Doctor Submits Fluvoxamine EUA Application to FDA: Group of physician-scientists believes data support authorization for treating COVID-19

It took about 4 days for David Boulware, MD, MPH, to write the FDA emergency use authorization (EUA) application for fluvoxamine.

Yes, a doctor wrote an EUA application -- a task that has typically been relegated to pharmaceutical companies -- and yes, it was for a generic drug that physicians could technically prescribe off-label.

But Boulware, of the University of Minnesota, who is involved in a trial that's investigating fluvoxamine and other repurposed drugs -- along with a handful of other doctors and researchers -- took it upon themselves to apply because they believe the data substantiate its use in COVID-19.

"The big thing is, the data [are] available," Boulware said in an interview, referring to two published randomized, double-blind, placebo-controlled trials. "There should be enough data that the FDA would approve this under the normal review process to add a new indication for the drug."

He added that doctors may be "reluctant" to prescribe a drug off-label, or that "some health systems may have policies against it."

"I think most providers would feel more comfortable doing it if that therapy were FDA approved for that indication," said Carolyn Bramante, MD, MPH, also of the University of Minnesota.

Supporting Data

Boulware said two randomized controlled trials support the use of fluvoxamine in preventing disease progression. In November 2020, the STOP-COVID study, led by Eric Lenze, MD, of Washington University in St. Louis, was published as a preliminary communication in JAMA. It showed that none of the 80 outpatients in the fluvoxamine group had clinical deterioration, compared with 6 of the 72 outpatients in the control group.

The TOGETHER trial, led by Brazilian researchers, included 1,497 COVID-19 positive outpatients with a risk factor for severe disease. Overall, those who took fluvoxamine spent less time in the emergency room and were less likely to transfer to the hospital than those who got placebo (RR 0.68, 95% CI 0.52-0.88).

Boulware also mentioned a study -- though not a randomized controlled trial -- by David Seftel, MD, a doctor and CEO of Enable Biosciences, an antibody diagnostics company. Seftel conducted his own experiment, offering fluvoxamine to patients exposed to COVID-19 at a racetrack, and comparing those who accepted it with those who did not. None of those who took the drug were hospitalized, while 12.5% of those who refused the drug were, they reported in Open Forum Infectious Diseases.

Boulware was interested by the early data and helped Seftel write up the racetrack study, but he knew more data were needed. So he launched the COVID-OUT trial, with plans to enroll 1,160 COVID-19 outpatients. In addition to fluvoxamine, it will also test metformin and ivermectin for the early treatment of COVID-19.

Pros and Cons

One of the main benefits of fluvoxamine is its decades-long safety track record. It's also easy and relatively inexpensive to manufacture, the researchers said.

Newer drugs like Pfizer and Merck's antivirals, meanwhile, are only available in limited supply. In Minnesota, Boulware said, only 880 treatment courses of molnupiravir have been distributed so far. And molnupiravir had a similarly modest effect on hospitalization and death.

Like the antivirals, fluvoxamine's effects won't be variant-dependent, unlike some of the monoclonal antibodies that have been rendered useless in the face of Omicron.

While the mechanism behind fluvoxamine's effects in COVID-19 isn't clear, one perspective published in Frontiers in Pharmacology posits that its sigma-1 receptor agonism has an anti-inflammatory effects. It also may reduce platelet activation, or increase melatonin, or act in other ways to help alleviate the "cytokine storm" brought on by COVID-19.

Also, Boulware said, fluvoxamine "is anti-inflammatory, but it's not necessarily [an] immunosuppressant," compared to using steroids to treat COVID-19, which he calls "kind of a big sledgehammer of an anti-inflammatory."

To be sure, the results of the TOGETHER trial aren't spectacular, Boulware said.

"It's a modest benefit, but 30% reduction in ER visits and hospitalization is a pretty good reduction if you think about it on a population scale, particularly if you have no alternative therapies," he said.

