Improving the lives and long-term outcomes of people affected by bleeding disorders since 1958

Read More

Promoting excellence in haemophilia 
care, education, advocacy and support.

Read More

10th WFH Global Forum

At the beginning of November HNZ Vice-President Catriona Gordon attended the 10th WFH Global Forum on Treatment Products for Bleeding Disorders. These are always full of interesting information, and are a very good opportunity for our people to connect with other organisations from around the world. 

The 10th Global Forum was held, as the previous nine have been, in Montreal, where the head office of the WFH is situated. Those attending are a mix of treaters, patient representatives, researchers and pharmaceutical staff. The attendees number around 170, and given the location there is a large proportion of people from North America (Canada and the USA). A small number come from developing countries, including Dr Sophal from Cambodia, who attended this year for the first time. Europe is well-represented, and there are many names which will be familiar to those who have attended Congresses in the past. Suffice to say there are a lot of amazing brains in the room, who have devoted, for some, their careers, and for others their lives and careers to the advancement of the treatment of haemophilia.

The WFH organisers poll the attendees throughout the sessions on various aspects that are going to be discussed in sessions, and then after the session itself, to ascertain the effect on the participants once they have heard the presentations on particular topics. The questions are multi-choice, and the attendees answer using an electronic device, enabling the results to be displayed to everyone immediately. A question which is always asked at the beginning and at the end of each bi-annual meeting is “What is the greatest risk in haemophilia currently?”. The options are:

  1. Inhibitors
  2. Price and access to treatment
  3. Unknown viruses
  4. Something else

These first three answers summarise the focus of the meeting each year, and this year was no different.


The meeting commenced with presentations by David Lillicrap, Steven Pipe and Christine Keipert, in a session entitled Inhibitors – solving the problem. Before you get too excited, I should say that the problem was not solved at this meeting. The occurrence of inhibitors in pwHA is around 30%, meaning that during their lifetime, up to 3 out of 10 pwHA will experience an inhibitor at some level. Inhibitors in pwHB is around 4%. Sometimes the inhibitor is not significant, othertimes, especially when diagnosed when the patient is young, the inhibitor can be successfully tolerised, but in the worst scenario the inhibitor is untreatable and seriously affects the patient for life.

Dr Pipe noted that there has been no evidence of any significant reduction in incidence or prevalence over several decades of care, and there may actually have been an increase over the past 20 years. In the US the Medical Scientific and Advisory Council (MASAC) have set up a working group, the primary goal of which is to be a catalyse for the development and implementation of a national agenda to lead toward the prevention and eradication of inhibitors within the US haemophilia population. A national inhibitor surveillance programme has been set up and it is intended to enroll all new previously untreated patients (PUP) on diagnosis into this programme. Both David Lillicrap and Steven Pipe in their talks discussed the fact that while we know some of the risk profiles for developing inhibitors, the treatment of such patients is not being tailored with this risk in mind. The surveillance programme is intended to ensure that treatment is delivered with recognition of the individual patient’s risk of developing inhibitors.

David Lillicrap discussed the difficulties with diagnosis at present, given that the primary test for inhibitors is very unreliable. He noted that there are other enzymes which are noticeable at an increased level before the inhibitors occur, and that these could be tested as an alternative. Inhibitor prevention needs to be a major priority, and to do this there needs to be close attention to the patient during their first 20 Exposure Days (EDs). Alternative therapies for patients with inhibitors, such as Emicizumab, hemostasis rebalancing strategies and gene therapy also need to be a focus in the ongoing treatment and management these patients.

Extended Half-Life Products

Dr Manuel Carcao from the Hospital for Sick Children, Toronto, gave a presentation on how extended half life products were made available to the Canadian population in 2016. Having been put onto the pharmaceutical schedule in Canada (they have a similar system to Pharmac here in NZ), all patients were advised by letter of the availability of Eloctate and Alprolix, the extended F VIII and F IX therapies (EHL). At the same time, due to the result of a tender change, Advate was being withdrawn, which meant that all those patients using Advate would have to switch to something else. Those patients on the other Standard Half-Life therapies (SHL) still being purchased for the patient population could choose to remain on their existing treatment or switch to the EHL.

There were different rates of switching to the EHL in different HTCs, which is likely due to the different approaches by doctors. No one on a continuing SHL was forced to change, and the result was that in this population only 30% chose to change to the EHL. Amongst those patients who had to change from Advate to something else, either the EHL or another SHL, 96% changed to the EHL. Dr Carcao also presented data on the difference in treatment regimens pre and post switch at his hospital. Of the 57 F XIII child patients, 40 were on “full dose” prophylaxis, being every other day (EOD) or 3 X/wk pre-switch. Following the switch, 21 changed to every 3 days (Q3D), 35 were 2/wk and one treated once a week. With respect to factor usage, there was an overall decrease of 15%

In the FIX population 9 patients switched to Alprolix. All these patients moved from 2/wk or EOD pre-switch to 1/wk, although 2 changed to %5D within 4 months of switching due to bleeding on D5-6 post prophylaxis. There was a 40% decrease in factor usage post-switch.

Frequent trough levels were also done, although no formal PK studies were done. The mean FVIII levels were 13% after 48 hours, 4.1% after 72 hours and 1.8% after 96 hours. The estimated average half life was 16-17 hours.

The overall impression of these patients on EHL is that they are bleeding less. As an indicator of patient satisfaction it was noted that no patient had asked to switch back.

