Famotidine, Histamine, and the Coronavirus

Here’s a new preprint on a drug-repurposing effort that many people have been wondering about: famotidine, the histamine antagonist that is sold under the brand name of Pepcid. There have been some retrospective data that have suggested that famotidine use can have a beneficial effect on the course of the disease, and a controlled trial is currently underway in New York. The idea is an attractive one, since famotidine has been on the market for many years, is inexpensive, and has a good safety profile. But as with all such drug repurposing efforts, you naturally wonder (a) if the effect is real and can be reproduced, and (b) what’s going on mechanistically, if it is real.
The aforementioned trial should go a long way towards answering the first question, and I can add at this point that it’s very good to have such an effort at the very start, rather than some of the more chaotic things we’ve been seeing with other drugs. Some of that has of course been understandable, given the course of the epidemic, but we’ve also had people who have been adding to the confusion, or at the very least doing nothing to dispel it. So that’s good, but what about the mode of action? Is there any reason for famotidine to be doing something useful here?
The preprint, a large multicenter effort, has some interesting things to say about that. It has already been noted that use of cimetidine (another H2 receptor antagonist, sold under the brand name Tagamet) does not seem to be associated with any benefit in coronavirus patients, so naturally enough the speculation has been that there is some off-target effect associated with famotidine. As this new work details, an initial hypothesis was that the compound had some effect on one of the viral proteases, and you can still find that rationale if you start looking around for comments on the drug’s MOA. That hasn’t held up, though – the compound does not seem to be an inhibitor of these enzymes. Moreover, it is not effective in a cell-based infection model with the virus, either – basically, it’s not an antiviral in any sense of the term.
What does that leave you with? The downstream effects of being infected – all the cytokine storm stuff, the inappropriate immune response that gets so many patients into trouble. And that brings the histamine receptor mechanism back around again. The paper confirms that famotidine is a much more potent H2 ligand than is cimetidine (technically, it’s more of an inverse agonist than a classic antagonist), and moreover it seems to have different consequences on receptor binding. It seems to stimulate beta-arrestin binding to the receptor and subsequent internalization (a mechanism that complicates all sorts of G-protein coupled receptor signaling), and it appears that cimetidine doesn’t do this, either. There is also a possibility that the compound acts on the CCR2L and CXCR3 chemokine receptors, which would certainly be of interest, but this needs to be firmed up.
But one of the biggest differences between famotidine and cimetidine is in their pharmacokinetics. As the preprint illustrates, the higher potency and better blood levels of famotidine mean that it has much stronger coverage of the H2 mechanism in general, especially at the dosages that seem to have an effect in coronavirus infections. So here’s the paper’s mechanistic summary:

The most straightforward explanation of the apparent famotidine activity as a COVID-19 therapy is that the drug acts via its antagonism or inverse-agonism of histamine signaling and via its arrestin biased activation—all a result of its binding to H2. If true, then it is reasonable to infer that a SARS-CoV-2 infection that results in COVID-19 is at least partially mediated by pathologic histamine release.

That’s an interesting and plausible idea – mast cells are what are involved in sudden histamine release – they’re sitting there loaded up with granules of the stuff, which can be dumped out on short notice. That’s an important part of a sudden anaphylaxis reaction, and mast cells are also involved in other immune response pathways, tissue permeability, and other processes. It’s certainly possible that they could be part of the inappropriate response to coronavirus infection and that inhibiting histamine release could be beneficial. The paper goes into details about lung physiology that tie the receptor’s action to some of the pathology seen in patients – for example, one thing that’s been noted is a lack of neutrophils and eosinophils in lung tissue samples, and both of these cell types have their activities inhibited by histamine release. In addition, the edema seen in coronavirus-affected lung tissue is unusual by the standards of viral infection, but makes more sense in light of a histamine-driven response. Mast cell degranulation also matches up with some of the other well-known symptoms (effects on smell and taste sensation, etc.)
The authors advance the idea, then, that many of the unusual features of the current virus in the clinic can be tied to histaminergic effects, and finish up this way:

If COVID-19 is partially driven by dysfunctional mast cell degranulation, then a variety of medical interventions employing marketed drugs useful for treating mast cell-related disorders may help to reduce death and disease associated with SARS-CoV-2 infection. Examples include drugs with mast cell stabilizing activity, other histamine antagonists (for example H1 and H4 types), leukotriene antagonists and leukotriene receptor antagonists, anti-inflammatory agents such as those developed for inflammatory bowel diseases, and mast cell activation inhibitors. If such repurposed drugs are used in combination with pharmaceuticals that directly inhibit SARS-CoV-2 infection or replication, it may be possible to rapidly develop potent, safe and effective outpatient treatments for preventing or treating COVID-19 until such time as a safe and effective SARS-CoV-2 vaccine becomes available.

Famotidine itself could be part of this treatment regime, of course, and there are several other agents that would seem worth investigating, especially in combination with something like remdesivir. Something to keep an eye on!
https://blogs.sciencemag.org/pipeline/archives/2020/05/29/famotidine-histamine-and-the-coronavirus