Analyzing The Plazomicin AdCom Briefing Documents

The just-released briefing documents for Wednesday’s advisory committee (AdCom) for the evaluation of Achaogen’s (AKAO) NDA submission for their best-in-class antibiotic Plazomicin can be found here: https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm587657.htm

They include the participant roster, questions to be voted upon by the committee and the ‘briefing information’, which includes documents provided by the sponsor (AKAO) and analysis / remarks by the FDA.

Of interest to us:

• Content of the questions with a view on labeling
• Content of the briefing documents with a view on identifying potentially negative bias, if any, by the FDA towards the drug.

We previously discussed the written submission by Dr. John Rex - head of Carb-X - which can be found in .pdf form on regulations.gov, as a substantial endorsement of Plazomicin and of the need to include data from the CRE-directed CARE study on the drug’s label. Rex features a nearly unequalled track record in the development of new antifungals and antibiotics which together with his tenure at Carb-X vests him with rare authority in the sector. While his endorsement of a ‘CRE label’ for Plazomicin is meaningful, some have wondered why Rex felt it was necessary to provide us with this written submission, having read the draft meeting documents for the AdCom.

Is he intent on counterbalancing an overtly negative FDA with regards to a key drug in the fight against multi-drug-resistant pathogens? Will such negativity be reflected in the final meeting documents? Let’s find out.

Questions being put to the vote:

1. VOTE: Has the applicant provided substantial evidence of the safety and effectiveness of plazomicin for the treatment of complicated urinary tract infections in patients with limited or no treatment options? a. If yes, please provide any recommendations regarding labeling. b. If no, what additional studies/analyses are needed?
2. VOTE: Has the applicant provided substantial evidence of the safety and effectiveness of plazomicin for the treatment of bloodstream infections in patients with limited or no treatment options? a. If yes, please provide any recommendations regarding labeling. b. If no, what additional studies/analyses are needed

My take: Q1 will result in an unequivocally positive vote with no additional studies required. Q2 paves the way for a ‘CRE label’ but there’s a wildcard: what will panelists come up with in terms of precise labelling suggestions?

Overall this is very positive as it enables the dual cUTI / CRE BSI label. Shorts can exploit the uncertainty around Q2a but they are likely in for a surprise during the AdCom itself.

FDA briefing document

Work in progress. Initial impressions following a quick scan:

• cUTI Plazo non-inferiority to meropenem is incontrovertible: “Results of these analyses also showed that plazomicin was noninferior to meropenem, allowing us to conclude that the NI conclusions of the primary analysis are not sensitive to the method for handling missing data.” - FDA page 15
• nephrotoxicity: class-specific and monitoring only required in renally impaired patients. - FDA page 18
• CARE: FDA briefing doc provides an important reminder of the evolution of the CARE trial, which should give uninformed AKAO-bears some pause. The FDA was informed of, and had no objection to, ending the trial with smaller enrolment than initially planned. This goes back to Dr. Rex’ written submission: we should be very worried as a society if a trial like CARE could easily enrol hundreds of patients. Interestingly, Plazo-treated subjects in the CARE cohort 1 appear to have been an overall more fragile / sicker sample, which together with the strong mortality benefit provided by Plazo over Colistin bodes very well for an unprecedented label:

[Figure omitted: baseline characteristics of the CARE cohort 1 arms, from the FDA briefing document. Caption: “Source: page 28”]

Futhermore, comparing the Colistin arm to the Plazomicin arm, CRE bacteremia confirmation by means of blood culture was fairly equal but still ultimately more pronounced in the Plazomicin arm:

[Figure omitted: baseline blood-culture confirmation by arm, from the FDA briefing document. Caption: “Source: page 29”]

“Numerical trends for both primary endpoints favored plazomicin.” Page 30.

“The study population was dominated by patients with BSI rather than HABP/VABP, and numerical trends favored plazomicin in the BSI subgroup. There were too few patients with HABP/VABP (5 in the colistin group and 3 in the plazomicin group) to allow exploratory analysis.” Page 31: this points towards inclusion of the BSI CRE data whereas already planned investigator-inititated PhIV trials evaluating Plazo in pneumoniae could be used, some years down the road, for label expansion to HABP/VABP.

Page 32: outside HABP/VABP with an insufficient sample size, the mortality benefit for Plazo over Colistin is extremely pronounced regardless of adjunctive therapy.

Additional sub-group analysis conducted by the FDA for BSI shows that not only does Plazo provide substantial benefit in terms of mortality; the drug is also associated with dramatically lower serious complications (‘SDRCs’).

[Figure omitted: the FDA’s BSI subgroup analysis of day-28 all-cause mortality and SDRC.]

Page 37: the FDA leans in favor of all-cause mortality as a benchmark, apparently paying heed to Dr. Rex’ suggestions! This is a major boon for AKAO.

Page 44 overall conclusion with regards to CARE:

“A statistically significant benefit of plazomicin over colistin was noted with regard to 28 Day mortality (or 28 Day mortality plus SDRC) in the BSI subgroup, but not in the overall study population. In addition to concerns such as a lack of prespecified statistical significance on the primary endpoint in the overall mMITT population and given the concerns including imbalances in subject/disease factors, uncertainty in clinical condition due to negative blood cultures at baseline, source of the bacteremia, and presence of intravascular catheters, a conclusion of superiority of plazomicin is difficult. The limitations in assessing NI have also been discussed.”

This points towards inclusion of the BSI CRE data on the label whereas additional studies will be required if AKAO wish to extend the label, which as I mentioned prior, is already in the making.

Conclusions and discussion

This is a home-run for AKAO. There are no bombshells in the FDA report and the only real question is whether additional CRE-related data, beyond the BSI subset, should be included in the drug’s label. In that regard, the written submission by Dr. Rex as well as the exposé provided by AKAO will be highly relevant: the AdCom panel will consider the questions put before them, especially question number 2, not in the vacuum of the FDA’s statistical analysis but in the context of an ever-increasing need for alternatives to Colistin in the treatment of highly resistant bacterial infections.

AKAO investors should also remain mindful of additional context: during its most recent conference call, management has flagged significant investigator interest in running post-approval ‘PhIV’ studies in additional indications beyond cUTI and BSI. Successful outcomes in such studies would enable expanded use of the drug further out.

On the dealmaking front, it is worth keeping in mind that AKAO will upon approval own a unique asset, a neo-aminoglycoside, which is highly complimentary to the abundant beta-lactam / beta-lactamase inhibitor combos on the market and currently being developed. Synergistic benefit between aminos and beta-lactams are well documented. Plazo would be an exceptionally strong addition to the ID portfolio of a number of large pharma players including Pfizer (PFE), Merck (MRK) and Allergan (AGN). Additionally, AKAO management’s strong ties across the industry, including with Glaxo’s (GSK) new head of R&D, Hal Barron, bode well for future dealmaking.

Trading considerations: I believe that the gains we are seeing today are sustainable as they reflect positioning ahead of the AdCom. Shorts may attempt to push the stock a little lower tomorrow but will find themselves overwhelmed at the very latest Thursday as the market reacts to (in my estimate) a positive AdCom vote on both questions.

If you are already comfortably positioned with an average cost basis below the current share price, sit tight. If you had been waiting on the sidelines, it should be worthwhile entering the stock later today or tomorrow ahead of the AdCom.

Disclosure: I am/we are long AKAO. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.