Dalbavancin For The Treatment of Gram Positive Osteoarticular Infections

Dalbavancin, currently FDA approved for the treatment of skin and soft tissue infections
(SSTI), is a lipoglycopedptide with bactericidal activity in vitro against Staphylococcus
aureus, including MRSA and VISA strains, and Streptococcus pyogenes. Its bactericidal action
results primarily from inhibition of cell-wall biosynthesis, specifically the prevention of
N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG)-peptide subunits incorporation into
the peptidoglycan matrix. Dalbavancin alters bacterial-cell-membrane permeability and RNA
synthesis. It is highly protein bound, primarily to albumin, with a half-life of 346 hours.
Approximately 33% of unchanged drug is excreted in the urine, 20% via feces and 12% as the
minor metabolite, hydroxyl-dalbavancin. There is minimal potential for drug-drug
interactions; it is not a substrate, inducer or inhibitor of hepatic CYP450 isoenzymes and
the administration of CYP450 substrates, inhibitors or inducers does not affect its clearance
rate. In SSTI trials, Dalbavancin was demonstrated to be non-inferior to vancomycin and
linezolid.

Prosthetic joint infections (PJI) are an emerging health problem. Although the incidence of
these infections is historically low (approximately 0.5%-1.0of implants), because of the
rapid increase in the number of hip, knee and other joint implants, the absolute number of
cases of infection is increasing. In 2010, 332,000 hip joints and 719,000 knee joints were
implanted. This alone conservatively translates to 5,000-10,000 cases, with an economic
impact of $1 billion. Management of PJI is particularly challenging because long term
antibiotic therapy in most cases is accompanied by removal of the prosthesis and
re-implantation.

For long term antimicrobial administration, current standard of care requires a peripherally
inserted central catheter (PICC) or other indwelling intravascular catheter, and
daily/multiple daily infusions. There is substantial cost of maintaining the intravascular
access, drugs, home health care and monitoring, as well as the infection risk of the chronic
indwelling line which is being accessed frequently. There is a clear need for alternative
care models to the current approach. Dalbavancin, because of its activity profile against
Gram-positive organisms and its pharmacokinetics which would allow weekly or every other week
dosing, is a favorable option. This option would eliminate the need for long term IV access,
because at most, weekly IV infusions would be performed.

In terms of bone infection, dalbavancin has favorable pharmacokinetic properties. A PK study
performed in subjects undergoing elective orthopedic surgery found that dalbavancin (dosed at
1000mg IV at enrollment and then 500mg weekly for up to 7 weeks) maintained levels in
cortical bone at bactericidal levels , at >50X the MIC of typical staphylococcal organism
(including MRSA). Animal studies in a rat osteomyelitis model also found that dalvabancin was
comparable to vancomycin. Because of these same PK properties, dalbavancin offers the
opportunity to substantially reduce costs and morbidity in native joint and prosthetic joint
infections.

This is a two-center, randomized, open label trial of dalbavancin versus standard intravenous
therapy control comparator in the treatment of subjects with gram positive native joint or
prosthetic joint infections. The primary outcome variable is clinical cure at day 42 after
start of treatment in all randomized patients. Safety and tolerability will also be assessed
throughout the study period via laboratory measurements and AE monitoring. Additionally,
clinical response will be measured by patient reported outcomes with change from baseline
symptoms and by Quality of Life questionnaire.

Eligible subjects with confirmed gram positive joint infections, will be randomized in a
ratio of 2:1 to receive open label dalbavancin or standard IV therapy. Standard IV therapy
will depend on the antibiotic susceptibility of the causative pathogen. Subjects randomized
to dalbavancin may have received standard of care therapy for no more than 120 hours prior to
first dalbavancin dose. Subjects randomized to standard of care can continue with treatment
course if already started, or receive the first dose at the baseline visit.

Inclusion Criteria:

1. Written informed consent obtained from the patient (if possible) or from either the
caregiver or legally authorized representative (if different from the caregiver)
before the initiation of any study specific procedures.

2. Male or female patients, aged 18-80, with the following osteoarticular infections:

1. Infected shoulder, knee or hip (1st or 2nd episode) as defined by a diagnostic
culture positive arthrocentesis

2. An infected prosthetic shoulder, knee or hip as defined by a diagnostic culture
positive arthrocentesis, or intraoperative diagnosis of infection with positive
culture; an infected prosthetic knee or hip (1st or 2nd episode). Preoperative
diagnosis by diagnostic, culture positive arthrocentesis

3. Demonstrated by a positive culture for one of the following gram positive organisms:
Methicillin susceptible Staphyloccocus aureus, methicillin resistant Staphylococcus
aureus, Streptococcus pyogenes, Group B streptococcus, Streptococcus anginosus group,
Vancomycin susceptible Enterococcus faecalis

4. If female, meet the following criteria:

1. Not breastfeeding

2. Not planning to become pregnant during the study

3. Be surgically sterile, or at least 2-years postmenopausal, or have a negative
pregnancy test at Baseline (Visit 1)

4. If of childbearing potential, agree to be strictly abstinent, or practice 2 of
the following effective methods of birth control throughout the study: systemic
contraception (e.g., oral contraceptives of estrogen and progestin combinations);
depot injection (e.g., Depo-Provera); contraceptive implant (e.g., Norplant,
Implanon); transdermally delivered contraceptive (e.g., Ortho Evra); intrauterine
device; vaginal contraceptive ring (e.g.,NuvaRing); diaphragm plus spermicide;
cervical cap; or male condom plus spermicide; partner vasectomy at least 6 months
prior to baseline

5. Vision and hearing (hearing aid permissible) sufficient for compliance with testing
procedures

Exclusion Criteria:

1. Subjects with culture proven gram negative infection

2. Concurrent diseases that, in the Investigator's medical judgment, would interfere with
the conduct of the study, confound the interpretation of the study results, or
endanger the patient's well-being

3. Any other conditions that, in the investigator's opinion, might indicate that the
patient is unsuitable for the study, the exception is, if there is a history of such
disease but the condition has been stable for at least more than 3 year(s) and the
investigator determines that it would not interfere with the patient's participation
in the study

4. Current malignancy under treatment with chemotherapeutic agents

5. Any unapproved concomitant medication excluded in section 6.3 that could not be
discontinued or switched to an allowable alternative medication before the Baseline
(Visit 2)

6. Currently participating in or previously participated in an investigational study of
Dalbavancin or treatment with an investigational product within 3 months or 5
half-lives, whichever is longer, of Screening (Visit 1)

7. HIV infection with a CD4 count <200

8. Solid organ transplantation or bone marrow transplantation within 6 months

9. History of severe neutropenia, defined as an absolute neutrophil count (ANC) <500
cells per microliter, in the last three months

10. History of severe liver disease, i.e. Child-Pugh Class C or aspartate aminotransferase
(AST) or alanine aminotransferase (ALT) more than five times the upper limit of normal
(ULN), in the last three months

11. Positive blood culture in the past 14 days, evidence of multiple sites of joint
infection, or evidence of concomitant infections at other body sites related to
bacteremia

12. Positive test on a urine drug screening for drugs of abuse, for which the patient does
not have prescription

13. History of drug or alcohol abuse that, in the Investigator's medical judgment, would
interfere with the conduct of the study

14. History of hypersensitivity reaction to Dalbavancin or other drugs of the same class