The Food and Drug Administration is holding firm that not enough evidence has been gathered to support an approval filing for a closely watched genetic medicine targeting Huntington’s disease, a position that further rattled the treatment’s developer and its shareholders.

Netherlands-based UniQure met with the FDA on Jan. 30 to discuss potential paths forward for its “AMT-130” gene therapy, which is designed to address the underlying cause of Huntington’s. According to UniQure, the agency disagreed that a couple ongoing studies backing AMT-130 could serve as the core of a marketing application, in part because they used so-called external controls to measure effectiveness.

UniQure said FDA staff “strongly recommended” the company conduct another trial that’s randomized and double-blind, with a control group that receives a “sham surgery.” (AMT-130 is administered directly to the brain via a tiny catheter that’s fed through small holes drilled into patients’ skulls.) UniQure plans to keep engaging with the agency about late-stage development, and to request another meeting between April and June to “further discuss potential study design approaches.”

Joseph Schwartz, an analyst at Leerink Partners, wrote in a note to clients that UniQure’s update is the “worst case scenario for many investors.” Company shares had plummeted 35%, to a little over $10 apiece, by late morning Monday.

With AMT-130, UniQure finds itself in the crosshairs of an FDA that has given conflicting signals about how it views genetic medicines as well as drugs for rare diseases. Last month, the FDA published a roadmap on testing therapies for extremely uncommon conditions — a move the agency claims is meant to speed the development of bespoke treatments. Several rare disease therapies have also been the recipients of a new, controversial voucher program that drastically shortens approval review timelines.

Yet, a series of surprise delays, rejections and changes in regulatory guidance have left some drugmakers and industry experts confused about the FDA’s goals and standards.

UniQure, for example, had met extensively with agency staff to ensure the two parties were on the same page about what would be needed for an AMT-130 approval application. The company thought it met those requirements in late September, when it impressed both investors and the Huntington’s research community with positive results from a mid-stage clinical trial. The study found that treatment with AMT-130 had slowed signs of disease progression by 75% after three years.

UniQure was therefore surprised when, during a meeting later that fall, the FDA didn’t view its data as adequate. This “key shift from prior communications” — as UniQure described it — raised significant doubts about the program’s future. Vinay Prasad, head of the FDA office that regulates gene therapies, adds another layer of complexity, since he has criticized the ways in which the agency has tried to expedite the review of certain genetic medicines.

Paul Matteis, an analyst at Stifel, caught up with UniQure executives after that mid-fall meeting. Though they confirmed Prasad was not in attendance, Matteis wrote in a note to clients that it’s “hard to believe that this ... about face happened without him knowing or being involved.”

In the months since, UniQure hasn’t been able to reassure shareholders. A recent appearance by FDA Commissioner Martin Makary on CNBC didn’t help either, as some investors interpreted his comments as critical of AMT-130 specifically.

“Obviously this is disappointing, albeit not super surprising after ... Makary's unorthodox CNBC interview last week,” Matteis wrote in a client note Monday, referring to UniQure’s latest update. The bottom line, Matteis added, is that “a sham-controlled study introduces meaningful risk and the broader question is whether there's any other avenues [the company] can explore to put pressure on the agency.”

UniQure believes “the totality and durability of our data warrant continued substantive dialogue regarding how the FDA’s stated commitment to regulatory flexibility may be appropriately applied in this setting,” said Matt Kapusta, the company’s CEO, in a statement.