Reasons to be cautious about new haemophilia therapies

Roche’s novel haemophilia therapy Hemlibra is expected to become a $4bn drug by 2024. Impressive data from the Haven 3 trial in the largest population, haemophilia A patients without inhibitors, have only fuelled excitement around the product.

But Haven 3’s lead investigator, Dr Johnny Mahlangu, of the University of the Witwatersrand in Johannesburg, has sounded a note of caution based on haemophilia history. When longer-acting factor replacement products hit the market in 2014 “we were asked if [these] were going to wipe out the standard half-life molecules. In fact, that has not happened,” he told EP Vantage on the sidelines of last week’s World Federation of Hemophilia (WFH) meeting.

The notoriously conservative haemophilia market could have been to blame. However, Dr Mahlangu put the lacklustre uptake of extended half-life products down to affordability.

On this point, Roche has given itself a good chance of competing by setting Hemlibra’s price at less than $500,000 per year, in line with current factor VIII replacement therapies. The US Institute for Clinical and Economic Review (Icer) has already deemed Hemlibra cost effective in its approved population of patients who have developed inhibitors, antibodies rendering front-line factor VIII clotting factors ineffective (Hemlibra shows it is cheaper and better, January 30, 2018).

It will be interesting to see the organisation’s verdict in the non-inhibitor market, the bigger indication where Roche hopes to get approval by the end of the year.

If the company has got Hemlibra’s price right favourable efficacy could help the drug become the biggest haemophilia A therapy by 2021 – data from Haven 3 presented at the WFH congress found that the product was superior to prophylactic factor VIII (WFH 2018 – Roche takes haemophilia fight to factor developers, May 21, 2018).

And Dr Mahlangu agreed that demand would be high: “Given that we’re all pushing for prophylaxis as optimum care I would not be surprised, given the safety and efficacy profile, to see more and more patients wanting to use [Hemlibra] instead of their current standard or extended half-life products.”

On safety Haven 3 did not find anything untoward, which should go some way towards reassuring those worried about the risk of thromboembolic events.

Dr Mahlangu, like others, blamed the combination of Hemlibra and high doses of Shire’s bypassing agent Feiba for the thrombotic events seen previously in inhibitor patients. As these bypassing agents are not used in non-inhibitor patients, this issue should not arise in this population.

And there were no problems seen in Haven 3 with a combination of Hemlibra and factor VIII replacement therapies, he added. Overall, there were 215 instances of such co-exposures in 64 patients. “I do not have any reservations on the safety of this product,” Dr Mahlangu concluded.

Still, not everyone is completely satisfied with Hemlibra’s safety profile. In a presentation at WFH Dr David Lillicrap of Queen’s University in Kingston, Canada, noted that it was “not easy to interpret” information about the six deaths that have so far been linked with the drug. Roche says none of the fatalities were related to therapy.

Dr Lillicrap added that many of the deaths had occurred during compassionate use, pointing out: “Once that happens you have little control over how the agent is used.” He recommended that novel therapies like Hemlibra be confined to comprehensive haemophilia treatment centres where they could be better monitored – a move that Roche is likely to resist as it would hinder sales.

New contenders

Roche will need to make the most of its head start; various other novel projects are on its tail, including Alnylam/Sanofi’s fitusiran and gene therapies from Biomarin and Spark Therapeutics. Biomarin's valoctocogene roxaparvovec (valrox) generated updated data from its phase I/II 201 study at WFH.

Even in the long-acting factor VIII space there is still activity. At the conference there was excitement about first-in-human data with Bioverativ’s – now Sanofi’s – BIVV001, which is designed to be given prophylactically once weekly or less frequently, compared with twice a week for existing extended half-life products. Hemlibra, a subcutaneous injection, has been approved for once-weekly dosing.

The phase I/II Exten-A trial found that the lower dose of BIVV001 had a half-life of 37 hours, versus 13 for standard recombinant FVIII therapy, supporting claims that the product is the first to avoid clearance mediated by von Willebrand factor, which has limited the half-life of older products.

Dr Mahlangu described the results as “extremely impressive. I have no doubt that the high-dose data will be even better.” But he did add that the project still had a long way to go.

He also expressed excitement about the prospect of a cure for haemophilia in the shape of gene therapies. If these are shown to be safe and effective Dr Mahlangu was confident that, even with Hemlibra on the market, "there’s room for these therapies to co-exist”.

Again, Dr Lillicrap was more cautious, pointing to the small number of patients studied so far, with relatively short follow-up. He discussed potential adverse events with gene therapy, including liver toxicity and the possibility of patients developing cancer years after treatment – although he added that the risk of the latter was “extraordinarily low”.

In another WFH presentation, Ilan Irony of the FDA said the agency would likely ask for at least five years' follow-up for gene therapies using AAV vectors, such as the Biomarin and Spark projects.

But Dr Lillicrap suggested that gene therapy patients would need to be followed indefinitely.

When asked if patients might be put off by these potential risks, Dr Mahlangu replied: “If you follow your logic, why would someone want to use an extended half-life [product] when there are already safe, standard half-life clotting factors?”

Dr Lillicrap concluded: “A lot of very positive things are coming from these innovations. But an appropriate level of caution must be exercised as we proceed.”