The problem, Boulware said, is that fluvoxamine "is a generic medicine and so there's no big pharmaceutical company that's going to take the effort and the time to apply [for an EUA] because it's made by six different companies or so in the U.S., and it's an inexpensive, $5-to-$10-treatment-course, kind of medicine."

Taking Matters Into Their Own Hands

So Boulware decided to file the application himself. He spent about 4 days compiling the data, explaining why there were few alternatives to the drug, and illustrating that the benefits outweighed potential risks of taking an antidepressant.

He said prior experience writing investigational new drug (IND) applications proved helpful, and he followed the agency's EUA submission guidance to a tee. He also had colleagues proofread the application.

Boulware noted that a company has expressed interest in supporting fluvoxamine, Boulware said. This company, which he said asked not to be named, provided the manufacturing information for the EUA application. It might also be first in line to make the drug should the EUA come through.

Other caveats, Boulware said, are the lack of clarity on proper dosage of the drug. A number of study participants in the TOGETHER trial couldn't tolerate the dose of 100 mg twice a day, quitting before the treatment was done. Nausea, sexual dysfunction, excess alertness, and sleep changes are among the side effects that might stop someone from taking the fluvoxamine. Researchers still need to pin down an appropriate dose, which will likely fall somewhere in between 100 mg twice a day and 50 mg twice a day -- the dose used in the racetrack study and in COVID-OUT.

There's also a stigma around taking antidepressants and similar drugs. "It's been brought to my attention that people may refuse it because it's an antidepressant, so that is unfortunate -- the concern that it might cause changes in psyche," said Bramante.

Still, "most people who are eligible would not have a bad effect from it," she noted.

Boulware and Bramante said SSRIs take weeks to affect mood, and would be highly unlikely to have a noticeable effect in just 10 days of treatment.

Boulware says he doesn't know when he'll hear back from the FDA about the EUA, but he said he received an emailed response from the agency confirming his submission.

His best guess is that he'll have a response in a matter of weeks: "There will be more trials coming, and so [the COVID-OUT] trial will be done in a month from now," he said. "And so if they say no, we need more data, we'll just reapply a month from now."

Florida is way ahead of this.

See here:
https://www.brudirect.com/news.php?id=134985

Dr. Joseph Ladapo, Florida surgeon general and secretary of the Florida Department of Health, issued a statewide public service announcement supporting commonsense Wuhan coronavirus (COVID-19) prevention strategies, including optimizing vitamin D levels, staying active, eating nutrient-dense food and boosting the immune system with supplements.

Florida’s Health Department also highlighted emerging treatments for COVID, such as fluvoxamine and inhaled budesonide. Fluvoxamine is an antidepressant pill, while inhaled budesonide is commonly used for asthma patients.

The department stated that physicians should now use their clinical judgment when recommending treatment options for patients’ health care needs, and may include emerging treatment options so long as there is appropriate informed consent of patients.

The evidence of vitamin D against COVID satisfies the criteria for causality in a biological system, with dozens of studies having been demonstrated that it helps reduce all risks associated with the disease.

The HealthierYouFL.org website has been urging Floridians to talk to their health care providers about how certain supplements or foods containing vitamins and minerals might help boost the immune system. These vitamins and minerals include zinc, vitamin D, vitamin C and quercetin, which are all known to have shown a positive impact on mitigating COVID-19 risks.

Vitamin D important for immune function

As early as September 2020, data from 14 observational studies showed that vitamin D blood levels are inversely correlated with the incidence or severity of COVID.

The body is well-equipped to handle infections, provided the immune system is working properly. Vitamin D receptors are found in large numbers of different tissues and cells, including immune cells. Meaning, vitamin D plays an important role in immune function.

