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Clinical Trials

Date: 2017-12-09

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting

Company: Biomarin Pharmaceutical (USA - CA)

Product: BMN 270 - valoctocogene roxaparvovec- adeno-associated viral vector serotype 5 containing a B-domain deleted variant of human coagulation factor VIII gene

Action mechanism:

  • gene therapy. BMN 270 is an AAV-factor VIII vector, designed to restore factor VIII plasma concentrations, essential for blood clotting in patients with hemophilia A. The gene therapy program for Hemophilia A was originally licensed from University College London and St. Jude Children's Research Hospital in February 2013 and has since been developed at BioMarin's facilities.
  • BMN 270 has received orphan drug designation from the European Commission and the FDA.
  • The European Medicines Agency (EMA) has granted access to its Priority Medicines (PRIME) regulatory initiative for valoctocogene roxaparvovec. To be accepted for PRIME, an investigational therapy has to show its potential to benefit patients with unmet medical needs based on early clinical data. PRIME focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients with no treatment options. These medicines are considered priority medicines within the European Union (EU).
  • Regulatory Status The U.S. Food and Drug Administration (FDA) granted valoctocogene roxaparvovec Breakthrough Therapy Designation. The FDA's Breakthrough Therapy Designation program is intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious condition. To qualify for Breakthrough Therapy Designation, preliminary clinical evidence must show that that the drug may demonstrate substantial improvement over existing therapies.

Disease: hemophilia A

Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases

Country: UK

Trial details:

  • The global Phase 3 program includes two studies with valoctocogene roxaparvovec, one with the 6e13 vg/kg dose (GENEr8-1) and one with the 4e13 vg/kg dose (GENEr8-2). Both Phase 3 GENEr8 studies will be open-label single-arm studies to evaluate the efficacy and safety of valoctocogene roxaparvovec. GENEr8-1 will enroll its first patient this month, and GENEr8-2 will enroll the first patient at the start of 2018. The primary endpoint will be a change from baseline FVIII activity level, and the secondary endpoints will measure annualized FVIII replacement therapy use rate and annualized bleed rate.

Latest news:

  • • On December 9, 2017, BioMarin Pharmaceutical announced  an update to its previously reported results of an open-label Phase 1/2 study of valoctocogene roxaparvovec (formerly BMN 270), an investigational gene therapy treatment for severe hemophilia A. The updated results have been presented at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition by John Pasi, M.B., Ch.B., Ph.D., from Barts and the London School of Medicine and Dentistry and primary investigator for this Phase 1/2 study.  The data presented at ASH is the most current data (Nov. 16, 2017 cut off) and includes 78 weeks of data for the 6e13 vg/kg dose and 48 weeks of data for the 4e13 vg/kg dose.

    The data presented at ASH is the most current data (Nov. 16, 2017 cut off) and includes 78 weeks of data for the 6e13 vg/kg dose and 48 weeks of data for the 4e13 vg/kg dose.

    Efficacy Data of 4e13 vg/kg Dose as Presented at ASH

    As of Nov. 16, 2017, a total of six patients with severe hemophilia A, who had all been treated with prophylactic Factor VIII pre-study, received a single dose of valoctocogene roxaparvovec at 4e13 vg/kg.  Since the last data update provided on Oct. 18, 2017, the three patients with the longest follow-up (at week 48) have Factor VIII activity levels that are in or near to the normal range with both median and mean values of 49%. Median annualized bleed and factor VIII use rates for the 4e13 vg/kg cohort were zero after Week 4 when their Factor VIII activity rose above 5%.  According to the World Federation of Hemophilia rankings of severity of hemophilia A, the mild hemophilia A range of Factor VIII activity levels is between 5% and 40%, and the normal range of Factor VIII activity levels for people without disease is between 50% and 150%, in each case expressed as a percentage of normal factor activity in blood.

