Courting the US FDA on a rare disease program is a little like online dating. Everyone swears they want the same things, the early messages are warm, and then somewhere around the third meeting you discover the two of you had very different definitions of “substantial and robust.” One of you thought this was going somewhere. The other had concerns the whole time and assumed you knew.
The relationship has been especially confusing in 2026. In the first six weeks of the year, the FDA fell hard for the first-ever treatment for Menkes disease, a fatal ultrarare condition and committed despite some genuinely alarming data on the first date. In that same stretch, the agency ghosted four other rare disease programs that thought they were practically engaged. Hot and cold, all in one quarter. It would be easy to conclude that FDA simply does not know what it wants.
It does. Orphan therapies still made up nearly half of the agency’s novel approvals through May, several of them firsts for their disease, so the flexibility is real and the agency is very much still saying yes. The trouble is that sponsors keep misreading the signals. The encouraging news for cash-strapped developers is that the FDA’s type is remarkably consistent. Learn to read the green flags and the red ones, and you stop taking the rejections so personally.
The One Green Flag That Outshines the Rest
If you learn to spot only one thing, spot the size of the treatment effect. It is the trait FDA falls for again and again. When the effect is large, unambiguous and mechanistically grounded, the agency will overlook an astonishing amount, accepting single-arm studies, external controls, biomarker surrogates, even published case reports. When the effect is modest, the FDA suddenly remembers it has standards.
Sentynl Therapeutics’ Zycubo for Menkes is the clearest example of being so charming that your flaws stop mattering. The package leaned on a pair of small open-label studies against an external control, and it showed a 78% reduction in the risk of death. The agency more or less said out loud that a survival benefit that large lets it tolerate greater uncertainty everywhere else, including on safety. And there was real baggage to overlook here, including a damning inspection finding over data reliability. The FDA committed anyway. A big enough green flag forgives a lot of red ones.