Old drug fluvoxamine, new hope for COVID-19

The coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by the novel coronavirus SARS-CoV-2. Despite the second vaccination for SARS-CoV-2, the number of individuals infected with SARS-CoV-2 variants (i.e., delta and lambda) has markedly increased worldwide. Although approximately 80% of individuals infected with SARS-CoV-2 is mild to moderate, a part of them may convert to severe clinical stages in about 1 week, ultimately resulting in the intubation or death. Using drug repurposing, it is, therefore, necessary to discover drugs that can prevent clinical deterioration [1]. Here, we discuss the emergent use of the old antidepressant fluvoxamine which may block clinical deterioration in mild to moderate patients infected with SARS-CoV-2.

In November 2020, Dr. Lenze and his colleagues reported that fluvoxamine could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In the study, clinical deterioration occurred in 0 of the fluvoxamine group (n = 80) and in 6 of placebo group (n = 72) [2]. Although sample size of this study was small, this study strongly encouraged further trials using a large sample size. In February 2021, Dr. Seftel and his colleague reported a prospective, non-randomized observational cohort study of fluvoxamine in outpatients (n = 113) infected with SARS-CoV-2 at the Golden Gate Fields horse racing track in Berkeley, California [3]. Incidence of hospitalization was 0 of the fluvoxamine-treated group (n = 65) and 6 of the observation alone group (n = 48). Two patients required intensive care unit stay with mechanical ventilation, one of them died. On April 23, 2021, fluvoxamine was added in the US National Institutes of Health (NIH) COVID-19 Guidelines Panel although there is insufficient evidence for the efficacy of fluvoxamine.

On August 6, 2021, the interim results of TOGETHER trial ( SEE HERE ) by a multinational group in Canada and Brazil were presented at the NIH symposium. They compared three compounds, fluvoxamine, the antidiabetic drug metformin, and the antiparasitic drug ivermectin. Although metformin and ivermectin did not show beneficial effects, fluvoxamine was much more promising. Among the randomized participants (n = 1,480), fluvoxamine significantly reduced the risk of disease progression by 29% (95% confidence interval 0.54–0.93) [4].

Detailed mechanisms of action of fluvoxamine for COVID-19 are currently unknown. In 1996, we reported that fluvoxamine binds to endoplasmic reticulum (ER) protein sigma-1 receptor with high affinity, suggesting a role of sigma-1 receptor in the mechanisms of its action [5]. Subsequent studies suggest that fluvoxamine is a potent agonist at sigma-1 receptor which plays a key role in inflammation [1, 5, 6]. Among the antidepressants, fluvoxamine was the most potent at sigma-1 receptor [1, 5, 6]. Furthermore, fluvoxamine has several beneficial effects, including reduction in platelet aggregation by serotonin transporter inhibition, decreased mast cell degranulation, interference with lysosomal trafficking of virus, inhibition of acid sphingomyelinase (ASM), and increased levels of metatonin by cytochrome P450 inhibition [7].

In October 2020, Gordon et al. [8] identified the sigma-1 receptor (encoded by SIGMAR1) as a functional host-dependency factor for SARS-CoV-2. Knockout or knockdown of SIGMAR1 produced robust reductions in SARS-CoV-2 replication, indicating a key role of the sigma-1 receptor in SARS-CoV-2 replication (Fig. 1). In 2019, Rosen et al. [9] demonstrated that the sigma-1 receptor is essential for the cytokine production in a mouse model of septic shock, and that fluvoxamine could protect against inflammatory response and lethal septic shock. Taken together, it is likely that the potent sigma-1 receptor agonists, such as fluvoxamine, might ameliorate inflammatory events (i.e., cytokine storm) associated with ER stress due to SARS-CoV-2 replication.

