Most Anti-Infective Guidelines Don’t Get No Respect (Let Alone Use!)

It is no secret that most existing antibiotic guidelines are not getting much use these days.  The only indications pursued with any regularity are the feasible ones: ABSSSI, cUTI, and cIAI, much less CABP.  Yes, the occasional HABP/VABP trial is being undertaken by the intrepid but no company has taken up the FDA on its offer to garner the ABOM, ABECB, or ABECS indication by running a placebo-controlled superiority trials.

Here the current list of existing FDA Guidances[1], [2] which I am separating into 2 categories:

1. CLASSICAL ORGAN INDICATIONS
   1. Acute Bacterial Exacerbations of Chronic Bronchitis in Patients With Chronic Obstructive Pulmonary Disease: Developing Antimicrobial Drugs for Treatment 10/1/2012 [3]
   2. Acute Bacterial Sinusitis: Developing Drugs for Treatment 10/05/12
   3. Acute Bacterial Otitis Media: Developing Drugs for Treatment 10/2/2012
   4. Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment 10/23/2013
   5. Acute Bacterial Sinusitis: Developing Drugs for Treatment 10/9/2012
   6. Acute Bacterial Meningitis; Developing Antimicrobial Drugs for Treatment (I) 7/22/1998
   7. Acute or Chronic Bacterial Prostatitis; Developing Antimicrobial Drugs for Treatment (I) 8/27/2010
   8. Community-Acquired Pneumonia — Developing Antimicrobial Drugs for Treatment 1/10/2014
   9. Complicated Intra-Abdominal Infections: Developing Drugs for Treatment 10/1/2012
   10. Complicated Urinary Tract Infections: Developing Drugs for Treatment 2/24/2012
   11. Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment 5/7/2014
   12. Bacterial Vaginosis; Developing Antimicrobial Drugs for Treatment (I) 10/15/2007
2. SINGLE PATHOGEN INDICATIONS
   1. Catheter-Related Bloodstream Infections – Developing Antimicrobial Drugs for Treatment (I) 10/18/1999
   2. Uncomplicated Gonorrhea — Developing Antimicrobial Drugs for Treatment 6/19/2014
   3. Helicobacter pylori-Associated Duodenal Ulcer Disease in Adults: Developing Drugs for Treatment (I) 10/5/2009
   4. Developing Antimicrobial Drugs to Treat Inhalational Anthrax (Post Exposure) 03/15/02
   5. Pulmonary Tuberculosis: Developing Drugs for Treatment 11/05/13
   6. Surprisingly, there is no Guidance for C. difficile infections although Fidaxomicin has blazed a path that others will follow.

Looking at recently approved drugs and the indications they pursued shows that most companies choose the easy the path, with feasibility trumping risk-taking. The ABSSSI indication is the all-time favorite, for obvious reasons (feasibility, low cost):

• ABSSSI:  Dalbavancin (Dalvance), Oritavancin (Orbactiv), Tedizolid (Sivextro), and Ceftaroline (Teflaro)
• cUTI: Ceftolozane/Tazobactam (Zerbaxa), Ceftazidime/Avibactam (Avycaz)
• cIAI: Ceftolozane/Tazobactam (Zerbaxa), Ceftazidime/Avibactam (Avycaz)
• CABP: Ceftaroline (Teflaro)

Most MRSA-drugs have a narrow in spectrum making ABSSSI a reasonable indication to pursue.  However, all BL/BLI combination drugs would seem to have excellent potential for broader use than the indications studied for approval. There is no reason to believe that Avycaz or Zerbaxa would not do well in nosocomial pneumonia (HABP and VABP) or PID, or other gram-negative infection indications which companies in former years would have wanted to include in their package inserts.

Very rare are Phase 4 studies designed to expand an existing label, or help define differentiating features not well characterized in the Phase 2 and 3 studies.  The information provided on www.clinicaltrials.gov does not specify whether a study is for label expansion, or for publication only.  For instance, a surgical prophylaxis study is underway for Teflaro, but a CABP study for Dalvance has not started yet.  With good results, both could become SNDAs.  But they also may just make it into a publication.

There are, however, some interesting trials underway:  For instance, a Phase 3 study of telavancin / Vibativ in S. aureus bacteremia is open for recruitment.  But if you are looking for a new endocarditis trials like the one initiated by Francis Tally for daptomycin (which brought fame and glory to Cubist/Cubicin) you will be disappointed.

How about osteomyelitis and prosthetic joint infections?  With S. aureus a main offender, you may think that there is much competition for study patients out there.  The opposite is the case:  Ceftaroline stopped its osteomyelitis trial recently.  There are only pediatric osteomyelitis trials listed for Dalvance – make this ‘hematogenous osteomyelitis’, a very different disease from the S. aureus osteomyelitis in adults by being much more responsive to therapy with anti-staphylococcal agents.  No Phase 3 or 4 prosthetic joint infection trials are currently ongoing according www.clinicaltrials.gov.

After years of failed sepsis trials there seems to be little appetite for yet another trial in this indication.  Undeterred by history, ART-123 from Asahi Kasei Pharma is now undergoing Phase 3 testing in severe sepsis patients with coagulopathy. After the demise of TFPI (tifacogin) and drotrecogin, this recombinant thrombomodulin is going to have an uphill battle.  May the Force be with them!

Then there is bacteremia, esp. MRSA bacteremia.  Where are the study results for the 56 MRSA persisters treated with ceftaroline/Teflaro which was probably the largest prospective study of this patient population?  Tedizolid (BAY1192631) is studied in Japan, thankfully at the same dose (200 mg IV/PO qd) as in the Western World.  Unfortunately, it is an open trial with some very Japan-specific features.

Meningitis is the domain of many vaccine trials, not of antibacterials.  A tuberculous meningitis trial with rifampin and a high-dose ceftriaxone trial are recruiting at this time.

The development of drugs with unique features (MDR pathogen, narrow spectrum, adjunctive therapy) is not captured in the traditional FDA Guideline categories listed above; it requires innovative approaches tailored to a specific drug and its clinical application.  This is the space where individualized solutions are required and one shoe does not fit all situations.  It is also the area where Allphase Pharma Consulting is predominantly active.

Welcome to the Brave New World of anti-infective drug development.

References:
[1] http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079645.pdf
[2] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064980.htm
[3] Prulifloxacin vs Levofloxacin/Levaquin Ph3 study is not a superiority design trial as required by FDA