EMA starts review of Rocket’s Falconi anaemia gene therapy

Patients in the EU with Fanconi anaemia (FA) could soon have the first gene therapy option for the disorder, as the EMA starts a review of Rocket Pharma’s RP-L102 candidate.

FA is an inherited syndrome that impairs the body’s chromosomal repair systems, causing bone marrow failure, and leads to congenital malformations and a broad range of symptoms including an increased risk of cancers. It is usually diagnosed in children under 12 but, in some cases, there are no symptoms until adulthood.

RP-L102 is based on stem cells harvested from FA patients’ peripheral blood that are modified with a lentiviral vector to contain a function copy of the FANCA gene, which codes for a protein essential for DNA repair. Around 60% to 70% of patients with FA have a FANCA mutation, causing what is known as FA complement group A or FA-A.

The hope is that the gene therapy could provide the first alternative to allogeneic haematological stem cell transplantation (HSCT), which is associated with significant toxicities due to the need for a cytotoxic conditioning regimen to clear the way for the donor cells to colonise the bone marrow. Toxicity is exacerbated in the approximately 80% of FA patients who don’t have an HLA-identical sibling donor.

Across the EU and US – where a filing is due in the next few weeks – there are estimated to be between 200 and 275 new cases of FA diagnosed per year, with somewhere between 5,500 and 7,000 patients living with the disease.

The EMA has started its review of RP-L102 based on the results of a phase 1/2 trial in patients with FA-A, which showed that the one-shot treatment was able to achieve “phenotypic correction” in eight of 12 evaluable patients with at least 12 months of follow-up, and extending out to 42 months.

That was demonstrated by increased resistance to mitomycin-C (MMC) in bone marrow (BM)-derived colony-forming cells – a biomarker for DNA repair – along with genetic correction and stabilisation in blood cell levels. There were no significant safety signals with the treatment, which unlike HSCT can be administered without any cytotoxic conditioning.

Rocket has filed RP-L102 with the EMA to prevent bone marrow failure in patients with FA, a catastrophic event that affects 80% of patients within the first decade of life. It also plans to test RP-L102 in additional forms of the disease caused by FANC C and G mutations.

Meanwhile, as the FA programme approaches the finish line, Rocket is also waiting for a decision from the FDA on Kresladi (marnetegragene autotemcel) for severe leukocyte adhesion deficiency-I (LAD-I), its lead product, which is due by 30th June after a priority review. That application has been delayed by three months by a request for more chemistry, manufacturing and controls (CMC) data.

The company also has two phase 2 trials ongoing of gene therapies for Danon disease, an X-linked disorder leading to severe heart disease, and pyruvate kinase deficiency (PKD), a blood disorder characterised by excessive rupture of red blood cells.

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