New treatments

At each meeting the WFH invites pharmaceuticals to present updates from clinical trials they are carrying out. It is always interesting, although highly technical. The following trials were presented this year:

Emicizumab (ACE910)

Michael Callaghan from Roche presented data on the Phase 3 Studies being carried out with ACE910 as prophylaxis for adolescents and paediatric patients with Haemophilia A with Inhibitors. The treatment requires a once-weekly subcutaneous injection. The results of the studies shows a statistically significant reductions in bleed rate of 87% compared with on-demand treatment with Bypassing agents (FEIBA or Novo7). Adverse events occurred in 5% of more of the patients, and included injection site reactions, headache,  fatigue, upper respiratory tract infection and arthralgia (joint stiffness). Serious adverse events of thromboembolic events (TE) and thrombotic microangiopathy (TMA) – both are blood clots – occurred in two and three patients respectively.
These events were associated with the patients receiving repeated high doses of a BPA to treat a break-through bleed. Put simply, ACE910 worked so well that the blood clotted due to an overload of clotting factor.

Spark Therapeutics – Over-view of Gene Therapy for Haemophilia A and B

Marcus Carr presented on the gene therapy phase 1 and 2 trials being undertaken for both Haemophilia A and B. The inclusion criteria for patients to take part in the FIX trial were as follows:

  • Males over 18 with FIX levels less than 2%
  • More than 50 factor exposure days, with no history of inhibitor
  • No active HBV or HCV, liver fibrosis less than stage 2
  • Negative HIV viral load
  • Baseline treatment either on prophylaxis or on demand with more than 4 bleeding events
  • per year or arthropathy

The 15 participants were divided into three groups, with each group receiving a different level of dosage. The actual injection involved a one hour outpatient intravenous injection, followed by 52 weeks of monitoring and a long term extension study after this.

A known effect of the gene therapy is an immune response which is indicated by raised levels of ALT (alanine aminotransferase). Patients with this indication are treated with steroids. In past trials, the sustained elevation of FIX levels seems to have been negatively affected by the immune response, but there is indications that treating with steroids early can avoid the factor level drops.

The results of the FIX levels in the 8 patients who did not require steroids after 52 weeks are very encouraging – between 18% and 44%. The first 10 patients who were treated have shown a 96% reductions in the mean ABR.

The FVIII trial is also a Phase 1/2 study. As at August 2017 there are 3 patients on the trial. The FXIII levels as at that date range between 7% and 14%. This study will continue and we would expect to hear more about it and the data obtained in 2019.

BioMarin Pharmaceuticals – Gene Therapy trials

Benjamin Kim presented result of a Phase 1/2 Study which has been completed for their FVIII gene therapy. Nine patients were on the trial, with 6 receiving a low dose and 7 receiving a high dose. In both cohorts tests showed a sustained increased level of FXIII expression after up to 32 weeks of monitoring, ranging between 5% - 51% for the low dose trial. The mean FXIII levels of the 7 patients on the high dose trial after 52 weeks was 51%.

BioMarin are starting a Phase 3 trial in 2018.

uniQure Inc.

Eileen Sawyer presented the results of a Phase 1/2 gene therapy trial of 10 FIX patients, again divided into 2 groups of 5 and receiving different doses of the drug as follows:

  • All 10 patients in the study have demonstrated improvements in their disease state as measured by reduced FIX replacement therapy and bleeding frequency.
  • In the second-dose cohort, no spontaneous bleeds were reported in the last six months of follow-up, with a reduction in the annualized spontaneous bleed rate of 84% compared to the one-year period prior to administration of AMT-060. Total bleeds were reduced by
  • 64%.
  • Eight of the nine patients that required chronic FIX infusions prior to administration of AMT-060 have discontinued prophylaxis after treatment. All eight patients remained prophylaxisfree at the last follow up.
  • Across both dose cohorts, cumulative annualized FIX consumption decreased by 79%, from 2.64 million to 544,741 IU.
  • Through up to 12 months of follow-up among the five patients in the second-dose cohort, the mean steady-state FIX activity persisted at approximately 7% of normal. The mean FIX activity at the last follow-up (52 weeks) was 8.82%, ranging from 5.2% to 10.7%.
  • AMT-060 continues to be well-tolerated, and there have been no severe adverse events.
  • In both dose cohorts, FIX activity remained consistent and stable through up to 18 months of follow-up with no emergence of late immune response or loss of FIX activity in any of the patients.
  • Three patients experienced mild, asymptomatic elevations of alanine aminotransferase (ALT) soon after administration. For these patients, ALT levels returned to their baseline readings, no recurrence of ALT elevation has occurred, and no loss of FIX activity was observed.
  • No patients across either cohort have developed inhibitory antibodies against FIX, or demonstrated sustained AAV5 capsid-specific T-cell activation.

Alnylam Pharmaceuticals

Pratima Chowdary presented on a Phase 2 extension study for Fitusiran. Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding. Fitusiran utilizes Alnylam's ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability. This drug is novel in that instead of replacing the missing factor it depresses the enzymes which promote blood thinning. This trial has been put on hold after the death of a patient while on the trial. The cause of death was a cerebral haemorrhage.


The key “take home” messages from this meeting for me were the following:

  • Progress on dealing with inhibitors has been unremarkable but there is a will and intention to do more and better to solve this issue
  • ELT are providing patients with raised trough levels which provide protection against bleeds and overall improves Quality of Life
  • Emicizumab with its sub-cutaneous delivery and excellent elevation of FVIII levels shows that there is a new way of treating which transcends the level of care we currently receive
  • Gene therapy is coming soon – a poll of the room showed that the majority saw it as being available within 5 years.

These are incredible times. We need to be very be advocating to ensure these new therapies are available to our members in a timely fashion.