    Factor VIII Levels (%) of 4e13 vg/kg Dose Patients* by Visit (N=6) at Nov. 16, 2017 data cut
    Week**   4 8 12 16 20 24 28 32 36 40 44 48
    4e13 vg/kg Dose
    n 6 6 6 6 6 6 6 6 6 3 3 3
    Median Factor VIII Level*** (%) 4 15 21 29 34 28 34 42 38 48 56 49
    Mean Factor VIII Level*** (%) 5 13 19 26 31 29 31 37 35 50 61 49
    Range ( low, high) (2,10) (3,21) (6,32) (5,38) (7,45) (7,43) (4,44) (4,54) (4,55) (37,64)   (45,83) (38,60)
    *All patients had severe hemophilia A at baseline, defined as less than or equal to 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 to normal range of Factor VIII activity as defined by the World Federation of Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current as of Dec. 6, 2017). Factor VIII levels are determined by one-stage assay.

    Valoctocogene Roxaparvovec Reduces Bleeds and Factor VIII Use:  Summary of Annualized Bleeding Rate (ABR) and FVIII Use Rate of 4e13 vg/kg Dose for Patients Previously on Prophylaxis (N=6) at Nov. 16, 2017 data cut

    Before valoctocogene roxaparvovec Infusion After valoctocogene roxaparvovec Infusion
    Median (mean, SD) Median (mean, SD)

    Annualized Bleeding Rate* (bleeding episodes per year per subject)

    8.0 (12.2, 15.4) 0.0 (0.6, 1.4)

    Annualized FVIII Use Rate*

    (infusions per year per subject)

    155.5 (146.5, 41.6) 0.0 (2.0, 4.8)

    *Post-infusion data were based on data after Week 4.

    Efficacy Data on 6e13 vg/kg Dose as Presented at ASH

    As of the Nov. 16, 2017 data cutoff, all seven patients at the 6e13 vg/kg dose had been followed for at least 78 weeks post infusion.  Median and mean Factor VIII levels from week 20 through 78 for the 6e13 vg/kg dose cohort have been consistently within the normal range, expressed as a percentage of normal factor activity in blood.  At 78 weeks post infusion, the median and mean Factor VIII levels of the 6e13 vg/kg cohort are 90 and 89% respectively.  Median annualized bleed and factor VIII use rates for the 6e13 vg/kg were zero after Week 4.  After 52 weeks of follow-up, the phase 1/2 study protocol specified that planned patient visits were reduced in frequency from once every one to two weeks to once every three months.  Consequently, as of May 31, 2017 when all patients in the 6e13 vg/kg dose had reached 52 weeks of follow up, all patients in the 6e13 vg/kg dose converted to a quarterly follow-up visit schedule.

    Factor VIII Levels (%) of 6e13 vg/kg Dose Patients* by Visit (N=7) at Nov. 16, 2017 data cut

    Week**

    20 24 28 32 36 40 44 48 52 65 78
    6e13 vg/kg Dose
    N*** 7   7 7 6 7 7 7 7 7 7 7
    Median Factor VIII Level**** (%) 97 101 122 99 99 111 105 105 89 98 90
    Mean Factor VIII Level**** (%) 118 129 123 122 116 124 122 106 104 93 89
    Range (low, high) (12, 254) (12, 227) (15, 257) (26, 316) (31, 273) (17, 264) (20,242) (23,195) (20, 218) (16,145) (11,179)
    *All patients had severe hemophilia A at baseline, defined as less than or equal to 1% of Factor VIII activity levels, expressed as a percentage of normal factor activity in blood. **Weeks were windowed by +/- 2 weeks and after 52 weeks, measurements were taken every 3 months *** For week 32, one patient did not have a Factor VIII activity level available. ****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 Dec. 6, 2017). Factor VIII levels are determined by one-stage assay.