Fig. 1

Proposed biological mechanisms of fluvoxamine in the treatment of SARS-CoV-2-infected patients. SARS-CoV-2 binds to ACE2 receptor on the cells, resulting in activation of the acid sphingomyelinase (ASM) which converts sphingomyelin to ceramide. ASM/ceramide system can facilitate viral entry. Antidepressants such as fluvoxamine inhibit ASM and formation of ceramide-enriched membrane domains, resulting in decreased viral entry. Recent study shows that sigma-1-receptor ligands can attenuate SARS-CoV-2 replication [8]. Through sigma-1 receptor chaperone activity [1], the sigma-1-receptor agonist fluvoxamine may attenuate ER stress due to SARS-CoV-2 replication in cells, thus resulting in a blockade against inflammatory events (i.e., cytokine storm). Thus, early intervention using fluvoxamine may block or delay clinical deterioration in individuals with SARS-CoV-2 infection. A slight modification with Fig. 1 in the reference [10] and Fig. 3 in the reference [1]

A recent observational multicenter study (n = 2846) showed association between the use of functional inhibitors of ASM and reduced risk of intubation or death in hospitalized patients with severe COVID-19 [10]. The functional inhibitors of ASM include the antidepressants such as fluvoxamine, fluoxetine, and escitalopram. Interestingly, fluoxetine and escitalopram are also sigma-1 receptor agonists although they are less potent than fluvoxamine [1]. Considering the role of sigma-1 receptor and ASM in biological actions of SARS-CoV-2 in cells (Fig. 1), both fluoxetine and escitalopram may be prophylactic drugs for mild to moderate patients infected with SARS-CoV-2 although further clinical study is needed.

The advantages of fluvoxamine are favorable safety profiles, widespread availability, very low cost, oral administration and use for children and adolescents. If fluvoxamine is used in individuals with COVID-19 as quickly as possible after confirmation of SARS-CoV-2 infection, clinical deterioration might be prevented [1]. Importantly, fluvoxamine could be a prophylactic drug for COVID-19 in countries with low vaccination rates or low health system.

Author contributions

The authors did the reference search and wrote the commentary.

Declarations

Conflict of interest

Dr. Y. Hashimoto and Dr. Suzuki have no conflict of interest. Dr. K. Hashimoto has received speakers’ honoraria from Abbott and Meiji Seika.

References

1. Hashimoto K. Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor. Eur Arch psychiatry Clin Neurosci. 2021;271(1):249–258. doi: 10.1007/s00406-020-01231-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Lenze E, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, Miller JP, Yang L, Yingling M, Avidan MS, Reiersen AM. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19. A randomized clinical trial. JAMA. 2020;324(22):2292–2300. doi: 10.1001/jama.2020.22760. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infect Dis. 2021;8(2):ofab050. doi: 10.1093/ofid/ofab050. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

4. Sax PE (2021) Could this be our first effective, inexpensive, widely available outpatient treatment for COVID-19? NEJM J Watch. https://blogs.jwatch.org/hiv-id-observations/index.php/could-this-be-our-first-effective-inexpensive-widely-available-outpatient-treatment-for-covid-19/2021/08/12/

5. Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interaction of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol. 1996;307(1):117–119. doi: 10.1016/0014-2999(96)00254-3. [PubMed] [CrossRef] [Google Scholar]

6. Hashimoto K. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication. J Pharmacol Sci. 2015;127(1):6–9. doi: 10.1016/j.jphs.2014.11.010. [PubMed] [CrossRef] [Google Scholar]

7. Sukhatme VP, Reiersen AM, Vayttaden SJ, Sukhatme V. Fluvoxamine: a review of its mechanisms of actions and its role in COVID-19. Front Pharmacol. 2021;12:652688. doi: 10.3389/fphar.2021.652688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

