Biomarin hopes long-term valrox data can stem the bleeding

Expectations are low for a three-year update on the group’s haemophilia A gene therapy, and Biomarin’s rivals could capitalise on any slip-up.

Investors in Biomarin have had a turbulent year, and the next few weeks might get even rockier ahead of three-year data with the group’s haemophilia A gene therapy candidate valoctocogene roxaparvovec (valrox).

Valrox will need to show a durable long-term response if it is to become a once-and-done therapy and justify what is likely to be a high price. However, this is far from a given after last year’s disappointing two-year update from the same study, which showed factor VIII levels waning over time.

Project Valrox
Company Biomarin Pharmaceutical
Market cap $15.9bn
Product NPV $4.5bn
NPV as % market cap 28%
Event Three-year phase I/II data
Timing May/June 2019

Haemophilia A gene therapies aim to spur production of factor VIII (FVIII), a blood clotting protein that is missing or defective in patients. The ultimate point of treatment is to stop or decrease the bleeding events that characterise the disorder.

FVIII replacement therapies are already available, but these are given intravenously several times a week so gene therapy, if it works, promises to be much more convenient.

If successful valrox would also have Roche’s subcutaneous therapy Hemlibra to contend with. This can be given as infrequently as once a month and has taken the market by storm since being launched in 2017.

The imminent valrox update will therefore be crucial for gauging the project’s chances of approval but also of grabbing market share. If, for example, valrox’s effect lasts for only four or five years, patients and payers might prefer to stick to the existing options, or wait for potentially better gene therapies that are further behind in development.

Late breaker?

Top-line three-year data from valrox’s phase I/II trial are expected before June 7, the late-breaker abstract submission deadline for the International Society on Thrombosis and Haemostasis (ISTH) conference, being held in Melbourne, Australia, on July 6-10. Biomarin hopes to present more detailed results at this meeting.

The trial is testing two doses of valrox, 4x1013vg/kg and 6x1013vg/kg, although interest will be focused on the latter, which has been shown to bring FVIII into a normal range.

The finding fuelled excitement around valrox at the 2017 Ash meeting. This was tempered last year by a two-year update showing FVIII activity falling, although mean levels were – only just – still classed as normal.

Source: Leerink note May 2, 2019

The fear is that FVIII levels will show further declines at three years. Indeed, the question for many investors is how big the decline will be.

Evaluating this is complicated by the fact that Biomarin has switched focus from one test of FVIII activity, the one-stage assay, to another, called the chromogenic assay. The data shown above come from the one-stage assay, but the company said during its first-quarter earnings presentation that it had agreed with the FDA that the chromogenic assay could support accelerated approval.

The two tests produce different results: with high-dose valrox at two years median FVIII levels were 46% per the one-stage assay, but 27% according to the chromogenic assay.

Stifel analysts noted that, at three years, anything above 20% on the chromogenic assay would represent success, and 25% or more would be “a massive win”. The latter would suggest that FVIII levels were plateauing – a good sign for valrox’s durability.

Still, some expect FVIII levels to drop into the teens. Indeed, Stifel postulated that if this happened, and the decline continued at the same rate, FVIII levels could hit 5% – the minimum thought to be needed for a clinical benefit – within four to five years. In this scenario patients would need to return to regular prophylactic therapy after this time, and the viability of the gene therapy would be called into question.

Biomarin should also report three-year data on annualised bleed rate, a hard endpoint that is important to regulators and payers. However, this is of less interest to investors as it is expected to remain low: FVIII activity is unlikely to drop below levels that would translate into an increase in bleeding.

The company plans to decide whether to file for accelerated approval of valrox in the second half of this year. Phase III studies are ongoing, including the 130-patient Gener8-1 trial of 6x1013vg/kg.

Queuing up

If Biomarin does slip, other haemophilia A gene therapy players will hope to make the most of their rival’s misfortune. The next most advanced project is SPK-8011, being developed by the Roche target Spark Therapeutics. The candidate is in a six-month run-in study for its phase III trial. 

Data on SPK-8011 are also due in mid-2019, perhaps at the ISTH meeting; this will consist of results from a new cohort of Spark’s phase I/II trial that involved prophylactic steroid treatment. It is hoped that using steroids up front, rather than as needed, could address concerns about immunogenicity with the project.

In addition to the immunogenicity issue, SPK-8011 has not managed to return FVIII levels to within the normal range. Perhaps more worrying for Biomarin is Sangamo’s Pfizer-partnered asset, SB-525, which recently yielded promising results, albeit in only two patients (Two haemophilia A subjects help Sangamo erase 2019's losses, April 2, 2019). 

For now, however, valrox’s main competitor is Hemlibra. Biomarin will need its project to surpass current expectations for any chance of knocking Roche off its perch.

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