    Valoctocogene Roxaparvovec Reduces Bleeds and Factor VIII Use:  Summary of Annualized Bleeding Rate (ABR) and FVIII Infusions of 6e13 vg/kg Dose Patients Previously on Prophylaxis (N=6)* at Nov. 16, 2017 data cut

    Before valoctocogene roxaparvovec Infusion*** After valoctocogene roxaparvovec Infusion****
    Median (mean, SD) Median (mean, SD)
    Annualized Bleeding** Rate(bleeding episodes per year per subject) 16.5 (16.3, 15.7) 0.0 (0.5, 1.2)

    Annualized FVIII Infusions**

    (infusions per year per subject)
    138.5 (136.7, 22.4) 0.0 (6.1, 14.9)

    *A 7th patient received Factor VIII on demand and was not included in analysis. **Post infusion data were based on data after Week 4 ***Obtained from medical records. ****5 of 6 patients had 0 bleeds requiring Factor VIII infusions and 0 Factor VIII infusions after Week 4.

    Quality of Life (QoL)

    Patients who received the 6e13 vg/kg dose demonstrated improved total scores when assessed with the Haemo-QoL-A questionnaire, a validated health-related quality of life (hrQoL) measurement tool for patients with hemophilia, as early as 16 weeks, with maintenance of hrQoL scores above the minimal clinically important difference (MCID) range (i.e., total score increase of 5.2 to 7.9, based on prior studies) through 78 weeks after receiving a single dose of valoctocogene roxaparvovec.  By week 16, patients achieved a clinically meaningful improvement from baseline, with a mean hrQoL score increase of 13.4 and a standard deviation (SD) of 11.2.  At week 78, the mean hrQoL score increase was 16.6 with an SD of 11.9.  The improvements above the MCID range of the Haemo-QoL-A total scores were supported by improvements achieved across all six domains tested, i.e. Consequences of Bleeding, Physical Functioning, Role Functioning, Emotional Impact, Treatment Concern, and Worry.

    Change from Baseline in Total Health-Related Quality of Life (hrQoL) Score of 6e13 vg/kg Dose Cohort at Nov. 16, 2017 data cut
    6E13 vg/kg Dose Cohort (N=7)
    Total hrQoL Score Change from Baseline
    Baseline Mean (SD) 71.9 (16.6) (na)
    Median 76.2 (na)
    Week 16 Mean (SD) 85.3 (13.0) 13.4 (11.2)
    Median 84.7 6.0
    Week 28 Mean (SD) 84.8 (12.5) 12.9 (13.7)
    Median 87.5 8.0
    Week 52 Mean (SD) 81.6 (15.1) 9.6 (12.7)
    Median 86.7 7.0
    Week 78 (n=5) Mean (SD) 80.6 (14.4) 16.6 (11.9)
    Median 87.6 13.7

    SD = standard deviation; na = not applicable.

    New England Journal of Medicine Publishes 1 Year Data on 6e13 vg/kg Dose Data

    The company also announced that the New England Journal of Medicine (NEJM) published an independent peer-reviewed article on the  ongoing Phase 1/2 study to evaluate safety and efficacy of investigational gene therapy, valoctocogene roxaparvovec, at the 6e13 dose in men with severe hemophilia A at 52 weeks.

    The NEJM article, "AAV Gene Transfer in Patients with Severe Hemophilia A," concluded that valoctocogene roxaparvovec is associated with the "sustained normalization" of Factor VIII activity over a period of one year in six of seven study participants who received the 6e13 vg/kg dose with stabilization of hemostasis and a "profound" reduction in Factor VIII use in all seven participants.  The article also concluded that safety findings were limited to elevations in liver function tests and notes the relatively small sample size. For additional safety data, see Safetysection in press release.

