Briefing documents for Thursday's FDA advisory panel reviewing Rockwell Medical's (RMTI) Triferic iron replacement therapy were posted to the agency's Web site this morning. Overall, the FDA's assessment of Triferic raises questions about the clinical meaningfulness of the data supporting the product's proposed use as an iron replacement and treatment for maintenance of hemoglobin in kidney dialysis patients. This was the big risk for Rockwell Medical going into Thursday's FDA panel, as I described in a column two weeks ago.
Rockwell shares are up 13% to $9.90 Tuesday morning as investors read and digest the FDA's Triferic briefing documents. Why is the stock green if the product is in trouble? Because the FDA review reads fairly straight with little editorializing, which gives the company some hope for a positive vote on Thursday. I have my doubts, but crazier things have happened at FDA advisory panels so we'll see.
FDA and Rockwell agree that the two phase III studies of Triferic both met their respective primary endpoints of maintaining hemoglobin levels compared to placebo with statistical significance. FDA notes, however, that half of the dialysis patients in the phase III studies dropped out before the end of the year-long treatment period. In fact, only 20% of dialysis patients randomized actually finished the full treatment schedule. Most patients who discontinued from the Triferic study did so because they required treatment for anemia with erythropoietin stimulated agents (ESAs) or intravenous iron.
In other words, what's the point of using Triferic if dialysis patients still require ESAs or intravenous iron to maintain hemoglobin levels?
Here's FDA laying out the key efficacy issue for the experts on the panel to discuss Thursday:
Consequently, there is a considerable amount of "missing data" due to study drug discontinuation by the end of the study treatment period. It is noted that a large portion of the missing data due to withdrawn patients is due to protocol-mandated changes in anemia management, which were incorporated into the protocol to protect patient safety. The large proportion of patients with early withdrawal from study treatment necessitates examination of the study data to assess impact of the early discontinuation of patients on the validity and robustness of the efficacy results...
Given the extent of subjects who withdrew from the study early (including protocol mandated drop-out) and differential reasons for such early withdrawal, does the primary efficacy endpoint analysis adequately capture the benefit of the treatment? If yes, is the benefit of the treatment well estimated/established?
Rockwell conducted a third study designed to demonstrate Triferic's ability to reduce the use of costly ESAs by dialysis patients. FDA analyzed the data from this study, dubbed "PRIME," and basically threw out the results:
The results showed that the subjects receiving SFP [Triferic] had a mean increase of 7.3% in prescribed ESA dose at end-of-treatment as compared to a mean increase of 37.3% in the placebo group (p=0.045). However, the subjects receiving SFP had a mean 12.5% increase in actual ESA dose as compared to a mean 42.2% increase in the placebo group and the differences between the two treatment groups did not reach statistical significance (p=0.098). The secondary efficacy endpoint analysis showed a similar distribution of changes in the prescribed ESA dose between the SFP and the placebo groups (p=0.915). In addition, the NIH-FP-01 study protocol stated that this study was exploratory in nature and statistical tests were considered to be descriptive rather than conclusive. No formal sample size determination was provided in the protocol. Because of the inconsistent efficacy results and exploratory nature of the study, the submitted data is insufficient to support the proposed second indication to reduce the prescribed dose of ESA required to maintain desired hemoglobin levels. [Emphasis added.]
The inability to make a claim for reduced ESA use is a big blow to the commercial potential of Triferic, if Rockwell manages to win a positive recommendation from Thursday's FDA panel and eventually get the product approved.