Hemgenix first gene therapy approved in EU for haemophilia B

23rd February 2023

Hemgenix is the first gene-based therapy approved for use in the EU for patients with moderately severe to severe haemophilia B

Hemgenix (etranacogene dezaparvovec) has been granted a conditional marketing authorisation by the European Commission for the treatment of severe and moderately severe haemophilia B (congenital Factor IX deficiency) in adults without a history of Factor IX inhibitors.

Haemophilia B is an inherited and life-threatening rare disease affecting 1 in 40,000 live males which is about 15% of cases of haemophilia. It is a caused by missing or defective clotting protein, factor IX and sufferers are particularly vulnerable to bleeds in joints, muscles, and internal organs leading to pain, swelling and ultimately joint damage.

Patients with haemophilia B require lifelong treatment with intravenous infusions of Factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and wellbeing. HEMGENIX^® is an adeno-associated virus five (AAV5)-based gene therapy that is given as a one-time treatment for moderately severe to severe haemophilia B patients. HEMGENIX^® uses a specific type of AAV, called AAV5, as its vector. The AAV5 vector carries the naturally occurring Padua gene variant of Factor IX (Factor IX-Padua), which generates Factor IX proteins that are 5 to 8 times more active than normal.

Hemgenix clinical data

The main clinical study with Hemgenix is the HOPE-B trial which is an ongoing, multinational, open-label, single-arm study, designed to evaluate the safety and efficacy of HEMGENIX^®. Fifty-four adult haemophilia B patients classified as having a diagnosis of moderately severe or severe haemophilia B and requiring prophylactic Factor IX replacement therapy, were enrolled in a prospective, six-month observational period during which time they continued to use their current standard of care therapy to establish a baseline Annual Bleeding Rate (ABR). After the six-month lead-in period, patients received a single intravenous administration of HEMGENIX^® with 53 patients completing at least 18 months of follow-up. The primary endpoint in the pivotal HOPE-B study was 52-week ABR after achievement of stable Factor IX expression compared with the six-month lead-in period.

Results from the pivotal HOPE-B study demonstrated that HEMGENIX^® produced mean Factor IX activity of 36.9 IU/dL at 18 months post infusion. At 24 months follow-up, Factor IX activity remained stable at 36.7 IU/DL. After the six-month lead-in period post-infusion, the adjusted annualized bleeding rate (ABR) (1.51) for all bleeds was reduced by 64 percent (p = 0.0002) and all Factor IX-treated bleeds was reduced by 77 percent (3.65 to 0.83; p<0.0001) over months seven to 18. From day 21 through to months 7 to 24, 52 of 54 (96.3%) treated patients remained free of continuous routine Factor IX prophylaxis. The mean consumption of Factor IX replacement therapy significantly decreased by 248,392.6 IU/year/patient (96.52%; 1-sided p< 0.0001) between month 7 to 24 following treatment with HEMGENIX^® compared to standard of care routine Factor IX prophylaxis during the lead-in period.

Fortunately, there were no serious adverse reactions identified. One death resulting from urosepsis and cardiogenic shock in a patient at 65 weeks following dosing was considered unrelated to treatment by investigators and the company sponsor. A serious adverse event of hepatocellular carcinoma was determined to be unrelated to treatment with HEMGENIX^® by independent molecular tumour characterization and vector integration analysis. No inhibitors to Factor IX were reported.

In the press release, Professor Wolfgang Miesbach, Head of Coagulation Disorders at the Comprehensive Care Centre, University Hospital of Frankfurt, said “this approval marks an important step forward in the treatment of haemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints and internal organs, alleviating the burden of lifelong intravenous infusions of Factor IX products,” They added that “data from the HOPE-B study demonstrate the potential of HEMGENIX^® to remove the need for routine prophylaxis, by providing durable Factor IX activity, as well as improved bleeding outcomes and quality of life for people with haemophilia B.”

Fidanacogene elaparvovec gene therapy effective for haemophilia B

11th January 2023

Fidanacogene elaparvovec is a novel gene therapy which has been found to effective and well tolerated in adult males with haemophilia B

Pfizer has reported that its candidate gene therapy, fidanacogene elaparvovec, is effective in reducing the annualised bleeding rate (ABR) of total bleeds compared to a prophylaxis regimen with Factor IX (FIX) administered as part of usual care.

Haemophilia B is a rare, X-linked inherited bleeding disorders caused by mutations in the F9 gene, which results in missing or reduced production/function of clotting factor IX (FIX). The prevalence of haemophilia B is one in 40,000 live males although female carriers may also show some signs of bleeding.

An absence or reduced level of of FIX can result in spontaneous bleeding into the joints, muscles or brain causing serious complications. Currently, the mainstay of treatment for haemophilia B involves replacement of factor IX although adeno-associated viral (AAV)-based gene therapy is one of the most emerging treatment approaches. Fidanacogene elaparvovec is a novel, investigational vector that contains a bio-engineered AAV capsid (i.e. protein shell) and a high-activity human coagulation FIX gene.