    Valoctocogene Roxaparvovec Safety

    Overall, valoctogogene roxaparvovec has been well-tolerated by patients across all doses, including the two patients who received the lowest doses of 6e12 and 2e13 vg/kg, respectively.  No patients developed inhibitors to Factor VIII, and no patients withdrew from the study.  The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase (ALT) elevation (11 patients, 73%); arthralgia (9 patients, 60%); aspartate aminotransferase elevation (8 patients, 53%); headache (7 patients, 47%); back pain, fatigue and upper respiratory tract infection (5 patients, 33%).  Two patients reported serious adverse events (SAEs) during the study.  One patient was hospitalized for observation after developing Grade 2 pyrexia with myalgia and headache within 24 hours of receiving valoctocogene roxaparvovec.  The event resolved within 48 hours following treatment with paracetamol, an over-the-counter treatment for pain and fever.  The event was assessed as related to valoctocogene roxaparvovec.  The other SAE was assessed as not related to valoctocogene roxaparvovec, attributed to a planned knee surgery to treat hemophilic arthropathy, and Grade 1 in severity.  No complications were reported.

  • BioMarin will also begin a Phase 1/2 Study with the 6E13kg/vg dose and with approximately 10 patients who are AAV5 positive. The first patient is expected to enroll in the first half of 2018.   • On October 18, 2017, BioMarin Pharmaceutical provided an update on  the ongoing open-label Phase 1/2 study of the 4e13 vg/kg dose at up to 36 weeks of observation at the September 14, 2017 data cut. Since the last data update provided during the Q2 earnings call on August 2, 2017, five of the six patients at the 4e13 vg/kg dose tracked to the low range of normal, and the sixth is in the mild range for Factor VIII levels. Median annualized bleed and factor VIII use rates for 4e13 and 6e13 vg/kg were zero after Week 4.
    Factor VIII Levels (%) of 4e13 vg/kg Dose Patients* by Visit (N=6)
    Week** 4 8 12 16 20 24 28 32 36
    4e13 vg/kg Dose
    n 6 6 6 6 6 6 6 3 3
    Median Factor VIII Level*** (%) 4 15 21 29 34 28 31 51 45
    Mean Factor VIII Level*** (%) 5 13 19 26 31 29 30 51 47
    Range (low, high) (2,10) (3,21) (6,32) (5,38) (7,45) (7,43) (4,44) (48,54) (41,55)
    *All patients had severe hemophilia A, defined as less than or equal to 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 to normal range of Factor VIII activity as defined by the World Federation of Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current as of Oct. 17, 2017). Factor VIII levels are determined by one-stage assay.
     
    BMN 270 Reduces Bleeds and Factor VIII Use:  Summary of Mean Annualized Bleeding Rate (ABR) and FVIII Use Rate of 4e13 vg/kg Dose for Patients Previously on Prophylaxis (N=6) at September 14, 2017 data cut
    Before BMN 270 Infusion After BMN 270 Infusion
    Median (mean, SD) Median (mean, SD)
    Annualized Bleeding Rate* (bleeding episodes per year per subject) 8.0 (12.2, 15.4) 0.0 (0.8, 1.9)
    Annualized FVIII Use Rate* (infusions per year per subject) 155.5 (146.5, 41.6) 0.0 (2.7, 6.7)
    *Post-infusion data were based on data after Week
  • • On July 11, 2017, BioMarin announced an update to its previously reported interim results of an open-label Phase 1/2 study of BMN 270. 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.
  • In the open-label Phase 1/2 study, a total of 15 patients with severe hemophilia A (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)*
  • Before BMN 270 Infusion*** After BMN 270 Infusion****
    Mean (median, SD) Mean (median, SD)
    Annualized Bleeding** Rate(bleeding episodes per year per subject)

    16.3 (16.5, 15.7)

    0.5 (0.0, 1.1)

    Annualized FVIII Infusions** (infusions per year per subject)

    136.7 (138.5, 22.4)

    8.5 (0.0, 20.8)

  • *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 Rate (ABR) and FVIII Infusions of 4e13 vg/kg Dose Patients Previously on Prophylaxis (N=6)
  • Before BMN 270 Infusion** After BMN 270 Infusion***
    Mean (median, SD) Mean (median, SD)
    Annualized Bleeding Rate* (bleeding episodes per year per subject)

