Wednesday, December 21, 2016

Aminoglycosides in the News

The title of this blog almost sounds like an oxymoron.  Aminoglycosides are boring, aren’t they? And they’re old! But with the onward march of antibiotic-resistant infections, could it be that the aminoglycosides are going to become not only news but clinically relevant as well? Well . . . . .maybe.

Achaogen has announced the top line results from their pivotal trials of plazomicin, a (not so) new aminoglycoside with activity against highly resistant Gram-negative pathogens. They ran two trials.  The first was a non-inferiority trail using plazomicin compared to meropenem to treat complicated urinary tract infections. The results are shown here.
Results for FDA pre-specified composite endpoint of clinical cure and microbiological eradication in the microbiological modified intent-to-treat (mMITT) population were as follows:
   Day 5: 88.0% plazomicin vs. 91.4% meropenem (difference -3.4%, 95% CI: -10.0, 3.1%), indicating statistical non-inferiority
   Test-of-Cure: 81.7% plazomicin vs. 70.1% meropenem (difference 11.6%, 95% CI: 2.7, 20.3%), indicating statistical superiority
Results for EMA-specified endpoints of microbiological eradication at the test-of-cure visit were as follows:
   mMITT: 87.4% plazomicin vs. 72.1% meropenem (difference 15.4%, 95% CI: 7.5, 23.2%), indicating statistical superiority
   ME: 90.5% plazomicin vs. 76.6% meropenem (difference 13.9%, 95% CI: 6.3, 21.7%), indicating statistical superiority.
  These data indcaite that plazomicin is at least as effective as meropnem and may even be superior for cUTI. The trial excluded meropenem-resistant pathogens so it is hard to see why this would be so – but the data are the data.

 The other trial that Achaogen ran was the CARE trail that they discussed at the recent FDA workshop that was the subject of a previous blog. The results they reported were from patients with (apparently) known carbapenem-resistant infections treated with either plazomicin + meropenem or tigecycline vs. colistin + meropenem or tigecycline.  Thus it was a comparison of combination therapy where the aminoglycoside plazomicin was used as one part of the combination vs. using colistin. The infections treated were either nosocomial pneumonia or bacteremia. No breakdown as to the source of the bacteremia was reported and in an email response to my questions, Achaogen replied that they were still analyzing the data and had no further information to share as yet. This is a crucial question (see below).  The results are shown below. 

Plazomicin Colistin
28 day all cause mortality 4/17 (23.5%) 10/20 (50%)
or significant complications
28 day all cause mortality 2/17 (11.8%) 8/20 (40%)

Clearly the numbers here are very small. My quick statistical analysis suggests that on the first endpoint there would be a P value of around 0.07 – a clear trend towards superiority of plazomicin.  But on the second endpoint, the P value would be closer to 0.2. Yet these are the kind of data that the regulatory agencies will have to try to interpret as they get into these small and extraordinarily difficult trials. That an aminoglycoside would be superior to colistin is not surprising.  And I’m sure these clinical data will be buttressed by strong PK/PD justifications for the activity of the drug.  Finally, when seen in the light of the large trial in urinary tract infection, the case for plazomicin becomes stronger.

At the same time, Sanofi has announced that they are taking over further progression of Warp Drive’s aminoglycoside program. It seems like 2016 is the year of the aminoglycosides.  What the Warp Drive compounds look like – I have no idea.

The remaining question for clinicians is, do we really need or want new aminoglycosides? Aminoglycosides are useful in the treatment of TB and serious Enterococcal infections - but our current aminoglycosides are probably adequate there. Among Gram-negative infections, one  area where combination therapy with aminoglycosides might be important is in the treatment of Pseudomonas infections in severely immunocompromised patients. Aminoglycosides are clearly effective in cUTI caused by Gram-negative pathogens. Otherwise, the data suggesting that these compounds work as well as other classes of antibiotics in Gram-negative infections remains controversial. I reviewed some of these data in a recent blog. My own clinical experience plus data from several studies where my lab participated suggested that combination therapy of Gram-negative infections with aminoglycosides did not prevent emergence of resistance and did not reduce mortality compared to treatment with beta-lactam antibiotics alone. Yet, in these days of increasing numbers of infections with highly resistant pathogens where colistin is the only available therapy, an active aminoglycoside might be a welcome alternative. Opposing this inclination is the market entry of other beta-lactam antibiotics active against highly resistant pathogens such as Avicaz and others in the late stage pipeline might that make these new aminoglycosides somewhat less relevant. Analysts have estimated a $340 million peak year sales for plazomicin.

