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BioMarin's Investigational Gene Therapy for Hemophilia A at 6e13 vg/kg Dose Maintains Average Factor VIII Levels within Normal Range for over One Year

BioMarin's Investigational Gene Therapy for Hemophilia A at 6e13 vg/kg Dose Maintains Average Factor VIII Levels within Normal Range for over One Year

  • BioMarin Provides BMN 270 Data at International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress
  • Initiation of Phase 3 Registrational Study Planned for Q4 2017 with 6e13 vg/kg Dose
  • 97% Reduction in Mean Annualized Bleed Rate (ABR) with 6e13 vg/kg Dose Compared to Prophylaxis
  • 94% Reduction in Mean Annual Factor VIII Infusions with 6e13 vg/kg Dose Compared to Prophylaxis
  • Gene Therapy Facility in U.S. Constructed

BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced today an update to its previously reported interim results of an open-label Phase 1/2 study of BMN 270, an investigational gene therapy treatment for severe hemophilia A. The updated results will be presented by John Pasi, Ph.D. F.R.C.P, at Barts and the London School of Medicine and Dentistry and Haemophilia Clinical Director at Barts Health NHS Trust and primary investigator for the BMN 270 Phase 1/2 clinical trial, during an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress being held July 8-13, 2017 in Berlin, Germany. Professor Pasi will present the data in a late breaking abstract on July 11, 2017, which will be the only clinical data in gene therapy for hemophilia A to be presented at the meeting.

In the open-label Phase 1/2 study, a total of 15 patients with severe hemophilia A1 (defined by the World Federation of Hemophilia (WFH) as having Factor VIII activity levels less than 1%, expressed as a percentage of normal factor activity in blood) received a single dose of BMN 270, seven of whom were treated at a dose of 6e13 vg/kg and an additional six of whom were subsequently treated at a lower dose of 4e13 vg/kg. The other two patients in the study were treated at lower doses as part of dose escalation in the study and did not achieve therapeutic efficacy. According to the WFH rankings of severity of hemophilia A, the normal range of Factor VIII activity levels for people without disease is between 50% and 150%, expressed as a percentage of normal factor activity in blood, and the mild hemophilia A range of Factor VIII activity levels is between 5% and 40%. (See Table 6 for further information on severity levels)

As of the May 31, 2017 data cutoff, all patients at the 6e13 vg/kg dose had reached 52 weeks of post-treatment follow-up. Median and mean Factor VIII levels from week 20 through 52 for the 6e13 vg/kg dose cohort have been consistently within the normal levels post treatment as a percentage calculated based on the numbers of International Units per deciliter (IU/dL) of plasma. (See Table 1). At one year after dosing, the median and mean Factor VIII levels of the 6e13 vg/kg cohort continue to be above 50%. (See Table 6)

Table 1: Factor VIII 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

Factor VIII Level**** (%)

97

101

122

99

99

111

105

105

89

Mean

Factor VIII 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)

*All patients had severe hemophilia A, defined as less than 1% of Factor VIII activity levels, expressed as a percentage of normal factor activity in blood.
**Weeks were windowed by +/- 2 weeks
*** For week 32, one patient had no Factor VIII reading
****Bolded numbers are in the normal range of Factor VIII as defined by the World Federation of Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current as of June 30, 2017). Factor VIII levels are determined by one-stage assay.

The median and mean Factor VIII levels from week 8 to 24 for all patients observed at the 4e13 vg/kg dose are in the mild level. Three of these subjects who have been observed for 24 weeks are at the upper end of mild. (See Table 2 for Factor VIII levels and Table 6 for severity levels)

Table 2: Factor VIII 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

Factor VIII Level*** (%)

4

15

21

35

37

33

Mean

Factor VIII Level*** (%)

5

13

19

33

38

33

Range

(low, high)

(2,10)

(3,21)

(6,32)

(28,38)

(31,45)

(24,41)

*All patients had severe hemophilia A, defined as less than 1% of Factor VIII activity levels, expressed as a percentage of normal factor activity in blood.
**Weeks were windowed by +/- 2 weeks
*** Bolded numbers are in the mild range of Factor VIII as defined by the World Federation of Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current as of June 30, 2017). Factor VIII levels are determined by one-stage assay.

Annualized Bleed Rate (ABR) and Factor VIII Infusions

For the six patients who were on pre-study prophylaxis after receiving a single dose of BMN 270 at 6e13 vg/kg dose and after reaching a Factor VIII level above 5%, the mean ABR was reduced by 97% from 16.3 to 0.5. The median ABR for those same patients was reduced from 16.5 to zero. The mean annualized Factor VIII infusions were reduced by 94% from 136.7 to 8.5. The median annualized Factor VIII infusions were reduced from 138.5 to zero. The 7th patient was receiving Factor VIII on demand treatment before the study and was not included in this summary. (See Table 3)

Table 3: Summary of Mean Annualized Bleeding Rate (ABR) and FVIII Infusions of 6e13 vg/kg Dose Patients Previously on Prophylaxis (N=6)*

*A 7th patient received Factor VIII on demand and was not included in analysis.
**Post infusion data were based on data after Factor VIII levels were above 5%
***Obtained from medical records.
****5 of 6 patients had 0 bleeds requiring Factor VIII infusions and 0 Factor VIII infusions after Factor VIII levels were above 5%.

For the six patients who were on pre-study prophylaxis after receiving a single dose of BMN 270 at 4e13 vg/kg dose and after reaching a Factor VIII level above 5%, the mean ABR was reduced from 12.2 to zero. The median ABR for those same patients was reduced from 8.0 to zero. The mean annualized Factor VIII infusions were reduced from 144.2 to zero. The median annualized Factor VIII infusions were reduced from 155.5 to zero. (See Table 4)

Table 4: Summary of Mean Annualized Bleeding...


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