    12.2 (8.0, 15.4)

    0.0 (0.0, 0.0)

    Annualized FVIII Infusions* (infusions per year per subject)

    144.2 (155.5, 43.3)

    0.0 (0.0, 0.0)

  • * Post infusion data were based on data after Factor VIII levels were above 5% **Obtained from medical records. ***6 patients had 0 bleeds requiring Factor VIII infusions and 0 Factor VIII infusions after Factor VIII levels were above 5%.
  • Quality of Life (QoL)
  • Patients on the 6e13 vg/kg dose demonstrated improvement in Haemo-QoL-A (HRQOL), a validated health related quality of life measurement tool for patients with hemophilia, as early as 16 weeks with maintenance through 52 weeks after receiving a single dose of BMN 270.  By week 16, patients achieved a clinically meaningful difference from baseline with a mean score change of 13.4 with a standard deviation (SD) of 11.2.  The minimal clinically important difference (MCID) based on prior studies ranges from 5.2 to 7.9. Patients demonstrated sustained clinically meaningful HRQOL score changes through to week 52 with a mean score change from baseline of 9.6 with an SD of 12.7.  (See Table 5).  The score improvement achieved an MCID, which was observed across all six domains tested, i.e. Consequences of Bleeding, Physical Functioning, Role Functioning, Emotional Impact, Treatment Concern and Worry.
  • Table 5:  Change from Baseline in Total Health-Related Quality of Life (HRQOL) Score of 6e13 vg/kg Dose Cohort
  • 6E13 vg/kg Dose Cohort (N=7)
    Total HRQOL Score Change from Baseline
    Baseline Mean (SD)

    71.9 (16.6)

    (na)
    Median

    76.2

    (na)

    Week 16 Mean (SD)

    85.3 (13.0)

    13.4 (11.2)

    Median

    84.7

    6.0

    Week 28 Mean (SD)

    84.8 (12.5)

    12.9 (13.7)

    Median

    87.5

    8.0

    Week 52 Mean (SD)

    81.6 (15.1)

    9.6 (12.7)

