Date: 2017-10-18
Type of
information: Clinical trial authorisation
phase: 3
Announcement: clinical trial authorization
Company: Biomarin Pharmaceutical (USA - CA)
Product: BMN 270 (valoctocogene roxaparvovec)
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.
Disease: hemophilia A
Therapeutic
area: Rare diseases - Genetic diseases - Hematological diseases
Country:
Trial
details:
Latest
news:
- • On October 18, 2017, BioMarin Pharmaceutical provided an update on its development portfolio. The company announced that the FDA has completed their review of the IND application for BMN 270 for severe hemophilia A, and concluded that it can proceed. The IND application included 52-week data at the 6e13 vg/kg dose and the protocol for the Phase 3 study using the 6e13 vg/kg dose. The protocol for the second Phase 3 study using the 4e13 vg/kg dose has also been submitted to the FDA. BioMarin also announced that the Phase 3 Clinical Trial Application was approved by the UK Medicines and Healthcare Products Regulatory Agency (MHRA). The company expects to initiate the global Phase 3 program in the fourth quarter of 2017.
- • On August 2, 2017, BioMarin Pharmaceutical announced that it will expand its development plan for BMN 270, its investigational gene therapy for hemophilia A, to include an additional Phase 3 study of the 4e13 vg/kg dose based on updated data as of July 28, 2017 from its ongoing open-label Phase 1/2 study of BMN 270. BioMarin now plans to initiate two Phase 3 studies with BMN 270, one with a dose of 4e13 vg/kg and the other with 6e13 vg/kg dose. Final determination of the design of the studies in severe hemophilia A patients is underway; the studies will each likely include fewer than 100 patients.
- Since the last data update presented at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress, the Factor VIII activity levels in the 4e13 vg/kg cohort have continued to trend upwards and now support an additional Phase 3 study to the development program.
- Based on these updated results, BioMarin plans to initiate two separate Phase 3 studies as soon as possible, one with the 4e13 vg/kg dose and one with the 6e13 vg/kg dose. In addition, the Company has commissioned its commercial gene therapy manufacturing facility and expects to start the Phase 3 program in the fourth quarter of 2017.
- A total of six patients received a single dose of BMN 270 at the 4e13 vg/kg dose. Based on the most recent data, for the three patients who were given the 4e13 vg/kg dose in November/December 2016, at week 32, all are in or near to the normal range of Factor VIII activity levels, with both median and mean Factor VIII levels of 51%. For the cohort of three patients who were given the 4e13 vg/kg dose in February/March 2017, at week 20, their Factor VIII activity levels have all moved into the mild range and two of the three are continuing to trend upward. For all six patients who received a dose of 4e13 vg/kg, at week 20, the median Factor VIII level was 34% and the mean was 31%. (See Table 1)
Table 1: Factor VIII Levels (%) of 4e13 vg/kg Dose Patients* by Visit (N=6)
|
Week**
|
4
|
8 |
12 |
16 |
20 |
24 |
28 |
32
|
|
4e13 vg/kg Dose
|
|
|
|
|
|
|
|
|
|
n
|
6
|
6
|
6 |
6
|
6
|
3 |
3 |
3
|
| Median
Factor VIII Level*** (%) |
4
|
15 |
21
|
29 |
34 |
29
|
41 |
51
|
| Mean
Factor VIII Level*** (%) |
5
|
13 |
19 |
26 |
31 |
32 |
39
|
51
|
| Range
( low, high) |
(2,10) |
(3,21) |
(6,32) |
(5,38) |
(7,45) |
(24,42) |
(32,44) |
(48,54)
|
All six patients who received a single dose of BMN 270 at 4e13 vg/kg dose had severe hemophilia A and had been treated with prophylactic Factor VIII pre-study. After receiving BMN 270 and then reaching a Factor VIII activity level above 5%, through the July 28th data cut, the mean Annualized Bleed Rate (ABR) was reduced by 92% from 12.2 to 1.0. The median ABR for those same patients was reduced from 8.0 to zero. The mean annualized Factor VIII infusions were reduced by 97% from 144.2 to 4.8. The median annualized Factor VIII infusions were reduced from 155.5 to zero. (See Table 2)
-
Table 2: Summary of Mean Annualized Bleeding Rate (ABR) and FVIII Infusions of 4e13 vg/kg Dose Patients Previously on Prophylaxis (N=6) up to 32 Weeks
|
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) |
1.0 (0.0, 2.3) |
|
Annualized FVIII Infusions*
(infusions per year per subject)
|
144.2 (155.5, 43.3) |
4.8 (0.0, 11.6) |
* Post infusion data were based on data after Factor VIII levels were above 5%
Efficacy Data on 6e13 vg/kg Dose as Announced at ISTH July 11, 2017: As of the May 31, 2017 data cutoff, all seven 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, expressed as a percentage of normal factor activity in blood. (See Press Release). At one year after dosing, the median and mean Factor VIII levels of the 6e13 vg/kg cohort continue to be above 50%. After 52 weeks of follow-up, the phase 1/2 study protocol specifies that planned patient visits are reduced in frequency from once a week to once every twelve weeks. 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.
- Safety: Overall, BMN 270 has been well-tolerated by patients across all doses, including the two patients that 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, aspartate aminotransferase elevation, and headache (7 patients each, 47%); back pain and fatigue (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. 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, attributed to a planned knee surgery to treat hemophilic arthropathy, and Grade 1 in severity. No complications were reported.
- AEs of ALT elevation were reported in 11 of the 15 patients. All events of ALT elevation were mild (Grade 1) and non-serious. All seven patients at the 6e13 vg/kg dose remain off of corticosteroids with no lasting significant impact on Factor VIII expression and have normal ALT levels. Four of the six patients at the 4e13 vg/kg dose received corticosteroids for ALT elevation, three have successfully tapered off corticosteroids and one is tapering off of corticosteroids.
Is
general: Yes
