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).
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| VisualDx - ABSSI |
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.
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 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.
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.
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 see 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.
On August 6, 2012, $TSRX reported that they have $84M in cash and R&D expense for
the three month (April, May and June) was $16.4M so when we extrapolate that or
multiply that by 4 it gives us a rough estimation of their burn rate compared
to their net cash that they have. $16M x 4 = $64M. Since they have enough cash on their hand
going into the top-line Phase 3 trial results, I believe the possibility of
offering is low. The share price has gone up 8%-10% in month of September 2012.
They recently reported data on Broad-spectrum Antibiotic at 52nd Annual ICAAC
Meeting. With the release of the abstracts and various presentations at
academic centers and financial firms, TSRX is creating a lot of buzz in the
investor community, medical community as well as retail investors. The upcoming
Phase 3 (ESTABLISH-2) trial will certainly add on to the anticipation and
excitement to the company. I also feel strong about the management and their
expertise and seeing great potential in TSRX. Once again, I am looking forward
to the announcement by TSRX soon about the potential completion PR or more
update on their Phase 3 trial result.
Resources: Trius Therapeutics Investor Presentation and Corporate presentations, PubMed, Bloomberg, MicroMedex drug database, Clinicaltrial.gov
Disclosure: May initiate a position in next 72hours
