**Background:** Patients with severe haemophilia A are living longer due to treatment advances and consequently face age-related comorbidities—including hypertension, cardiovascular disease, obesity, diabetes, chronic liver disease from hepatitis B/C or HIV—alongside haemophilia-associated morbidities such as arthropathy. Limited data exist on treatment outcomes specifically in older haemophilia patients with comorbidities. Damoctocog alfa pegol is a PEGylated extended half-life factor VIII previously shown efficacious and safe in the overall PROTECT VIII population over ≥5 years with dosing intervals up to every 7 days.
**Methods:** This post hoc analysis of the phase 2/3 PROTECT VIII study (NCT01580293) and its extension included patients aged ≥40 years at study entry who received damoctocog alfa pegol prophylaxis during both the main 36-week study and the extension, and had ≥1 comorbidity of interest (infections [HIV, hepatitis B, hepatitis C], metabolism/nutrition disorders [hyperlipidaemia, diabetes, obesity], hypertension, or cardiac disorders) as recorded by investigators using MedDRA version 22.1. During the main study, patients were randomised to 30–40 IU/kg twice weekly, 45–60 IU/kg every 5 days, or 60 IU/kg every 7 days; regimens could be adapted in the extension. Bleeding events and infusions were recorded in electronic diaries. Annualised bleeding rates (ABRs) were calculated prestudy, during weeks 10–36 of the main study, and during the extension. Safety assessments included adverse events, renal (serum creatinine, creatinine clearance) and hepatic (AST, ALT) biomarkers. No formal statistical testing was performed; analyses were descriptive.
**Key Results:** Of 104 patients on prophylaxis in both study periods, 34 (34%) were aged ≥40 years with ≥1 comorbidity. Mean age at enrolment was 49.4 (SD 6.2) years; mean BMI was 25.0 kg/m². Comorbidities included hepatitis C (n=33; 23 chronic), hepatitis B (n=8 current infection), HIV (n=4), hypertension (n=11), hyperlipidaemia (n=4), obesity (n=1), arrhythmia (n=1), and mitral valve prolapse (n=1). Target joints were present in 19 patients (55.9%) at baseline. Median time in study was 3.9 (range 1.0–6.9) years. Prestudy median total ABR was 6.0 (Q1;Q3: 0.0;15.0); during the main study and extension, median total ABRs were 2.1 (0.0;5.8) and 2.2 (0.6;6.0), respectively. Median joint ABRs were 2.0 (0.0;12.0) prestudy, 1.9 (0.0;4.4) during the main study, and 1.6 (0.0;4.0) during the extension. All 19 patients with baseline target joints had ≥1 resolved by end of extension; 7 patients developed new target joints, of which 4 (57.1%) resolved. During the main study, 26 patients (76.5%) reported adverse events (AEs); 2 (5.9%) had drug-related AEs (mild palpitations, moderate arthralgia). During the extension, 30 patients (88.2%) reported AEs; 1 (2.9%) had a drug-related AE (mild increase in urine beta 2 microglobulin). No drug-related serious AEs, deaths, thrombotic events, or cardiovascular events occurred. Median renal and hepatic biomarkers remained within normal ranges. Mean adherence exceeded 95% throughout. Median annual prophylaxis dose was 3245.5 IU/kg (main) and 3409.5 IU/kg (extension).
**Clinical Implications:** This analysis provides evidence that damoctocog alfa pegol prophylaxis is effective and well-tolerated in older patients with severe haemophilia A and comorbidities, including those on concomitant cardiovascular medications (73.5%) and antithrombotics (5.9%). The absence of thrombotic events and lack of deterioration in renal or hepatic function over up to 7 years of follow-up address key safety concerns in this population. Dosing flexibility (every 5 or 7 days) with high adherence supports individualised regimens that may reduce treatment burden for patients with comorbidities and age-related barriers to self-infusion. Limitations include the small sample size (N=34), lack of a comparator group, the relatively young mean age (~50 years, excluding those >65), and the post hoc design. These data support damoctocog alfa pegol as a long-term prophylactic option for older haemophilia A patients with comorbidities.