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DNA helix
BERLIN—New research suggests the investigational gene therapy BMN 270 can allow patients with severe hemophilia A to maintain normal factor VIII (FVIII) levels for over a year.
In a phase 1/2 study, patients who received the highest dose of BMN 270 had median and mean FVIII levels that were consistently within the normal range from week 20 to week 52 and beyond.
The highest dose of BMN 270 reduced the mean annual FVIII infusions by 94% and the mean annualized bleed rate (ABR) by 97%, when compared to prophylaxis.
BMN 270 was also considered well tolerated, and none of the patients developed FVIII inhibitors.
The most common adverse event (AE) in this study was alanine aminotransferase (ALT) elevations. In fact, the increase in ALT levels exceeded a pre-specified threshold, which resulted in the study being placed on hold last year.
However, the hold was ultimately lifted. All cases of ALT increase were non-serious, and all patients with ALT increases have either stopped receiving corticosteroids or are being tapered off of them.
John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, presented these results as a late-breaking abstract at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress. The research was sponsored by BioMarin.
In this phase 1/2 study, 15 patients with severe hemophilia A (FVIII activity levels less than 1%) received a single dose of BMN 270.
Seven patients received a dose of 6e13 vg/kg, 6 received 4e13 vg/kg, and 2 were treated at lower doses as part of dose-escalation and did not achieve therapeutic efficacy.
Safety
Overall, BMN 270 was considered well tolerated across all doses. None of the patients developed inhibitors to FVIII, and none of them withdrew from the study.
The most common AEs across all dose cohorts were ALT elevations (n=10, 67%), arthralgia (n=7, 47%), and back pain, fatigue, and headache (n=5, 33% each).
All ALT increases were non-serious, of limited duration (lasting 0.4 to 7 weeks), and grade 1 in severity. All 7 patients at the 6e13 vg/kg dose remain off of corticosteroids, with no lasting significant impact on FVIII expression and normal ALT levels.
Three of the 6 patients in the 4e13 vg/kg dose cohort received corticosteroids for ALT increases. One has successfully tapered off corticosteroids, and 2 are still tapering off of them.
Two patients reported serious AEs during the study.
One patient was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving BMN 270 (4e13 vg/kg dose). The event resolved within 48 hours following treatment with paracetamol. The event was considered related to BMN 270.
The other serious AE—planned total knee replacement for chronic arthropathy—was not related to BMN 270.
FVIII levels: 6e13 vg/kg
For patients in the 6e13 vg/kg dose cohort, median and mean FVIII levels from week 20 through 52 have been consistently within the normal levels post-treatment. At 1 year after dosing, the median and mean FVIII levels continue to be above 50%.
Table 1: FVIII levels (%) of 6e13 vg/kg dose patients by visit (n=7)
| Week* | 20 | 24 | 28 | 32 | 36 | 40 | 44 | 48 | 52 |
| 6e13 vg/kg dose | |||||||||
| N** | 7 | 7 | 7 | 6 | 7 | 7 | 7 | 7 | 7 |
| Median
FVIII level*** (%) |
97 | 101 | 122 | 99 | 99 | 111 | 105 | 105 | 89 |
| Mean
FVIII level*** (%) |
118 | 129 | 123 | 122 | 116 | 124 | 122 | 106 | 104 |
| Range
(low, high) |
(12, 254) | (12, 227) | (15, 257) | (26, 316) | (31, 273) | (17, 264) | (20,242) | (23,196) | (20, 218) |
* Weeks were windowed by +/- 2 weeks
** For week 32, one patient had no FVIII reading
***Bolded numbers are in the normal range of FVIII as defined by the World Federation of Hemophilia
FVIII levels: 4e13 vg/kg
For the 4e13 vg/kg dose cohort, the median and mean FVIII levels from week 8 to 24 are in the mild level. Three of these subjects, who have been observed for 24 weeks, are at the upper end of mild.
Table 2: FVIII levels (%) of 4e13 vg/kg dose patients* by visit (n=6)
| Week* | 4 | 8 | 12 | 16 | 20 | 24 |
|
4e13 vg/kg dose |
||||||
| N | 6 | 6 | 6 | 3 | 3 | 3 |
| Median
FVIII level** (%) |
4 | 15 | 21 | 35 | 37 | 33 |
| Mean
FVIII level** (%) |
5 | 13 | 19 | 33 | 38 | 33 |
| Range
(low, high) |
(2,10) | (3,21) | (6,32) | (28,38) | (31,45) | (24,41) |
*Weeks were windowed by +/- 2 weeks
** Bolded numbers are in the mild range of FVIII as defined by the World Federation of Hemophilia
ABR and FVIII infusions
Six of the 7 patients in the 6e13 vg/kg cohort were on pre-study prophylaxis.
After these patients received a single dose BMN270 and reached a FVIII level above 5%, the mean ABR was reduced by 97%, from 16.3 to 0.5. The median ABR for these patients was reduced from 16.5 to 0.
The mean annualized FVIII infusions were reduced by 94%, from 136.7 to 8.5. And the median annualized FVIII infusions were reduced from 138.5 to 0.
All 6 patients in the 4e13 vg/kg dose cohort were on pre-study prophylaxis.
The mean ABR was reduced from 12.2 pre-study to 0 after they reached an FVIII level above 5%. The median ABR for these patients was reduced from 8.0 to 0.
The mean annualized FVIII infusions were reduced from 144.2 to 0. The median annualized FVIII infusions were reduced from 155.5 to 0.
“Patients at the 2 highest doses have stopped prophylactic treatment and, to date, bleeds have effectively been eliminated,” Dr Pasi noted.
Based on these results, BioMarin is planning a phase 3 registrational study of BMN 270. The study will likely include fewer than 100 patients and collect data for no longer than a year after a single dose of BMN 270, with subsequent long-term follow-up.
The company is moving the 6e13 vg/kg dose forward but will consider doing an additional study with the 4e13 vg/kg dose at a later date.
