Impact case study database

Haemophilia affects approximately 1 in 10,000 males world-wide. It varies in its severity, but symptoms include frequent bruising and joint pain and, if left untreated, can in many cases result in uncontrolled internal bleeding. The condition has a significant impact on quality of life for all those affected. Standard treatments require injections of clotting factors several times per week for life. Although stringent safety procedures are in place for preparation of blood products, the standard treatment carries a theoretical risk of infection with new and emerging viruses.

The UCL team, led by Nathwani and Tuddenham, has pioneered a single-dose gene therapy that allows individuals to produce the missing clotting factor and removes the need for further prophylactic treatment, transforming quality of life and reducing ongoing healthcare costs . Successful UCL-led trails in small numbers of patients have been followed by at least six further trials involving approximately 300 patients with severe/moderate haemophilia who, to date, continue to benefit from the therapy. The technology platform has been commercialised and led to multibillion pound investments by large pharmaceutical companies in gene therapies for haemophilia and other genetic disorders. It has also resulted in creation of a spin-out company Freeline Therapeutics, founded by Nathwani, that has trialled an enhanced AAV vector/gene construct that returns Factor IX levels to near normal.

Patient benefits and cost savings

Following the first successful gene therapy trials for haemophilia at UCL, Phase 3 trials led by pharmaceutical companies including UniQure and Biomarin, have treated approximately 300 patients in total to date. The trials demonstrated that in 90% of cases, the gene therapy treatments for haemophilia lead to significant increases in levels of Factor VIII or IX, concomitant reduction in internal bleeds and no need for ongoing treatment. Based on data from the original UCL trial for haemophilia B, in which five of the seven participants who had previously relied on prophylactic treatment were able to stop injecting, with no spontaneous bleeding episodes, the UCL team estimated that trial alone had saved the NHS more than GBP1,500,000 in the first four years ( R5).

UniQure, a gene therapy specialist, has licensed the factor IX gene cassette developed by UCL and used in the 2011 trial led by UCL, to develop a proprietary factor IX replacement therapy for haemophilia B. Long term follow up data reported in December 2019, showed sustained factor IX activity in all 10 patients four years after treatment with AMT-060 at a level sufficient to eliminate or significantly reduce the risk of bleeding events ( S1). In a recent Phase 3 trial undertaken by Uniqure and based on the gene therapy construct developed at UCL 54 patients received treatment and by 26 weeks post-therapy, 96.3% had successfully discontinued routine prophylaxis and 72.2% had not experienced any bleeds post treatment ( S2) .

Among pipeline products for haemophilia A, BioMarin has trialled a therapeutic programme using a factor VIII vector licensed from UCL and St Jude, involving 135 patients with moderate/severe haemophilia. Three-year data released in 2019 showed that nearly all participants who had received a one-time dose of the vector were no longer having to infuse clotting factors, and that average annualised bleed rates had reduced by 96% ( S3).

Individuals who have received the gene therapy treatment in trials commonly report that, post treatment they are more active and enjoy greater confidence. One gene therapy recipient said “What I have experienced in the last 3 years is a factor level hovering around 40% and no bleeds at all, and nothing coming close to bleed. Some simple pleasures - not being so stiff in mornings, no limping and pain getting off airplanes or out of movie theatres, not worrying about how far away my fridge is, not having to bring treatments with me on out-of-town trips.” ( S4) . In a recent Haemophilia Society newsletter a gene-therapy recipient said his new Factor IX levels were “insane” and he hadn’t had any treatment for two years since the therapy. He added: “I don’t think about my haemophilia much anymore.” For another, this created an issue at first. He felt like he had lost part of his identity, saying “I was no longer ‘Paul the haemophiliac’” but added, “I haven’t had any treatment since 2018. I can’t stop smiling” ( S5).

Spin out company Freeline Therapeutics

In 2015, Professor Nathwani founded a spinout company, Freeline Therapeutics, to develop a commercial AAV-based therapy for haemophilia B, based on UCL’s research. The company, which has its headquarters in Stevenage, UK, now employs 200 FTEs in the UK, Germany and the US. Its product candidate, FLT180a, uses a synthetic AAVS3 vector to enhance the delivery of a highly functional form of the human factor IX gene to a patient’s liver cells. Data from a Phase 1/2 clinical trial of 10 patients released in July 2020 showed that, at the lowest dose, participants with severe or moderate symptoms achieved long-term durability, displaying a level of factor IV activity at 52 and 104 weeks normally associated with the mild form of the disorder. Individuals in the highest-dose group were able to sustain factor IX activity at 50-150% of normal levels ( S6). The company is now using this vector to develop a pipeline of therapies for other genetic disorders.

Freeline’s work has attracted significant investment, including USD40,000,000 (GBP30,600,000) of Series C funding from Syncona, a FTSE 250 healthcare company, and a further USD80,000,000 (GBP61,200,000) from investment firms Novo Holdings A/S, Eventide Asset Management and Wellington Management Company, among others ( S7). Following the announcement, Managing Partner, Novo Holdings A/S said: “Our investment strategy is to identify and invest in US and European life science companies which are true leaders in their area of expertise, developing innovative product candidates that significantly advance patient care. We have been impressed by the Freeline platform and its scientific co-founders, as well as their experienced management team, and we are delighted to support Freeline as they continue to build momentum.” An Initial Public Offering on NASDAQ in August 2020 raised an additional USD158,800,000 ( S8).

Large pharma licencing gene therapy to treat haemophilia A and haemophilia B

Gene therapy is becoming the treatment of choice for haemophilia and major pharmaceutical firms are investing heavily in the field. In recent years, Pfizer has acquired an interest in the haemophilia A candidate SB-525 through a licensing deal with its creator, Sangamo who in 2017, received an upfront payment of USD70,000,000 ( S9) and a further USD25,000,000 on early completion in 2019 . At the same time, the world’s largest biotech company, Roche, has acquired Spark Therapeutics, developer of the SPK-8011 platform (also for haemophilia A) ( S10).