ASH – Glaxo scores with second rare disease gene therapy

Earlier this year GlaxoSmithKline became the first big pharma group to file for European approval of a gene therapy targeting a rare disease in children, and data released at ASH on December 5 suggest that it has more up its sleeve.

The group’s 2010 collaboration with Telethon and Ospedale San Raffaele Institute, Italy, has yielded a second gene therapy asset, this time for the childhood disorder Wiskott-Aldrich syndrome (WAS). San Raffaele’s Dr Francesca Ferrua called the data “very exciting”, though she said a regulatory filing would not come for another two years.

Presenting the results at ASH today, Dr Ferrua said the study had been initiated over five years ago, with Glaxo taking over sponsorship in 2014. As of October eight children with WAS, with an average age of 2.2 years, had received the gene therapy, and all were still alive after a median 3.3 years.

WAS is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, bloody diarrhoea and immune deficiency. It results from a mutation in the WAS gene, and leaves children particularly vulnerable to autoimmune disorder and cancers.

It can be treated by stem cell transplantation, but this carries life-threatening complications, especially in the absence of matched donors. The Glaxo gene therapy circumvents this risk by engineering patients’ own stem cells with a correct copy of the WAS gene, transduced using a lentiviral vector.

Infections and bleeds

The key efficacy data concerned severe infections, with incidence of these cut from around 0.35 per person per month to under 0.1 after a year. All seven patients with over a year’s follow-up discontinued anti-infectious prophylactic treatment.

Equally important was the reduction of patients’ bleeding rates, and the severity of bleeding, said Dr Ferrua. Severe and moderate bleeds were almost completely eliminated after administration of the gene therapy, while mild bleeds fell in line with the length of follow-up.

All eight patients had the classical form of WAS, and lacked a matched donor. No serious adverse events related to the gene therapy were observed; the most frequent serious adverse events related to infections, seen in 85% of patients, and occurring mainly during the first year of follow-up.

A second success?

The WAS gene therapy data come on the heels of a separate project, GSK2696273, which Glaxo, Telethon and San Raffaele filed for approval with the EU regulator in May.

GSK2696273 was developed for a different rare disease – adenosine deaminase severe combined immunodeficiency syndrome (ADA-SCID, also known as “bubble boy”), in children for whom no suitable matched stem cell donor is available.

This gene therapy also involves engineering the patients’ own stem cells, but this time with a corrected copy of the ADA gene, and using a retroviral vector for transduction. GSK2696273 thus became the first gene therapy to be filed for a rare disease in children.

Not that gene therapies in general have met with great success. UniQure’s Glybera did become the first ever to get approved in a regulated market, securing the EU green light in October 2012 – under exceptional circumstances – for treating adults with the ultra-rare disease familial lipoprotein lipase deficiency.

But owing to several factors the first commercial patient was not treated until two months ago, and UniQure has given up on Glybera in the US (UniQure pivots to pipeline while Glybera sputters, December 1, 2015).

Glaxo and its Italian partners are also working on gene therapies for other rare diseases, including metachromatic leukodystrophy and beta-thalassemia. And separately, in April Italy’s MolMed exercised an option to buy San Raffaele’s CD44v6-directed CAR-T project.

Dr Ferrua said the WAS study was now closed for enrolment. While a regulatory filing would be sought in two years’ time, in the intervening period the partners will commit to treating additional patients on a compassionate-use basis.

One of the problems with Glybera is its cost, and it made headlines for being a therapy with a price tag of over $1m per treatment. The fact that none of Glaxo’s gene therapies is likely to be much cheaper could put a damper on expectations.

To contact the writer of this story email Jacob Plieth in Orlando at [email protected] or follow @JacobPlieth on Twitter