BioMarin hemophilia A gene therapy phase 3 follow-up data update, perhaps it is time to re-understand the "persistence" of efficacy

January 12, 2023 /eMedClub News/-- BioMarin today announced its AAV gene therapy Roctavian for the treatment of hemophilia A Valectocogene Roxaparvovec) has yielded positive results in Phase 3 clinical trials and has been followed for more than 3 years
.
According to the press release, this is also the largest and longest-running global Phase 3 clinical trial
of hemophilia gene therapy.

Hemophilia is divided into two types
: A and B.
Hemophilia A is a bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII), accounting for about 85% of congenital bleeding disorders and occurring approximately 4 times
more than hemophilia B.
At present, the standard treatment for this disease is 2-3 times a week with preventive factor VIII replacement therapy, although the course of the disease can be controlled to a certain extent, there is still a risk of bleeding, and it also brings many side effects and a large financial burden
to the patient.

Roctavian is a gene therapy that uses AAV5 viral vectors to deliver transgenic coagulation factor VIII, and its advantage is that patients may only need to receive one treatment for hepatocytes to continuously express factor VIII, eliminating the need for long-term prophylactic factor injections
.

Roctavian (Source: BioMarin website).

According to the phase 3 follow-up data published this time, the average activity of coagulation factor VIII in patients who received Roctavian for 3 and 4 years was 18.
8 and 15.
2, respectively, with a median value of 8.
4 and 7.
4
.
The mean annual bleeding event rates in both groups were 1.
0 and 0.
8, respectively, while the median value was 0.
0
for both.

In addition, the average number of annual coagulation factor uses in the two groups was 8.
4 and 11.
1, respectively, and the median value was 0
.
The press release notes that after the third year of treatment, patients had an 80% reduction in the average annual bleeding event rate and a 94%
reduction in the use of coagulation factor VIII compared to baseline values.
At the same time, the company notes that at year 3, 92% of patients still do not need preventive treatment
.

▲ Roctavian Phase 3 clinical trial 3 years and 4 years follow-up results (Source: BioMarin official website).

In August 2022, Roctavian was approved in the European Union for the treatment of adult patients
with severe hemophilia A who do not contain factor VIII inhibitors and AAV5 antibodies in the body.
This approval also makes Roctavian the first approved gene therapy
to treat hemophilia A.
In addition, the EU maintained orphan drug designation for the therapy and granted it a 10-year market exclusivity period
.

In fact, the Roctavia marketing process has not been smooth, BioMarin has launched the drug's IND since 2014, and it took nearly a decade to successfully bring it to the European market, but it has not yet been approved
by the FDA.
As early as 2019, the company submitted Roctavian's BLA to the FDA, but it was rejected by the FDA in August 2020 because of fluctuations in the average annualized bleeding rate (ABR) in the BioMarin Phase 1/2 study data and the continued decline in factor VIII levels in patients, which the FDA believes requires more complete follow-up data
.

As a result of this setback, BioMarin became more cautious and voluntarily submitted a withdrawal of Roctavian's listing application to the EMA in November 2020 and resubmitted its listing application
in June 2021.

It is undeniable that with the longer follow-up time, concerns about the decline in the efficacy of Roctavian have become more and more obvious
.
The FDA's refusal to grant BioMarin longer follow-up data for Phase 3 clinical trials also means that regulators still have doubts
about the durability of the gene therapy.

A trend of continuous decline in coagulation factor activity can indeed be seen from BioMarin's phase I/II clinical follow-up data, with average FVIII activity levels of 64.
3, 36.
4, 32.
7, 24.
2 and 11.
6 IU/dL
at one, two, three, four, and five years after Roctavian injection, respectively 。 Combined with the latest follow-up data published this time, FVIII activity levels also showed a consistent decline in phase III clinical studies with one to four years of follow-up (42.
8 IU/dL in the first year, 23.
0 IU/dL in the second year, 18.
8 IU/dL in the third year, and 15.
2 IU/dL in the fourth year).

▲Summary of key data of phase 1/2 research (Source: Star Wealth Research Institute).

From the above key follow-up data, it can be seen that the activity level of FVIII does decrease with the increase of time, but it is not difficult to observe the decline of the level of FVIII expression
.
Equally unexpectedly, even if the level of FVIII drops below the preset value, the inhibition of natural bleeding persists
.
This phenomenon also indicates that its therapeutic effect may be related to the activity level of coagulation factor VIII in the body, but it does not mean that its efficacy will disappear
with the decrease of FVIII activity level.
As BioMarin says, we need to rethink
the durability of this gene therapy.

Recommended reading: Ten-year review of the first hemophilia A gene therapy: Can it successfully pass the FDA?

It is worth mentioning that after Roctavian was approved by the EMA in August 2022, on October 12, the FDA has again accepted BioMarin's resubmitted marketing application
.
In addition, on November 23, 2022, FDA's review of Roctavian's BLA also made positive progress, and FDA will no longer plan to convene an advisory committee meeting to discuss Roctavian's BLA
.
The FDA's "green light" for it will also mean that Roctavian's road to market may be smoother
.

In this Phase 3 result, BioMarin has performed an annual bleeding event analysis for all bleeding types (with or without treatment with exogenous factor VIII)
in accordance with FDA requirements.
The results showed that the 3-year and 4-year averages were 1.
4 and 1.
6, and the median values were 0.
0 and 1.
0
, respectively.
BioMarin said the results will be shared with the FDA as part of
its regulatory review materials.

In any case, Roctavian has been accepted by the FDA, and this positive response also shows the FDA's affirmation
of the gene therapy.
We have reason to believe that this world's first hemophilia A gene therapy will bring hope to more patients this year!

Resources:

1.
com/article/releases/ biomarin-announces-stable-and-durable-annualized-bleed-control-for-roctavian-in-largest-phase-3-gene-therapy-study-in-adults-with-severe-hemophilia-a-134-participant-study-met-all-primary-and-secondary-effica cy-endpoints-at-3-year-analysis/