use of Cubicin and Zyvox is up 40%-50% over the past 12 months versus a near 50% decrease in use for generic vancomycin. Now there are many concerns about Vancomycin resistant S. auerus (VRSA). If TSRX is able to get the indications into pneumonia and bacteremia, it would provide tremendous success to the company. 

TSRX has already a commercialization deal with Bayer in Asia market. This deal would give TSRX $25million upfront with 25% of the development cost and another $69million in development milestones.  In US, they may plan to launch the drug themselves and license to a major pharmaceutical company in Europe which would also bring in additional licensing revenues. The news about Europe market will certainly lift the stock prices. While the price of TSRX may not show any strength since the results are expected in 2013 but this allows for a great opportunity for a strong run up into the 2nd PhaseIII results.

With all that said, TSRX has a great potential to run up to $6 range as we near February before ESTABLISH-2 data. 

Price Target: $7

Disclosure: Long TSRX

Resources: Trius Therapeutics Investor Presentation and Corporate presentations, PubMed, Bloomberg, MicroMedex drug database, Clinicaltrial.gov