Saturday, December 10, 2016

The Threat to FDA

As many of you know, I have had my “disagreements” with the FDA over the years.  But I have never questioned the fact that without the FDA, we would all be in a world of trouble. Just look at what’s happening with supplements and you’ll begin to understand what I’m talking about.

The very beginnings of the FDA were in the patent office in 1848. So-called “patented medicines” were being sold throughout the US as cures for whatever. A number of high-profile poisonings from tainted products had occurred including several affecting soldiers in the army. The patent office was given the task of identifying potential poisons among products being sold to the armed forces. In 1862, this effort was transferred to the newly created department of agriculture.  There, responsibility for the safety of food was also added. Chemical additives to preserve food included a number of poisons as well. These inspections fell to the department of chemistry within the department of agriculture.  By the end of the 19th century, over half of all newspaper advertisements were for nostrums claiming to cure everything from cancer to rheumatism. One chemist, M.J. Bailey, reported,"More than one half of the most important chemical and medicinal preparations … come to us so much adulterated, or otherwise deteriorated, as to render them not only worthless as a medicine, but often dangerous."  Europe started embargoes against American drugs and food. 

In 1905 Sinclair’s The Jungle was published.  The conditions described in slaughterhouses were so disgusting that Teddy Roosevelt decided to send inspectors to Chicago.  They found what Sinclair had described. The first food and drugs act was passed in 1906.

After passage of the law, the maker of Cuforhedake Brane-fude – claiming that this product provded certain and harmless relief and contained no poisons whatsoever – was charged under the new law for selling a product with acetanilide – a known poison that was responsible for at least 22 deaths. The product had brought in $2 million. The drugmaker was fined $700, changed the label and went on making the product for years.

The most famous case occurred in the 1930s when one of the new sulfa antibiotics was sold tainted with polyethylene glycol. Over 100 people died, many of them children.  But the company had broken no law. The label was not “misleading.” This, more than anything else, led to the passage of the Food Drug and Cosmetics Act of 1938. Proof of drug safety would be required before a drug could be marketed. But the 1938 law said that companies had to submit data showing safety and the FDA had 90 days to object before the drug would be marketed.

Then came thalidomide and thalidomide babies.  That led to passage of the Kefauver-Harris Amendment of 1962 – signed by JFK. This law required the demonstration of both safety and efficacy setting basic standards for what evidence could be considered. While the FDA has progressed since 1962, this law remains the basis of everything they do.

Today, some want to turn the clock back to 1938.  In particular, Jim O’Neill (no relation to the Jim O’Neill who led the UK’s Antimicrobial Resistance task force) wants to have drugs approved once they have shown to be “safe” and then have some sort of rolling approval where there would be an obligation to show efficacy. Not only would this be a terrible step back into a sad and destructive history, but it is completely irrational.  The concept of safety can only be understood in the context of benefit.  If the benefit outweighs the risk, a product can be considered safe even if there are some potential liabilities.  This has been our entire approach to the treatment of cancer and other serious diseases for decades. O’Neill is apparently under consideration for Commissioner of the FDA.  Are you kidding?  He is not a physician nor is he a scientist.  He is a Managing Director at Peter Thiel’s Mithril Capital Management.

Although to achieve what O’Neill would like, laws would have to be changed and probably the majority of people at the FDA would simply walk out if this were to occur. So, it seems unlikely that he would succeed in this particular quest.  But someone like him could do a great deal of damage.  Why would we ever want to go through the early 1900s of drug regulation again? Please – let’s not go there.