November 15th, 2020

Bamlanivimab for COVID-19 — Hard to Pronounce, Even Harder to Give

From Buffon and de Sève’s Quadrupeds (1754). This animal kind of looks like a bamlanivimab.

The latest COVID-19 treatment made available under Emergency Use Authorization (EUA) is bamlanivimab, a monoclonal antibody developed by Eli Lilly. For now, its use will be limited to outpatients who are at high risk for severe disease and/or hospitalization.

This EUA is based on the results of the phase 2 BLAZE-1 study, in which the treatment reduced the need for hospitalization among outpatients — especially those deemed at high risk for poor COVID-19 outcomes. For this group, 3% of bamlanivimab versus 10% of placebo recipients required admission.

And yes, you read that right — bamlanivimab.

The comedians sure had a field day with this tongue-twister, and boy it’s devilishly hard to say.

But let me focus instead on the difficulty of actually giving this product to a stable, high-risk outpatient with COVID-19 — because remember, that’s the only way it’s going to help anyone.

I’ve been ruminating over the challenges of implementing this treatment for a while, ever since research began on this class of drugs. Pharmacist Tim Gauthier’s outstanding summary amplified my concerns when he wrote that the logistics of administration would be “considerable” — which could be the understatement of the year.

Why so difficult? Let me list the ways:

  • Supply is limited. Even accounting for the high-risk criteria listed in the EUA, the potentially eligible recipients will greatly exceed the number of distributed doses. How bad is the mismatch? This excellent review by my ID colleagues Drs. Robert Goldstein and Rochelle Walensky estimates that based on current case counts, the supply could be exhausted in less than 2 weeks. How will we choose who gets it?
  • It must be given within 10 days of symptom onset. Some experts think even 10 days is too long a wait for effective intervention — the sooner the better. While we don’t know the precise window of opportunity for benefit, remember that these monoclonal antibody treatments (from both Lilly and Regeneron) don’t appear to help people already in the hospital.
  • It must be given intravenously. How many outpatient clinicians have the ability to give infusions in their clinics?
  • People with early COVID-19 disease are at their most contagious. Most secondary transmissions happen between 1 day before and 5 days after the onset of symptoms, during which time respiratory viral load peaks. And this is precisely when we’ll want to bring patients in for treatment.
  • Most infusion centers have a high proportion of patients who are immunocompromised. Rheumatology, GI, and neurology patients receiving intravenous immunosuppressive agents. Cancer patients receiving chemotherapy. How can we safely bring COVID-19 patients into these centers? Should we even try?
  • Many infusion centers are not set up for urgent referrals. Their regular patients have regularly scheduled infusions. Even setting up an urgent dose of ceftriaxone can be challenging if the schedule is already full.
  • Both the infusion and the post-treatment monitoring take a lot of time. This isn’t a simple matter of showing up, getting one quick shot, then leaving. The infusion takes 1 hour, and there is a 1-hour monitoring period afterward to ensure no severe allergic reactions ensue. Budgeting 3 hours seems about right.
  • Emergency departments do not want a 3-hour treatment clogging up their patient flow — especially if they don’t get paid. Unlike most infusion centers, hospital emergency departments do have the required infection control capabilities. However, would they welcome stable COVID-19 patients sitting around getting a 3-hour treatment? If so, how many? Not only would this distract from other critical activities, but under current systems of reimbursement for ED visits, there is no guarantee that the hospital will be paid for this service.
  • The formulation is tricky to prepare and not stable for very long. Tim’s a pharmacist, so let me just quote him directly:  “Preparation of the IV admixture is not simple and is stable for just 7 hours at room temperature or 24 hours under refrigeration (including infusion time).” Ugh.
  • Serious side effects may occur. Although not in the published paper, the package insert cites at least one case of anaphylaxis and another serious infusion reaction among banlanivimab-treated patients. As a result, we are advised that this treatment “may only be administered in settings in which health care providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis.”

Practically, these gargantuan logistical hurdles may make the limited supply moot — all of us are trying to figure out how to deliver this promising treatment to prevent hospitalizations, and it’s not an easy nut to crack.

But already there’s a sense that these difficulties could exacerbate existing disparities in COVID-19 outcomes, with underserved populations missing out again on the benefits of this tricky treatment.

Let’s imagine a hospital or other healthcare delivery system sets up a program to administer banlanivimab to people diagnosed with COVID-19 as outpatients. Because of drug supply constraints and the duration of the infusion and monitoring time, they limit the number of treated patients to two per day (a morning and an afternoon session), which is to be administered in a specialized infusion site separate from immunocompromised patients.

Patients are referred by their primary clinicians, or they can call themselves. An intake nurse or other health professional speaks with them, reviews the relevant medical history, and ultimately determines whether they meet the “high-risk” criteria for treatment. If so, they schedule the patient for one of the two daily treatment slots.

Sounds simple, right?

Now let’s consider two imaginary (but quite plausible) patients newly diagnosed with COVID-19, both of whom would meet eligibility criteria for banlamivimab therapy.

The first is a 74-year-old semi-retired lawyer with hypertension and adult-onset diabetes. He could lose a few pounds, so tries to play tennis at his club in Wellesley as often as possible. He gets regular check-ups in the hospital system’s primary care network. Because of that network, he periodically receives health alerts through his hospital’s patient portal, including reminders to schedule his eye exams, blood tests, and immunizations.