The aim of such gene therapy is that once treated, individuals are able to produce FIX rather than having to regularly receive exogenous FIX. In a Phase 1/2a study, 15 adult haemophilia B patients were infused with 5 x 10¹¹ vg/kg of fidanacogene elaparvovec and followed for at least one year. The study examined the ABR prior to and 52 weeks after the infusion. The results showed that the mean ABR during the first 52 weeks following fidanacogene elaparvovec infusion was 0.4 ± 1.1 compared to 8.9 ± 14.0 in the 52 weeks preceding infusion (p<0.001) and in fact, 12 patients reported zero bleeds in the 52 weeks post-infusion.

The BENEGENE-2 study was a single arm trial, designed to evaluate the efficacy and safety of fidanacogene elaparvovec in adult male participants with moderately severe to severe haemophilia B (defined by a Factor IX circulating activity of 2% or less). The primary outcome was the ABR for total bleeds from week 12 to month 15 post-infusion. In the trial, 45 eligible participants completed at least six months of routine exogenous FIX prophylaxis therapy during the study lead-in before receiving a single intravenous dose of fidanacogene elaparvovec (5e11 vg/kg).

Fidanacogene elaparvovec and annualised bleeding rate

The mean ABR for all bleeds was 1.3 for the 12 months from week 12 to month 15 compared to an ABR of 4.43 during the lead-in six months pre-treatment period, giving in a 71% reduction in ABR (p<0.0001) after a single dose of fidanacogene elaparvovec. 

For secondary endpoints, there was a 78% reduction in treated ABR (p=0.0001) and a 92% reduction in the annualised infusion rate (p<0.0001). The mean FIX activity was 27% after 15 months and 25% at 24 months and the mean steady-state FIX concentration was significantly higher than the pre-specified threshold of 5% (p<0.0001).

Fidanacogene elaparvovec has been granted breakthrough regenerative medicines advance therapy (RMAT) and orphan drug designations from the US Food and Drug Administration, as well as PRIority MEdicines (PRIME) and orphan drug designation from the European Medicines Agency.

Gene therapy induces sustained and normalised levels of factor IX in haemophilia B

29th July 2022

Gene therapy use in a Phase II trial for patients with haemophilia B induced sustained increases in factor IX levels in virtually all patients

Gene therapy with FLT180a given to patients who have haemophilia B resulted in elevation of factor IX levels to within the normal range and which was sustained for many months according to the findings of a small, Phase II trial by UK and US researchers.

Haemophilia is an inherited bleeding disorder where the blood fails to clot properly and can lead to spontaneous bleeding. There are two forms of haemophilia – A and B – both of which occur as a result of deficiency or dysfunction of blood clotting factors.

Haemophilia A is due to factor VIII dysfunction and haemophilia B due to factor IX dysfunction and because the genes for these two factors are located on the X chromosome, haemophilia occurs primarily in males.

The prevalence of haemophilia (per 100,000 males) has been estimated to be 17.1 cases for all severities of haemophilia A, 3.8 cases for all severities of haemophilia B and 1.1 cases for severe haemophilia B.

The current treatment for haemophilia B involves intravenous infusions of factor IX either regularly, i.e., prophylactic therapy, or ‘on demand’ and while the latter is highly effective at stopping bleeding, it cannot fully reverse the long-term damage that follows after a bleed. In recent years, studies have suggested that gene therapy with FLT180a has the the potential to deliver a durable, functional cure for haemophilia B.

FLT180a is an adeno-associated virus gene therapy that carries the factor IX gene and enters liver cells and produces factor IX protein.

For the present study, researchers described the efficacy and safety of FLT180a in patients with severe haemophilia B, defined as factor IX levels < 1% of the normal range (50 to 150IU/dl) and administered four different doses. In addition, all patients received glucocorticoids with or without tacrolimus to reduce the risk of a vector-related immune response.

The researchers set two primary endpoints as safety (based on adverse events) and efficacy, assessed in terms of the level of factor IX induced by FLT180a after 26 weeks. Secondary endpoints included the change in annualised bleeding rates and consumption of factor IX concentrate.

Gene therapy with FLT180a and factor IX levels

Ten male patients were administered a single dose of gene therapy and completed the 26-week trial and were then enrolled in a long-term follow-up. The study provides an individual assessment of each patient and after a median of 27.2 months, sustained factor IX levels were observed in nine patients, with one resuming factor IX prophylaxis. Overall, five patients had normal factor IX levels (ranging from 51% to 78%), three had levels ranging from 23 to 43% and one had a level of 260%.

In terms of safety, none of the patients withdrew because of toxic effects and 10% of all adverse events were deemed to be related to FLT180a although all patients had at least one adverse event related to immunosuppressant therapy.

Among all patients, the mean annualised bleeding rate at baseline was 2.93 events/year which reduced to 0.71 after gene therapy. In addition, the annualised factor IX consumption per patient also decreased from 226,026IU/year to to a mean of 9723 IU/year after treatment.

The authors concluded that normal factor IX levels can be achieved after the use of FLT180a gene therapy in patients with severe or moderately severe haemophilia B.

Citation
Chowdary P et al. Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med 2022