Retrospective studies led to European approval of the steroidogenesis inhibitor Metyrapone for the treatment of endogenous Cushings syndrome (CS). We prospectively showed good efficacy and safety of Metyrapone after 12 weeks (Wk12) treatment in the phase III/IV PROMPT study and now report results of an extension study (EXT) sponsored by HRA Pharma Rare Diseases.
This was a single arm, open-label, 24Wk extension of PROMPT that enrolled patients whose mean of 3 UFC (mUFC) was normal or less than 2-fold the upper limit of normal (ULN, 165 nmol/d) at Wk12. The EXT measured UFC at Wk24 (for dose titration) and Wk36 by liquid chromatography tandemmass spectrometry.
At the end of PROMPT (Wk 12), mUFC was normal in 23 of 49 patients and < 2-fold ULN in 19. The EXT baseline median mUFC was 0.96-fold ULN (159, range 5 333 nmol/d, n = 41). At Wk36, median mUFC in 35 completers was 1.04-fold ULN: mUFC was normal in 17 patients, < 2 × ULN in 11 and ≥ 2× ULN in 7. mUFC at Wk36 was normal in 5/14 evaluable patients with mUFC 1–2× normal at Wk12. mUFC at Wk24 was normal in all 20 patients with normal Wk12 mUFC; at Wk36 12 maintained normal values, 4 had mUFC < 2 × ULN, and 4 had mUFC ≥ 2× ULN. PROMPT and EXT response rates were similar (80%, 95% CI 66–89 vs 71%, 95% CI 55–84). Wk36 metyrapone dose was higher in mUFC 2-fold ULN group than others (2357 vs 1618–1750 mg/d). Median late night salivary cortisol was 4.8-fold ULN at Wk0 and 1.7-fold ULN at Wk36; 27% were normal. Clinical improvement of physical symptoms, cardiovascular and metabolic parameters continued. Adverse events (n = 3: hirsutism, acute glaucoma or hypotension) or patients or physicians decision (n = 3) prompted discontinuations. Compared to first 12-week period, good tolerability profile was maintained: no patient was treated for adrenal insufficiency and fewer patients reported nausea, vomiting, dizziness, or fatigue. There were 3 new cases of female hirsutism and one new case of hypertension.
mUFC was normal in 47–49% of completers at Wk12 and Wk36, and good tolerability continued. Normalization of mUFC during EXT validates continued titration after Wk12 in some patients. Variability of intra-patient steroidogenesis, baseline UFC and titration algorithms should be considered to improve overall UFC normalization. Late night salivary cortisol improvement was maintained during the extension and the distribution of metyrapone over the day should be considered to improve this rate.
22 May 2021 - 26 May 2021