The second imaginary patient is a 71-year-old woman from the Dominican Republic who moved to Boston five years ago to live with her daughter and grandchildren. Although she worked at a restaurant before she moved (gaining quite a few pounds with on-the-job snacking), she now finds the language barrier difficult here, so does not work. She mostly stays at home, sometimes socializing with other older people in her neighborhood who also speak Spanish. She receives some primary care at her local community health center; they have recommended that she start treatment for high blood pressure and diabetes, but the clinicians keep changing, and not all of them speak her language, so she never did.

Which patient is most likely to be referred for a banlanivimab infusion? Which one is more likely to call and advocate for themselves?

I suspect no one needs a medical degree to answer those questions.

12 Responses to “Bamlanivimab for COVID-19 — Hard to Pronounce, Even Harder to Give”

  1. Dan says:

    Most of the problems in implementing use of bamlanivumab are mentioned already but the usual hospital-based sites for infusions are problematic for the reasons stated. The currently limited supply makes it quite unlikely to be widely used at least initially. An alternative approach might be to stand up ‘pop-up’ clinics in areas that are hot spots and use the drug as part of a test – trace – isolate / prevent effort. Optimally state or local health departments would do this with state or federal funding to pay for the drug, premedication and nursing costs. Thus far, federal willingness to do this is less than confidence inspiring leaving many states unable to manage on their own. Pharmacy logistics would also be tricky. Regardless of where it is used, logistics will be a major headache and the cost of staffing, particularly nursing, will be high at a time when nurses are already stretched thin. The usual facility based infusion sites seem unwise for the reasons stated above so new sites will need to be developed. Even with an EUA, further clinical trial data is crucial to understanding when best to use this drug and in what patients.

  2. John says:

    Another area of concern: the effect this EUA will have on the ongoing ACTIV-2 trial.

    Our understanding of the safety and efficacy of this drug is limited and ongoing clinical trials are essential to know in which patients and at what times to use it.

    I’m worried this will cannibalize the patient pool for trial recruitment and while I know this isn’t unique to this drug I’m afraid we will see more and more therapies that we *think* work but we don’t really know where, when and how well.

    We don’t get a second chance to do this right.

  3. Arturo Azpiroz says:

    In general, it could be said that the therapeutic objective for COVID-19 is tending towards reducing hospital stay and / or avoiding hospitalization as much as possible, all because the main problem with this disease is saturation of available sanitary facilities. To achieve this, state-of-the-art treatments are designed that require a “millimetric” delimitation of groups of patients to which to apply them and a too exact time window so as not to expect that, shortly, another clinical trial will disprove the previous one. By the time it is known what to do there will be a majority of infected / immunized healthy (at least I hope so)

  4. vilma Drelichman says:

    Thank you for the information on BAMLANIVIMAB for COVID–19

  5. Yves Gebhardt says:

    Thank you Robert for sharing! We all needed to see this during these troubled times.

  6. Valerie says:

    The hydroxychloroquine regimen has been proven to be much safer for most of the people on the high risk group, extremely cost effective and is known to be safe for wee babes and the elderly. It prevents ER visits thus also preventing any hospitalizations.

  7. Aaron D Andersen says:

    This ‘solution’ typifies all the problems with our health care system. Rather than implement common-sense, cheap, effective solutions across the country–testing and tracing and other public health interventions didn’t need an EUA or RCTs–we opted to do what we wanted as a country and to wait for an over-priced miracle drug that, in this case, was approved with a tiny preliminary trial that will bring millions to Eli Lilly without much oversight, and which applies to a population destined to do well for the most part anyway, thus making the drug look like a ‘success’ when in fact, as noted in the article, it is unlikely to make any sort of a dent in the pandemic itself.

    The only drug I’m interested in is a vaccine, which, thankfully, seems close. Bamlanivumab is nothing but a cash grab, and one more thing for people to ‘ask their doctor’ about when they show up in my waiting room that has no seats left, nor beds to put them in.

  8. John Zurlo says:

    Also, let’s not forget the issue of dose effect. The “viral load” dropped in all groups, including placebo though most significantly in the 2,800 mg dose, more so than the 700 mg and 7,000 mg doses. I’m not sure how that makes sense if we are postulating that it is the antiviral effect of the MAB that results in a clinical benefit, in this case fewer hospitalizations. And as mentioned, the number of hospitalizations was very small – single digits in each group. This will be a lot of work for what we all believe will be low impact.

  9. Jason says:

    Switching COVID testing from posterior nasopharyngeal to anterior nares would allow MAs to collect swabs, freeing up RNs to staff outpatient infusion clinics. Might be too logical for our health system to handle however.

  10. Shiva Narayanan says:

    Excellent dissection of the logistical challenges. The eventual ask is of PO antivirals- waiting to see what the Merck antiviral results are. The Regeneron post exposure prophylaxis has the same agent formulated as a SQ injection. Their energies should be focused to develop that as an option for mild disease as well. With the challenges we have faced trying to do ambulatory clinical studies for COVID,I see in home OPAT as the only feasible option for any IV infusion therapy.

  11. Christine Dunbar says:

    In case your readers do want help pronouncing it, here’s a video I made to help people: https://youtu.be/P6ddvOc3Z38

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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