The results of this analysis of data from adults enrolled in the MAA demonstrate that asfotase alfa improved walking ability, physical functioning, and HRQoL, and reduced pain, confirming the results of earlier studies [3, 14, 16,17,18]. No participant met the criteria for stopping therapy because of clinical deterioration as measured by decreases in 6MWT or Bleck score greater than the MCID, increases in pain severity as measured by BPI-SF score, or worsening in HRQoL as measured by EQ-5D-3L utility score.

Patients in this analysis first displayed signs and symptoms of HPP at a median age of 5.5 years, with all experiencing signs and symptoms by age 15. Despite this, the median age of diagnosis was 27.0 years (range: 0–59.3 years). These findings are in agreement with previous reports showing median diagnostic delays of 13–25 years among adults with HPP and highlight chronic misdiagnosis as an outstanding problem in treatment of patients with HPP [13, 23].

The median increase in distance walked in the 6MWT was 157.3 m by 6 months of treatment, reaching a median distance of 294.0 m, and an increase was sustained through 36 months (169 m); these improvements were substantially greater than the prespecified MCID of 25 m. Similarly, the median percent predicted 6MWT distance walked increased by 30.7% by month 6, and improvement was sustained at more than the prespecified 10% MCID through 36 months. The median improvement in the Bleck score was two points from baseline to month 36, again reaching the prespecified MCID. The median Bleck score increased from 6.0 at baseline to 6.5 at month 36. Bleck scores of 6 and 7 correspond with the ability to walk up to 300 m (2–3 blocks) with use of crutches or canes and the ability to walk up to 300 m without any aids, respectively [24]. Taken together, these results demonstrate that the improvement in mobility and physical functioning are realised early and sustained through at least 3 years, validating and expanding on results of earlier studies [25].

All 24 participants had pain medications reported, including 20 participants with opioid use, before or after asfotase alfa initiation. More participants were taking at least one analgesic at the end of the study compared with time of enrolment. However, four participants were able to reduce the number of opioid medications they were taking during treatment with asfotase alfa, and another four participants were able to discontinue all opioids. The increased number of patients taking analgesics at the end of the study was potentially caused by increased mobility throughout the treatment period, as measured by the 6MWT and Bleck assessment—although increased analgesic use may have also contributed to improved mobility. Other potential reasons for the increase require further assessment.

Pain is one of the principal contributors to poor HRQoL in adults and children with HPP [10, 11, 26]. Overall, there was a substantial improvement in HRQoL measures, as determined using EQ-5D-3L in the current analysis, corresponding with the decrease in opioid analgesic use and decrease in BPI-SF scores. Some participants experienced a range of conditions unrelated to treatment or HPP, including a breast cancer diagnosis, depression, anxiety, and the effects of the COVID-19 pandemic that may have affected some of the responses to the quality-of-life questionnaires.

Asfotase alfa was generally well tolerated, with almost all adverse events being mild or moderate in severity. The most common adverse events related to treatment were injection site reactions and injection-associated reactions. This is consistent with results of prior studies [3, 14, 16,17,18]. Although three serious adverse events in this analysis were attributed to asfotase alfa, few serious adverse events have been reported in prior studies of asfotase alfa. Two of the five prior published studies reported serious adverse events [3, 14, 16,17,18]. In one study, of the 29 serious adverse events reported in 9 participants, eight events in 2 participants were assessed as being related to asfotase alfa treatment; one participant withdrew from this study after an anaphylactoid reaction [14].

The UK adult data submitted to the MAA, alongside the results of the prior studies of asfotase alfa, prompted NICE to recommend asfotase alfa as a treatment option for adults with paediatric-onset HPP whose symptoms started before age 6 months [27]. Asfotase alfa is also recommended for adults whose symptoms started between ages 6 months and 17 years if they have two or more of the following: current fractures with a history of non-traumatic, recurring, or non-healing or poorly healing fractures; limited mobility assessed by a specialist using the modified Bleck Ambulation Efficiency Score and a Bleck score between 1 and 6; or clinically significant continuing or recurring musculoskeletal pain which affects daily activities and HRQoL and has not improved after two different classes of analgesic recommended by a national pain specialist.

This analysis has some limitations. It is difficult to assess the fracture data in treated participants in the absence of an untreated comparator arm. However, there were few fractures in this cohort, with only 4/24 participants experiencing a fracture during follow-up. This compares with an overall observed history of fractures in the Global HPP Registry of 62.1% in untreated participants [12]. While BPI-SF pain scores showed improvement over time with asfotase alfa treatment, analgesic use also increased over time, limiting the interpretability of these results. The MAA took place during the COVID-19 pandemic, causing many participants to miss at least one assessment and limiting the amount of data collected. The COVID-19 pandemic-related lockdowns may also have affected the answers of the participants to the daily activities and depression/anxiety components of the EQ-5D-5L questionnaire. The data are also limited by the observational nature of the MAA in which data were collected under routine clinical care and by rolling enrolment of participants into the MAA, both of which result in variable participant numbers throughout follow-up.