Page 37 - Haematologica March 2020

Future of hemophilia therapy
the manufacturers, in the SPK-9001 study, a single vector infusion was accompanied by a 98% reduction in the ABR;75 this has led to a pivotal phase II study, which is cur- rently undergoing.76 Satisfactory plasma FIX levels were also obtained in the phase I-II studies BAX335 and AMT- 060, using an AAV8 vector.76-78 In both studies, FIX levels remained stable for 2-3 years and ABR were reduced, such that a phase III AMT-061 study has begun. On the whole, at least 56 HB patients have been treated with various serotypes of AAV vectors (mainly AAV5 and AAV8), and long-term expression of the transgene was obtained after a single intravenous infusion of the vector.73
The use of gene transfer was initially slower in HA, due to the much larger size of the FVIII gene that made it diffi- cult to pack the corresponding cDNA in AAV vectors. This problem was tackled by using a B-domain delated human FVIII cDNA endowed with a liver-specific promoter.79,80 Striking clinical results in HA were first published in 2017 using increasing dosages of the vector AAV5-hFVIII-SQ (valoctogene roxaparvovec).81 One year after a single administration, median FVIII in plasma was 77% and ranged from 19 to as high as 164%.81 Importantly, the mean ABR decreased by 97% from previous values. According to a recent update of the results obtained in 13 patients at year 2 after gene transfer,82 two of them had normal plasma FVIII levels (52% and 86%), ten had values within the range of mild HA (from 6% to 38%), and one had levels (4%) compatible with moderate HA. All these patients had experienced a dramatic reduction in the incidence of bleeds, in spite of the fact that they had stopped FVIII pro- phylaxis. These excellent results were substantially main- tained in the eight patients who were also evaluated at year 3 after gene transfer.82 Additional patients are currently being recruited into a phase III trial, which has set three ambitious goals: (i) enrollment of 130 patients; (ii) to obtain stable FVIII levels of at least 40%; and (iii) to demonstrate superiority over the traditional therapies. At least five addi- tional trials of gene therapy for HA are currently ongoing using various AAV serotypes as vectors. The results avail- able so far confirm the efficiency and durability of AAV- mediated gene therapy. However, at the moment, maxi- mum follow up is no longer than 1.5 years,73 and, as for all new therapeutic developments, long-term follow up is still required to firmly consolidate the safety profile.
There are still important problems and issues that need to be resolved before licensing procedures and availability of gene therapy for the hemophilias can be carried forward. Only adult patients have been enrolled in studies so far, because in pediatric patients, the active dividing hepato- cytes of children mean that there is no guarantee of achiev- ing a persistent expression of a non-integrating vector, such as AAV. On the other hand, the long-term expression that followed a single vector infusion in the first UK-based FIX- deficient patients is surprising, because, according to the physiological turnover rate of hepatocytes (10% per year in adults), a transgene expression drop by 50% should have
occurred within the first five years of treatment. Thus, some degree of integration of the transgene has perhaps taken place in the host DNA, with a theoretical risk of genotoxicity and cancer development.83,84 Only liver biop- sies can truly establish the fate of the AAV genome, and to what extent it is episomal or DNA integrated.85.86 Liver biop- sies would also be useful to establish the histological conse- quences of the most significant adverse effect observed so far in practically all the gene transfer studies, that is, a dose- dependent increase in transaminases that was controlled by means of short periods of corticosteroid administration.73,87 It remains to be established whether or not these flares of hepatocyte cell necrosis, called inappropriately “transamini- tis”, are causing chronic liver damage. Normally in the con- text of AAV only a small percentage of the hepatocyes are stably transduced and responsible for long-term expression (in a serotype and dose-dependent manner). However, liver biopsies are not necessary informative on the either acute (transient transaminitis) or histological changes if the results are “normal” or negative. Moreover, follow up beyond 2-3 years is still awaited for most studies, so it is not clear how long transgene expression is going to be maintained. This is important, because immune reactions to the AAV capsid lead to the formation of neutralizing antibodies that pre- vent effective repeat of vector delivery, at least with the same AAV serotype.73,87 Moreover, there are still no models of payment for gene therapy in hemophilia. BioMarin, the California-based pharmaceutical company that sponsored the forementioned study of gene transfer in HA,81,82 recently declared to the Wall Street Journal that, once licensed, they are planning to price their product (brand name: Valrox) between 2 and 3 million dollars. This would make it the most expensive medication in the world, even more expen- sive than the current 'leader' Zolgensma, priced at 2.1 mil- lion dollars for patients with spinal muscular dystrophy.
Once these challenges to gene therapy in the hemophil- ias are solved, for a number of reasons, this is likely to become the treatment of choice. Despite the major advances in prophylaxis obtained with EHL factor prod- ucts and non-factor therapies, breakthrough bleeding has still not been fully eliminated, and treatment is still inva- sive, both physically and psychologically, even when the subcutaneous route of administration is used. Patients with severe hemophilia live with the risk of bleeding every day of their lives, and no repeated dosing regimen will be able to replace the advantages of a one-off lifetime cure. Finally, we should not forget that 70% of patients worldwide have no treatment, either because nothing is available or because they cannot afford it; life expectancy at birth for these patients is still only ten years or less! The World Federation of Hemophilia has been attempting to tackle this formidable problem since its foundation in 1967, but despite great progress in medium-income coun- tries, the great majority of low-income countries are still in the same situation they were in 100 years ago: ice, splint- ing, bed rest, and blood transfusions when available!
References
1. JacksonM,MarksL,MayGHW,WilsonJB. The genetic basis of disease. Essays Biochem. 2018;62(5):643-723.
2. Khosla N, Valdez R. A compilation of national plans, policies and government
actions for rare diseases in 23 countries.
Intractable Rare Dis Res. 2018;7(4):213-222. 3. Iorio A, Stonebraker JS, Chambost H, et al. Establishing the prevalence and prevalence at birth of hemophilia in males: a meta-ana- lytic approach using national registries. Ann
InternMed.2019;171:540-546.
4. Palla R, Peyvandi F, Shapiro AD. Rare bleed- ing disorders: diagnosis and treatment. Blood. 2015;125(13):2052-2061.
5. Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood. 2019;133(5):415-424.
6. Leebeek FW, Eikenboom JC. Von
haematologica | 2020; 105(3)
551