8. Gordon DE, Hiatt J, Bouhaddou M, Rezelj VV, Ulferts S, Braberg H, Jureka AS, Obernier K, Guo JZ, Batra J, Kaake RM, Weckstein AR, Owens TW, Gupta M, Pourmal S, Titus EW, Cakir M, Soucheray M, McGregor M, Cakir Z, Jang G, O'Meara MJ, Tummino TA, Zhang Z, Foussard H, Rojc A, Zhou Y, Kuchenov D, Hüttenhain R, Xu J, Eckhardt M, Swaney DL, Fabius JM, Ummadi M, Tutuncuoglu B, Rathore U, Modak M, Haas P, Haas KM, Naing ZZC, Pulido EH, Shi Y, Barrio-Hernandez I, Memon D, Petsalaki E, Dunham A, Marrero MC, Burke D, Koh C, Vallet T, Silvas JA, Azumaya CM, Billesbølle C, Brilot AF, Campbell MG, Diallo A, Dickinson MS, Diwanji D, Herrera N, Hoppe N, Kratochvil HT, Liu Y, Merz GE, Moritz M, Nguyen HC, Nowotny C, Puchades C, Rizo AN, Schulze-Gahmen U, Smith AM, Sun M, Young ID, Zhao J, Asarnow D, Biel J, Bowen A, Braxton JR, Chen J, Chio CM, Chio US, Deshpande I, Doan L, Faust B, Flores S, Jin M, Kim K, Lam VL, Li F, Li J, Li YL, Li Y, Liu X, Lo M, Lopez KE, Melo AA, Moss FR, 3rd, Nguyen P, Paulino J, Pawar KI, Peters JK, Pospiech TH, Jr, Safari M, Sangwan S, Schaefer K, Thomas PV, Thwin AC, Trenker R, Tse E, Tsui TKM, Wang F, Whitis N, Yu Z, Zhang K, Zhang Y, Zhou F, Saltzberg D, QCRG Structural Biology Consortium. Hodder AJ, Shun-Shion AS, Williams DM, White KM, Rosales R, Kehrer T, Miorin L, Moreno E, Patel AH, Rihn S, Khalid MM, Vallejo-Gracia A, Fozouni P, Simoneau CR, Roth TL, Wu D, Karim MA, Ghoussaini M, Dunham I, Berardi F, Weigang S, Chazal M, Park J, Logue J, McGrath M, Weston S, Haupt R, Hastie CJ, Elliott M, Brown F, Burness KA, Reid E, Dorward M, Johnson C, Wilkinson SG, Geyer A, Giesel DM, Baillie C, Raggett S, Leech H, Toth R, Goodman N, Keough KC, Lind AL, Zoonomia Consortium. Klesh RJ, Hemphill KR, Carlson-Stevermer J, Oki J, Holden K, Maures T, Pollard KS, Sali A, Agard DA, Cheng Y, Fraser JS, Frost A, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Alessi DR, Davies P, Frieman MB, Ideker T, Abate C, Jouvenet N, Kochs G, Shoichet B, Ott M, Palmarini M, Shokat KM, García-Sastre A, Rassen JA, Grosse R, Rosenberg OS, Verba KA, Basler CF, Vignuzzi M, Peden AA, Beltrao P, Krogan NJ. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science. 2020;370(6521):eabe9403. doi: 10.1126/science.abe9403. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

9. Rosen DA, Seki SM, Fernández-Castañeda A, Beiter RM, Eccles JD, Woodfolk JA, Gaultier A. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 2019;11(478):eaau5266. doi: 10.1126/scitranslmed.aau5266. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

10. Hoertel N, Sánchez-Rico M, Gulbins E, Kornhuber J, Carpinteiro A, Lenze EJ, Reiersen AM, Abellán M, de la Muela P, Vernet R, Blanco C, Cougoule C, Beeker N, Neuraz A, Gorwood P, Alvarado JM, Meneton P, Limosin F. AP-HP / Université de Paris / INSERM COVID-19 research collaboration, AP-HP COVID CDR Initiative, “Entrepôt de Données de Santé” AP-HP Consortium (in press) Association between FIASMAs and reduced risk of intubation or death in individuals hospitalized for severe COVID-19: an observational multicenter study. Clin Pharmacol Ther. 2021 doi: 10.1002/cpt.2317.10.1002/cpt.2317. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

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