Plazomicin EU marketing application is withdrawn: Near zero market value of newly approved antibacterials

Dear All (with thanks to Kevin Outterson for co-authoring this newsletter),

Last week’s announcement of the AMR Action Fund was both exciting and sobering: $1b from 20+ pharma companies to fund antibacterials through Phase II-III to approval, with a goal 2-4 high quality new agents by 2030. If you missed it, please go here to read the newsletter, here for the YouTube channel where the event videos are being posted (as of today, only the DC event is shown … we assume others will follow), and here for the website of the fund itself. 18 Jul 2020 addendum: Lord Jim O’Neill has written an excellent commentary on the AMR Action Fund — read it here.

So now we have the funds to support progression of the best products from CARB-X and Novo REPAIR to approval … but what happens after that? The bitter and unacceptable truth is at present the most likely outcome for an approved antibacterial agent is bankruptcy for the developer and limited or no access to the drug for all of us

As a demonstration case, we have today some really distressing news from Europe. As a quick reminder, plazomicin (ZEMDRI) is a novel aminoglycoside antibacterial developed by Achaogen to treat infections caused by highly resistant Enterobacteriales (Enterobacteriaceae). At a technical level, it was designed to evade resistance mechanisms specific to aminoglycosides (bacteria become resistant by acquiring gene coding for aminoglycoside-modifying enzymes that inactivate aminoglycosides). In addition, it maintains activity in the presence of most mechanisms that lead to resistance in Enterobacteriales vs. other classes, including mutations in sites targeted by fluoroquinolones, the production of extended-spectrum β-lactamases, and carbapenemases, and plasmid-mediated colistin resistance that modifies the outer membrane of the bacterial cell (link to a general review; link to Phase 3 data in cUTI).

Based on $500m+ in support from BARDA and investors, it reached US approval mid-2018. But, the approved labeling was very narrow, the resulting sales were nil, and the company went bankrupt about a year later (see this newsletter for a review and go here for a summary of the bankruptcy process).

There did seem to be some hope when plazomicin was acquired a few months after bankruptcy by Cipla (at the bargain price of $16m, link) and it is available in the US per the ZEMDRI website (link). But, we now learn that it will not be brought to market in Europe…

Sources
  • 16 June 2020 letter from Cipla withdrawing its application (link)
  • 26 June 2020 EMA notice of withdrawal (link)
  • And here is the text of Cipla’s letter…

“Subject: Withdrawal of Zemdri (Plazomicin) 500mg/ 10ml injection  
Procedure no: EMEA/H/C/004457
Applicant Cipla Europe NV

Further to our letter dated May 5, 2020, Cipla Europe NV would like to inform you that, despite its best efforts thus far, at this point in time, Cipla finds itself unable to proceed with seeking the approval of the Marketing Authorization for Zemdri (plazomicin) 500mg/10ml injection which was intended to be used for Complicated urinary tract infection: infections due to carbapenem-resistant or aminoglycoside-resistant Enterobacteriaceae susceptible to plazomicin in patients with limited treatment options, for the reasons stated below and has therefore taken this difficult decision to withdraw the Application for Marketing Authorization.  

This withdrawal is based on pharmacoeconomic considerations concerning the company’s marketing strategy.  The conditions and work and cost expected to be required for approval and post-approval, including the PIP and terminal sterilization processing, were evaluated and assessed to result in the product being financially and commercially unviable with the limited indication that was to be accepted.  

On a scientifically grounded and standardized basis, investment of these development expenses does not indicate an optimal allocation of Cipla’s healthcare resources.

We reserve the right to make further submissions for a Marketing Authorization in this or other therapeutic indication(s) at a future date, in the event we forecast some commercial viability on account of, including if there are exemptions of requirements or commitments.”  

We agree for this letter to be published on the EMEA website.

Please do the necessary in confirming our withdrawal of the MA application.

 

Cipla is being very clear here about its inability to meet requests from the EMA: Why put more money into a drug that would have near zero sales? We don’t have the details, but we can see that work was requested on manufacturing (a bit hard to understand given that FDA had approved the manufacturing process) and the PIP (Pediatric Investigation Plan, to be expected as this is required for approval of all new drugs in Europe). 

So what would Cipla’s logic had been? To refresh your memory (or if you are new to this problem), it is important to know that Cipla’s challenge is shared by all new antibiotics. Here’s a quick reminder:

  1. After spending on average $1.3b over 10-15 years to reach approval (see 6 Mar 20 newsletter), the resulting sales of most new antibacterial agents will not sustain the drug on the market.
  2. As a simple demonstration of this, Alan Carr’s 2020 market review (28 Jan 20 newsletter) provided data showing that average sales for the 12 months ending Nov 2019 (i.e., most of 2019) were < $50m for the entire group of 17 antibiotics approved since 2009.
    • But, the average is misleading as the sales are not uniformly distributed: an astonishing 10 of these 17 drugs had sales < $15m.
  3. Further, a company needs ~$350m in sales over its first 10 years on the market simply to break even on a cash flow basis (7 Jan 20 newsletter).
    • That’s $350m just to (i) manufacture the drug, (ii) do minimal pharmacovigilance and resistance surveillance, and (iii) complete pediatric requirements.
    • In particular, it does not cover repayment of investors, additional clinical studies, additional indications, or anything else that would teach us more about the drug. 
  4. ZEMDRI’s sales in the US for the 12 months covered by Alan’s review were $1m.

Inhale, exhale. Yes, the net effect is that now nobody in Europe will have ready access to plazomicin as the costs to complete registration in Europe clearly outweighed the negligible potential sales.

