Bearing the usual perils of cross-trial comparisons in mind, the much larger Hope-B pivotal trial of Uniqures etranacogene dezaparvovec (AMT-061) found mean FIX activity of 37% of normal at 26 weeks, taking severe haemophilia B patients into the range seen in mild disease (Ash 2020 hints of durability emerge for Uniqure's gene therapy, December 8, 2020).

Although this has been heralded as a huge advance, around 30% of patients in Hope-B did not reach 30% FIX activity, and some participants still experienced bleeds.

Freeline hopes to go one step further and eliminate serious bleeds, returning haemophilia B patients to a normal life. The company noted that in B-Amaze there were no bleeds that needed FIX supplementation.

The increased FIX activity seen with verbrinacogene setparvov is down to Freelines novel synthetic capsid, called AAVS3, the companys founder, Professor Amit Nathwani of University College London, explained during yesterdays call. He said the capsid leads to three to sixfold higher levels of gene transfer compared with other, wild-type capsids, which in turn should spur high levels of protein expression using relatively low doses of vector.

However, Uniqures capsid might have an edge in one respect: Hope-B did not exclude patients with pre-existing neutralising antibodies to AAV.

Freelines trial did include some patients with neutralising antibodies, Ms Krop told Evaluate Vantage, although there was a cut-off over which patients with these antibodies were excluded. This was intentionally low, Ms Heggie added, without giving details.

Although the data from B-Amaze look promising, the patient numbers involved are small, and Freeline now needs to show that its claims hold up in a bigger population. The pivotal trial will enrol 20 patients initially, and the phase IIb portion will be used to confirm the dose before moving into the phase III portion.

Freeline hopes it will be able to file for accelerated approval based on 26-week FIX data along with 52-week annualised bleeding rate data in a subset of these patients. The study will then enrol up to 30 more patients to evaluate 52-week ABR, which is designed to support full approval.

It is too early to call a winner in haemophilia B gene therapy, according to Evercore ISIs Josh Schimmer, who added: Uniqure has a bird in the hand with its dataset while Freeline has a couple of promising ones in the bush.

Ms Heggie is not concerned about not being first to market. We know we're probably two years behind Uniqure, but we know patients will wait for the best treatment.

She also told Evaluate Vantage that, while Freeline is not yet discussing pricing, we expect to have really strong value proposition if, as we expect, itll be a functional cure.

Freeline still has a lot of work to do, but Uniqure might soon have some real competition.

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Freeline takes the haemophilia B gene therapy fight to Uniqure - Vantage