    Median 86.7

    7.0

  • SD = standard deviation; na = not applicable.
  • Safety: Overall, BMN 270 was well tolerated by patients across all doses.  No patients developed inhibitors to Factor VIII and no patients withdrew from the study.  The most common adverse events (AEs) across all dose cohorts were alanine aminotransferase (ALT) elevations (10 patients, 67%), arthralgia (7 patients, 47%) and back pain, fatigue, headache (5 patients each, 33%).  Two patients reported Serious Adverse Events (SAEs) 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, an over-the-counter treatment for pain and fever.  The event was assessed as related to BMN 270.  The other SAE was assessed as not related to BMN 270, and was attributed to a planned knee surgery to treat hemophilic arthropathy, and Grade 1 in severity.  It resolved without any further complications.
  • AEs of ALT elevation were reported in 10 of the 15 patients.  All events of ALT increases were non-serious and as of the data cutoff, seven of the 10 patients had durations of ALT greater than 1.5 times the Upper Limit of Normal (ULN) range from 0.4 to 7 weeks and Grade 1 in severity. All of the seven patients at the 6e13 vg/kg dose remain off of corticosteroids with no lasting significant impact on Factor VIII expression and normal ALT levels.  Three of the six patients at the 4e13 vg/kg dose received corticosteroids for ALT increases, one has successfully tapered off corticosteroids and two are tapering off of corticosteroids.
  • Phase 3 Study and Regulatory Status
  • BioMarin now plans to initiate a Phase 3 registrational study in Q4 2017 for BMN 270.  Final determination of the design of the study in severe hemophilia A patients is underway; the study will likely include fewer than 100 patients and collect data for not 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 based on the possibility to get most patients safely into the normal Factor VIII range, which could provide them the opportunity to engage in normal daily activities without concern for spontaneous bleeds or the need for additional Factor VIII due to trauma (including sports and minor injuries) or invasive procedures.  However, to evaluate a dose that may have a different drug profile, we will consider doing an additional 4e13 vg/kg dose clinical study later.  While we may do further study on a lower dose, by going forward with the 6e13 vg/kg dose now, we hope to bring this novel therapy to patients as quickly as possible.
  • The European Medicines Agency (EMA) has granted access to its Priority Medicines (PRIME) regulatory initiative for BMN 270.  To be accepted for PRIME, an investigational therapy has to show its potential to benefit patients with unmet medical needs based on early clinical data.
  • Gene Therapy Manufacturing: In addition, BioMarin has designed and constructed its first gene therapy manufacturing facility located in Novato, California.  Good Manufacturing Practices (GMP) production of BMN 270 is anticipated to commence imminently to support ongoing clinical development activities and if approved, commercial demand.
  • • On October 13, 2016, BioMarin Pharmaceutical announced that the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK approved continued enrollment into the open-label Phase 1/2 study of BMN 270.  BioMarin had previously announced that after enrolling the first 9 patients in the study, that dosing of patients had been suspended due to observed increases in alanine aminotransferase (ALT) levels that exceeded a pre specified threshold set by the company.  Following study suspension, the company reviewed safety and efficacy data on the 9 patients with the MHRA, and based on its review, the MHRA approved resumption of the study. The agency also approved the company's proposed amendments to the study, which included eliminating the requirement for prophylactic corticosteroids and increasing potential additional enrollment from up to three additional patients to up to six additional patients. BioMarin intends to resume enrollment in the Phase I/2 study before the end of 2016.  Based on protocol amendments, three patients will be enrolled at a dose of 4 x 1013 vg/kg, and an additional three may be enrolled at this dose or the previously tested high dose of 6 x 1013 vg/kg.  In the up to six additional patients, the requirement for prophylactic corticosteroids has been removed and the threshold for starting therapeutic corticosteroids has been increased.  Safety and efficacy data from these patients will inform the Phase 2b study planned to begin in the second half of 2017.
  • • On July 27, 2016, BioMarin Pharmaceutical announced interim results of an open-label Phase 1/2 study of BMN 270, at the XXXII International Congress of the World Federation of Hemophilia (WFH).  The data was presented in the Late Breaking Gene Therapy session by John Pasi, Professor of Haemostasis and Thrombosis, Barts and the London School of Medicine, Honorary Consultant Haematologist, The Royal London Hospital, and a lead investigator of the study.  The data presented at the congress is an update since the Company reported initial results on this same study on April 20, 2016.  A total of nine patients with severe hemophilia A received a single dose of BMN 270, seven of whom have been treated at the highest dose of 6 x 1013vg/kg. As of the July 6 data cut off, post-treatment follow-up ranges from 12 to 28 weeks.  For the seven patients treated with the high dose, as of each patients' most recent reading, six of seven patients had Factor VIII levels above 50%, as a percentage calculated based on the numbers of International Units per deciliter of plasma (IU/dL), and the seventh was above 10%.  In addition, four patients who have been followed the longest had a mean Factor VIII level of 146% at their 20 week visit.  Two patients with Factor VIII levels above 200% had no unexpected events or need for medical intervention. For the seven patients at the high dose, the median annualized bleeding rate measured from day of gene transfer to data cut of observation period fell to 5 from 20.