So, access to plazomicin will be limited going forward. There will be some access as Cipla can (and likely will) register with territories that accept as-is the FDA-approved package. Combined with fact that Cipla has the big financial advantage of having acquired plazomicin for $16m and without having to do the 10+ years of work required to complete the drug’s pivotal trials, even a little profit in those territories will be a reasonable return for them.

But the disastrous consequence is that this makes an iron-clad case for investors that investing in antibiotics is madness. And, anything that does get developed will be done with a rock-bottom minimum package, all of which will further contribute to the problem of limited and delayed global registration (Kållberg et al., 2018, link).


So, there you have it. This is why we need to think differently about paying for antibiotics. Plazomicin is a potentially life-saving antibacterial antibiotic that should be used with appropriate stewardship and only in specific patients. But, our current system of paying for antibiotics only when we use them in an individual patient entirely overlooks the fire extinguisher (or insurance) value of high-end antibiotics.

Antibiotics are the #FireExtinguishersOfMedicine (link), the critical enablers of all health care. And if we do a good job with clean food, clean water, sanitation, and vaccines then we don’t need them very often. But, when we do have an infection (fire), it is too late to start to develop the drug (build the fire station). We must do this in advance by maintaining our supply of diverse antibiotics (fire extinguishers) at all times — even when we are not currently pulling the ring and spraying the foam! 

With the $1b AMR Action Fund, pharma have donated the money needed to bring new agents to approval. But, if approval looks like the outcome for plazomicin, we will have built a bridge to nowhere.

As was stated repeatedly at the AMR Action Fund launch, we must now create sales-delinked innovation rewards (Pull incentives) for antibiotic developers. The potential reward on a global basis needs to be in the $1-4b range per antibiotic (see again that 7 Jun 20 newsletter cited above) and it needs to paid to ensure the availability of the given agent without regard to how often the drug is used to treat patients. This is clearly at a scale only possible for governments but only the UK (link) is currently implementing an appropriately sized such Pull incentive. The US might become country #2 if the PASTEUR Act now being drafted in the US gains traction (link). But even that won’t be enough — it will require the effort of the entire G20 to actually make this happen.

Fingers and toes crossed, the AMR Action Fund will use its creation of valuable new antibiotics to say loudly and clearly, “Pharma have gotten busy and created new life-saving antibacterial agents. Here they are! But, they are not going to be available to patients unless governments step up to do their part to support the antibiotic R&D ecosystem.”

 

Never let a good crisis go to waste! Let’s make this happen! All best wishes, John & Kevin

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

Kevin Outterson, JD, Professor of Law, Boston University & Executive Director, CARB-X (these views are personal and do not necessarily reflect the views of CARB-X or any of its funders) @koutterson  

Current funding opportunities:

  • Novo REPAIR Impact Fund is open for global applications through 31 Jul 2020. Go here for current details.
  • 2020 funding rounds for CARB-X have not been announced.
  • The Global AMR R&D Hub’s dynamic dashboard (link) summarizes funders and projects by geography, stage, and more.


Upcoming meetings of interest to the AMR community:

  • 16 Jul 2020 (online, 1-2.30pm EST): ASM Microbe 2020, President’s Forum. Go here for details.
  • 20 Jul 2020 (online, All-Day EST): ASM Microbe 2020, On-demand symposia, courses, and workshops. Go here for details.
  • 21-22 Jul 2020 (online, 11a-3p EST): ASM Microbe 2020, Live sessions. Go here for details.
  • 27-28 Jul 2020 (online, 11a-3p EST): ASM Microbe 2020, Live sessions. Go here for details.
  • 27 Jul-31 Jul 2020 (online): Small World Initiative Instructor Training Workshop – training for undergraduate professors and high school teachers in wet lab techniques, parallel curricula, & pedagogical instruction to engage students in the hunt to find new antibiotics in soil (also covering distancing learning options). Go here to register.
  • 4 Aug 2020 (Silver Spring): FDA workshop entitled “Development Considerations of Antifungal Drugs to Address Unmet Medical Need.” Go here to register.
  • 5 Aug 2020 (Silver Spring): FDA workshop entitled “Developing Antifungal Drugs for the Treatment of Coccidioidomycosis (Valley Fever) Infection.” Go here to register.
  • 17 Aug 2020 (online, 1-2.30p EST): ASM Microbe 2020, Industry & Science program. Go here for details.
  • [NEW] 24-28 Aug 2020 (online, 9.45a-18.30p CEST daily): BEAM Alliance-sponsored AMR Conference. Go here for details.
  • September 2020. University of Sheffield (UK). Applications are being taken for a new 1-year (full-time) or 2-year (part-time) Masters of Science course in Antimicrobial Resistance. The program runs annually from September and covers microbiology, clinical practice and policy. The course webpage is here.
  • 9-10 Sep 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
  • 26-29 Oct 2020 (online meeting), Annual ESPID meeting (European Society for Pediatric ID, #38)
  • 27 Oct 2020 (online meeting), BARDA Industry Day, a discussion of U.S. Government medical countermeasure priorities. Mark your calendar now and watch this website for details.
  • 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)
  • 20-24 June 2021 (Toronto): International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-12). Go here for details.
  • 3-7 Jun 2021 (Anaheim), ASM Microbe 2021. Go here for details.
  • 5-21 Aug 2021 (Marine Biology Laboratory, Woods Hole, MA): Residential course entitled “Molecular Mycology: Current Approaches to Fungal Pathogenesis.” This 2-week intensive training program has run annually for many years and gets outstanding reviews. Go here for details.
  • 8-11 Oct 2021 (Aberdeen, Scotland): 10th Trends in Medical Mycology. Go here for details.
  • 16-24 Oct 2021 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics, antibiotic resistance, and antibiotic R&D. The course is very intense, very detailed, and gets rave reviews. Registration is here and is limited to 40 students.
  • 18-21 May 2021 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.

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