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The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the investigational gene therapy AMT-060 as a treatment for patients with severe hemophilia B.
AMT-060 consists of a codon-optimized wild-type factor IX (FIX) gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform. uniQure is the company developing AMT-060.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Phase 1/2 trial
The breakthrough designation for AMT-060 is based on results from an ongoing phase 1/2 study. Updated data from this study were recently presented at the 2016 ASH Annual Meeting (abstract 2314).
In this trial, researchers are testing AMT-060 in 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.
Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5 x 1012 gc/kg, and 5 received AMT-060 at 2 x 1013 gc/kg.
The data presented at ASH included up to 52 weeks of follow-up from the low-dose cohort and up to 31 weeks of follow-up from the higher-dose cohort.
Data from the higher-dose cohort show a dose response with improvement in disease state in all 5 patients. Four patients who previously required prophylactic FIX replacement therapy were able to stop this therapy.
As of the data cutoff date for the ASH presentation, 1 unconfirmed spontaneous bleed had been reported during an aggregate of 94 weeks of follow-up after the discontinuation of prophylaxis.
Researchers previously reported that 4 patients in the low-dose cohort were able to discontinue prophylactic therapy. The 1 patient who
remained on prophylaxis sustained an improved disease
phenotype and also required materially less FIX concentrate after
treatment with AMT-060.
According to uniQure, all 5 patients in the low-dose cohort continue to maintain “constant and clinically meaningful” levels of FIX activity for up to 52 weeks post-treatment. In fact, there were no spontaneous bleeds in these patients in the last 14 weeks of observation.
uniQure also said AMT-060 continues to be well-tolerated, and there have been no severe adverse events.
Three patients (2 in the higher-dose cohort and 1 previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase and received a tapering course of corticosteroids per protocol.
These temporary alanine aminotransferase elevations were not associated with any loss of endogenous FIX activity or T-cell response to the AAV5 capsid.
None of the patients in either cohort have developed inhibitory antibodies against FIX, and none of the patients screened tested positive for anti-AAV5 antibodies.
