A total of 235 individuals were screened for CH-ACM-01, of whom 80 (34%) failed screening and 155 were enrolled. For CHIASMA OPTIMAL, 119 individuals were screened; 63 (53%) failed screening and 56 of were enrolled into the trial, 28 of whom were randomized to OOC. Baseline characteristics are described in Table 2. The baseline disease characteristics of patients enrolled in both trials were very similar despite the difference in biochemical values due to varying inclusion criteria (IGF-I < 1.3 × ULN for the CH-ACM-01 trial and IGF-I ≤ 1.0 × ULN for CHIASMA OPTIMAL).
For both trials, > 80% of patients reported active acromegaly symptoms at baseline despite long-term treatment with iSRLs (injectable long-acting forms of either octreotide or lanreotide) [18, 19]. In CH-ACM-01, at baseline, 81% of patients reported ≥ 1 acromegaly symptom, 61% had ≥ 2, and 43% had ≥ 3 (Table 2). In the OOC group of CHIASMA OPTIMAL, at baseline, 82% of patients had ≥ 1 symptom, 64% had ≥ 2, and 36% had ≥ 3. For the placebo group, 86% had ≥ 1 symptom, 68% had ≥ 2, and 50% had ≥ 3 (Table 2).
Eligibility in the CH-ACM-01 trial was based on a screening visit prior to the baseline visit, and for CHIASMA OPTIMAL, baseline IGF-I values were derived as an average of the second screening value and the baseline visit. Of interest, some patients had lost biochemical response between screening and the baseline visit in both trials: 12% of patients in CH-ACM-01 and 11% of patients in CHIASMA OPTIMAL no longer had IGF-I levels below the screening cutoff, suggesting variability in IGF-I levels in patients with biochemically controlled acromegaly (Table 2).
Efficacy of OOC
Both trials demonstrated the effectiveness of OOC in all prespecified analyses. Using LOCF imputation, 65% of patients in the CH-ACM-01 trial maintained response during the core phase (response defined as IGF-I ≤ 1.3 × ULN), and 64% of patients in the OOC group of the CHIASMA OPTIMAL trial maintained response at the end of the DPC period (response defined as IGF-I ≤ 1.0 × ULN). Using the WOCF imputation, maintenance of response was 53 and 58% in the CH-ACM-01 and CHIASMA OPTIMAL trials, respectively (Table 3) [18, 19]. More than 85% (86 and 90% in the CH-ACM-01 and CHIASMA OPTIMAL trials, respectively) of the patients enrolled in the extension phases of each trial. Efficacy outcomes of the OOC treatment arms of CH-ACM-01 and CHIASMA OPTIMAL trials are summarized in Table 3. Efficacy outcome data for the CHIASMA OPTIMAL placebo group were reported previously .
Post hoc analysis using longitudinal IGF-I and GH measurements were used to provide a time-weighted average (TWA) that included all measurements for CH-ACM-01. TWA is an integrated measure of response over the entirety of the treatment period, which is more clinically relevant because fluctuations of IGF-I (± 30%) are common [20,21,22]. Single timepoint responder analyses have limited utility in quantifying durability of response [23, 24]. Of the patients who entered the fixed-dose period, 80% completed the core period and were responders using TWA, in comparison to 75% using endpoint analysis. Additionally, 95% of patients maintained response throughout the extension period using TWA analysis versus 85% using endpoint analysis.
Outcomes by prior injectable dose
In CH-ACM-01, patients previously treated with low-mid doses versus high doses (dosing; Table 2) of long-acting SRLs had a 71.6 and 55.6% response rate at the end of treatment, respectively, but a formal between-group comparison was not performed. In CHIASMA OPTIMAL, maintenance of response was observed in 66.7% (4/6) of patients previously receiving low doses of iSRLs and 54.5% (12/22) of patients on medium-high injected doses. The treatment effect in CHIASMA OPTIMAL was consistent irrespective of prior dose of iSRL (odds ratio, 5.4 in low dose; 5.9 in medium-high dose).
Responders during the core treatment period of CH-ACM-01 (n = 82) had final OOC doses of 40 mg (n = 48), 60 mg (n = 19), and 80 mg (n = 15). Breakdown by prior iSRL dose did not indicate a clear relationship with OOC dose in CH-ACM-01 (Fig. 2). This was not assessed in CHIASMA OPTIMAL because it is difficult to extrapolate dose correlations from CHIASMA OPTIMAL in the same manner as CH-ACM-01 owing to the limited sample size.
80% of patients entering the fixed-dose phase improved or maintained acromegaly symptoms (36% maintained; 44% improved) at the end of the CH-ACM-01 trial. At the end of treatment, 80% of patients reported ≥ 1 acromegaly symptom, 56% had ≥ 2, and 38% had ≥ 3. Acromegaly symptoms were not an efficacy endpoint for the CHIASMA OPTIMAL trial; however, AESIs were observed more frequently in patients receiving placebo than those receiving OOC (92.9% vs. 53.6%), indicating the emergence of acromegaly signs and symptoms while off treatment. The most common AESIs observed were arthralgia, hyperhidrosis, fatigue, carpal tunnel syndrome, and headache.
Adverse events were consistent with the well-established AE profile of iSRLs (Table 4). In the CH-ACM-01 trial, commonly reported AEs included gastrointestinal (e.g., nausea, diarrhea, dyspepsia, abdominal pain/distension, flatulence, vomiting), neurological (e.g., headache, dizziness), and musculoskeletal events (e.g., arthralgia, back pain) . In the CHIASMA OPTIMAL trial, treatment-emergent AEs with ≥ 5% incidence that were more common in the OOC group than in the placebo group were diarrhea, nausea, abdominal discomfort, vomiting, dyspepsia, blood glucose increase, sinusitis, osteoarthritis, cholelithiasis, urinary tract infection, large intestine polyp, and pain.
In both trials, the majority of events occurred within the first 3 months of treatment, with AEs decreasing over time. There were no dose-related AEs observed in the CH-ACM-01 trial. This assessment was not possible in CHIASMA OPTIMAL because of the small number of patients.