A new experimental drug called NV-387 is entering human trials for monkeypox treatment, offering hope where current approved medications have shown limited effectiveness or serious safety concerns. The Phase II clinical trial will begin soon in the Democratic Republic of Congo, where monkeypox Clade I is endemic. This development matters because the two drugs currently in the U.S. Strategic National Stockpile for orthopoxviruses have significant limitations, leaving a critical gap in pandemic preparedness .

Why Are Current Monkeypox Treatments Failing?

The existing options for treating monkeypox are proving inadequate. Tecovirimat (TPOXX), one of the two approved drugs, failed to show any effectiveness over placebo in a clinical trial, according to a National Institutes of Health press release from August 2024. The other approved drug, brincidofovir (TEMBEXA), carries a black-box warning due to severe liver toxicity and gastrointestinal side effects. Additionally, three monkeypox patients treated with TEMBEXA developed liver dysfunction, making it unsuitable for widespread pandemic response .

Meanwhile, the Jynneos vaccine, originally developed for smallpox, offers limited protection against monkeypox. The vaccine shows only 36% effectiveness with one dose and 66% effectiveness with two doses against the less severe monkeypox Clade II. Protection is likely much lower against the more dangerous Clade I strain. Vaccines also provide no protection during the first few weeks after administration, limiting their usefulness during acute outbreaks .

How Does NV-387 Work Differently Than Other Antivirals?

NV-387 uses a fundamentally different approach called "host-mimicry." Instead of targeting specific viral proteins that can mutate and develop resistance, the drug mimics human cell structures that viruses must use to infect cells. Specifically, it displays ligands that mimic sulfated proteoglycans, which are attachment receptors that virtually all viruses require for cell entry .

"NV-387, our broad-spectrum antiviral drug is poised to cause a revolution in treatment of viral diseases, just as antibiotics revolutionized the treatment of bacterial diseases," said Anil R. Diwan, President and Executive Chairman of NanoViricides. "NV-387 is designed to mimic human cells to trap and destroy the virus. This single drug can target over 90-95% of human pathogenic viruses due to this biomimicry, which is reminiscent of the antibiotic penicillin that targets a large number of human pathogenic bacteria."

The key advantage is that viruses cannot easily escape this mechanism. Tecovirimat resistance can develop from a single point mutation in a viral protein called VP-37. In contrast, viruses cannot change their fundamental need for sulfated proteoglycans without losing their ability to infect cells. No matter how much the virus mutates in the field, it continues to require these attachment receptors, making escape from NV-387 highly unlikely .

In animal models, NV-387 demonstrated strong antiviral activity against orthopoxviruses, the family that includes monkeypox and smallpox. Its effectiveness matched that of tecovirimat in two different infection models: direct skin infection and direct lung infection .

What Makes Monkeypox a Growing Concern in the U.S.?

Monkeypox is becoming increasingly important for U.S. pandemic preparedness. As of March 23, 2026, there have been 15 cases of monkeypox Clade I in the United States since November 2025, with 4 cases occurring in March 2026 alone. More concerning, three cases of monkeypox Clade I in California showed no travel history to Africa and occurred in unconnected individuals, suggesting community spread is already underway .

Monkeypox Clade II has become endemic in the United States at low levels, primarily affecting men who have sex with men through sexual transmission. However, Clade I is substantially more severe and poses a greater pandemic risk. The combination of rising Clade I cases, evidence of community spread, and the failure of existing treatments creates an urgent need for new therapeutic options .

Steps to Understanding NV-387's Clinical Development Path

• Phase II Trial Location: The trial will take place in the Democratic Republic of Congo, where monkeypox Clade I is endemic, ensuring researchers study the most severe and clinically relevant form of the virus.
• Trial Timeline: Clinical trial site preparations are being conducted by Om Sai Clinical Research in India and associates in the DRC, with staff training expected in the first week of April 2026 and patient enrollment to follow.
• Regulatory Pathway: NanoViricides has applied for Orphan Drug Designation from the U.S. FDA, which would provide benefits including frequent FDA meetings, fee waivers, research and development credits, and extended marketing exclusivity worth tens of millions of dollars.
• Market Opportunity: If successful, NV-387 could become the primary pandemic response candidate for monkeypox, potentially capturing contracts similar to existing smallpox drug stockpiling agreements worth several hundred million dollars.

The trial will specifically evaluate the safety and effectiveness of NV-387 in patients with monkeypox disease caused by human monkeypox virus infection. All cases in the trial are expected to be Clade I, the more severe strain .

The development of NV-387 represents a significant shift in antiviral strategy. Rather than relying on vaccines and antibodies that viruses can escape through mutation, or small chemical drugs vulnerable to single-point mutations, NV-387 targets the fundamental cellular mechanisms viruses cannot abandon. As new viruses emerge and existing viruses acquire greater pathogenicity and infectivity, having a broad-spectrum drug arsenal that viruses cannot escape becomes increasingly critical for global health security .