  • No clinically relevant sustained rises in ALT levels or other markers of liver toxicity have been observed.  The maximum ALT levels were between 23 and 82 U/L (less than two times the upper limit of normal, which is 43 U/L for the central laboratory in this study) approximately 12 weeks after gene delivery and generally declined over the next few weeks. ALT rises have not been associated with any decrease in Factor VIII levels.  A steroid regimen administered to all high dose patients has been well-tolerated.  Patients are successfully tapering off of steroids with two subjects off steroid therapy for up to 2.5 weeks with no adverse impact on Factor VIII expression or ALT levels.  Study medication was generally well tolerated.  No serious adverse events were observed, and most common adverse events were mild in severity.  "We look forward to collaborating with experts and health authorities to design the next phase of investigation," said Hank Fuchs, M.D., Chief Medical Officer at BioMarin.  "Beginning in mid-2017, a Phase 2b study will seek to evaluate the optimal dose of BMN 270 using Factor VIII expression as the primary endpoint with material from the to-be-commercialized manufacturing process.  If successful, this study could support an accelerated approval given the severe unmet need, the substantial effect and tolerability of the treatment."
  • • On April 20, 2016, BioMarin Pharmaceutical announced preliminary data from an ongoing Phase 1/2 clinical trial with BMN 270.  A total of eight patients with severe hemophilia A received a single dose of BMN 270, six of whom have been treated at the highest dose of 6 x 1013 vg/kg, and to date, post-treatment follow-up ranges from five to 16 weeks.  At last observation, patients at the highest dose experienced increasing Factor VIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood), with five of six patients treated at the high dose now over 5% and two of six at over 50%. (See Table 1) All high dose patients improved from severe to either moderate, mild or normal range in terms of factor levels based on World Federation of Hemophilia criteria. (See Table 2)
  • Liver function tests have been monitored closely during the course of the trial.  The first three patients were not administered prophylactic corticosteroids.  Two of these patients experienced elevated alanine aminotransferase (ALT) levels.  Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.  Two weeks later a new corticosteroid regimen was initiated when ALT levels became minimally abnormal for the first time.  The expression of Factor VIII continued to increase during this elevation of ALT and is currently at 57%.  In addition, 28 weeks after dosing, Patient 1 treated at the lowest dose experienced a rise in ALT level to 128 IU/L, although this patient had never documented Factor VIII expression above 1%.  After the third patient, all patients were to be started on prophylactic corticosteroid therapy and to date no further patients have experienced abnormal ALT levels.  BioMarin plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients. Phase 3 design preparation and high volume manufacturing plans are underway.
  • Table 1:  Summary of 8 Patients Factor VIII Levels at Most Recent Evaluations
Patient # Dose* Most Recent Week of Observation Percentage Factor VIII activity Severity of Hemophilia at Latest Measurement**
1 Low 20 <1 Severe
2 Medium 16 2 Moderate
3 High 16 57 Normal
4 High 8 60 Normal
5 High 7 8 Mild
6 High 7 4 Moderate
7 High 6 21 Mild
8 High 5 10 Mild
  • * Low = (6 x 1012 vg/kg), Medium = (2 x 1013 vg/kg), High = (6 x 1013 vg/kg) ** Information sourced from World Federation of Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current as of April 20, 2016)
  • Table 2:  Severity of Hemophilia*
Level Percentage of normal factor activity in blood** Description of Severity***
Normal range 50-150%
Mild hemophilia 5-40% People with mild hemophilia usually bleed only as a result of surgery or major injury. They do not bleed often and, in fact, may never have a bleeding problem.
Moderate hemophilia 1-5% People with moderate hemophilia bleed less frequently, about once a month. They may bleed for a long time after surgery, a bad injury, or dental work. A person with moderate hemophilia will rarely experience spontaneous bleeding.
Severe hemophilia Less than 1% People with severe hemophilia usually bleed frequently into their muscles or joints. They may bleed one to two times per week. Bleeding is often spontaneous, which means it happens for no obvious reason.
  • *Information sourced from World Federation of Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current as of April 20, 2016) **Percentage calculated based on the number of international units (IU) per milliliter (ml) of whole blood. ***Severity describes how serious a problem is. The level of severity depends on the amount of clotting factor that is missing from a person's blood.
  • * On September 28, 2015, BioMarin Pharmaceutical announced that it has enrolled the first patient in a Phase 1/2 trial for BMN 270.
     

Is general: Yes