life-changing new products from europe’s pharma industry

It’s been a year of ‘firsts’ for the approval of novel classes of drug in Europe, Sarah Houlton reports.

The EU has given the green light to several new therapeutics in the past year. The first RNAi product to reach the market, Tegsedi (inotersen) from Ionis and Akcea Therapeutics, is designed to treat hereditary transthyretrin amyloidosis, an inherited, progressive rare disease for which treatment options are limited.

The drug is an antisense oligonucleotide. These products are short single strands of a nucleic acid that are designed to bind to the messenger RNA produced by a faulty gene, which blocks it from being able to replicate, and therefore effectively turns it off.

Europe’s first cell therapy products were also approved. While potentially life-changing for patients, they come at a significant cost – hundreds of thousands of euros per patient. Kite/Gilead’s Yescarta and Kymriah from Novartis are both CAR-T products designed to treat blood cancers, and manufacturing them represents a huge challenge.

The process is very different from those used to make small molecule drugs or biologic protein products, where large batches are made and distributed. Here, the first step is harvesting T-cells from the blood of individual patients. The cells are then genetically modified using a viral vector to insert a gene that codes for a chimeric antigen receptor, or CAR, which arms the cells to recognise and kill cancerous cells. They are then expanded to make more cells, before being returned to the patient.

This means that every patient receives an individually tailored product – and therefore each dose has to be manufactured individually. Both companies are ramping up production capability in anticipation of product launches around Europe. Novartis will make the cells in-house in Switzerland plus at CellforCure in France and the Fraunhofer Institute in Germany, while Kite has a facility in the Netherlands.

Altering the cells is not the only manufacturing challenge – the virus used to insert the new gene into the cells needs to be made too. There is a real shortage of capacity for manufacturing viruses, which are also used in gene therapy, and in May the UK government’s Cell & Gene Therapy Catapult opened an incubator in Stevenage for the scale-up and manufacture of these products.

It has six independent cleanroom modules for biotech companies to use, and the addition of further modules is already being planned. Four companies are already in situ – Adaptimmune and Freeline making viral vectors, and Autolus and Cell Medica producing cell therapies. The facility is adjacent to a cryo storage and distribution centre, run by Fisher Scientific.

The UK government’s Industrial Strategy is leading to further investment in pharma manufacturing, too, not least the Medicines Manufacturing Innovation Centre that is being

Credit - CGT Catapult Credit - CGT Catapult

set up in near Glasgow in Scotland. Its aim is to aid the development of new technologies and processes for the manufacture of small molecule drugs and fine chemicals. Brexit, however, continues to cause upheaval. The UK government is talking about stockpiling medicines so patients aren’t left without should the country crash out of the EU with no deal in place, and companies are having to spend large amounts of money on back-up plans for such an eventuality.

It also means that the European regulator, EMA, will be leaving its London home and setting up shop in Amsterdam instead. It remains unclear what future relationship the UK will be able to have with EMA, despite the government’s stated desire to be some form of associate member.

Pressure on branded medicines

According to IQVIA, over the past five years spending in developed markets rose from $326bn to $395bn, and 87 per cent of this $69bn net growth was in the US – in the other big markets, where costs and prices are largely managed by the healthcare system rather than left to the market to decide, growth has been slower or even declined.

A big driver for spending increases was the success Gilead had with drugs like Sovaldi and Harvoni, which promise a faster treatment that is more likely to lead to a cure for hepatitis C, as well as some incredibly expensive cancer drugs and the widespread use of monoclonal antibodies to treat autoimmune diseases.

While overall healthcare costs continue to rise, the amount spent on branded medicines is set to drop. IQVIA predicts that net brand spending will fall by 1–3 per cent in 2018. Patent expiry is set to raise its head again in the coming years, and with biosimilars – competitors to biologics – now gaining a foothold in the market in the US as well as Europe, spending is set to fall as prices drop in the face of competition.

The US is a decade behind Europe in the availability of biosimilars, but is catching up rapidly. And several more familiar brand name biologics are now facing competition in Europe. Versions of Remicade (infliximab) have been available to patients with autoimmune diseases for some time, and a biosimilar to breast cancer drug Herceptin, another monoclonal antibody, has also now been given the go-ahead.

The world’s biggest selling drug is currently Abbvie’s Humira (adalimumab) and, with its European patent set to expire in October 2018, several companies are poised to capitalise by launching biosimilars. These include Amgen, Boehringer Ingelheim and Samsung Bioepis, all of which already have EMA approval to launch once the patent situation allows.

Global sales for Humira topped $18m in 2017, more than double the second biggest seller, Bayer/Regeneron’s Eylea (aflibercept). Unsurprisingly, bearing in mind the amount of money involved, AbbVie issued legal challenges. These were settled in early 2018, with AbbVie granting licences that will allow biosimilars in Europe in October 2018, and in the US (where the patent expires later) in 2023.

Combating falsified drugs

However, Europe saw the withdrawal of generic versions of the blood pressure lowering drug valsartan from several manufacturers, including Sandoz, Actavis and Dexcel, after carcinogenic nitrosamine impurities were found. These came from the active pharmaceutical ingredient, which was sourced from Chinese manufacturer Zhejiang Huahai Pharmaceuticals. According to EMA, the Chinese company had changed its manufacturing process, which led to the presence of the impurity.

Recalls in future should be easier to coordinate after the Falsified Medicines Directive is implemented in early 2019. Designed to secure and prevent falsified medicines entering the legitimate supply chain, its requirements will affect manufacturers as well as distributors and dispensers.

Some of the Directive’s requirements are already in place, including rules around traceability of active ingredients, but as of February 2019, all packs of medicine destined for EU patients will have to bear a 2D code that is scanned at the point of dispensing. Each pack has an individual identity code, and if it does not exist on the EU database – either because it has been duplicated or is fake – then the pack cannot be dispensed.

Manufacturers will have to upload these codes to the European Medicines Verification System when the packs are released to the market. If a pack gets flagged up as problematic at the pharmacy, then the manufacturer, the national regulator and the European Medicines Verification Organisation will all be notified. Manufacturers will also be required to apply an anti-tampering device to all the packs, to prevent the contents being removed and replaced with counterfeits.

The serialisation of all the packs will make issuing recalls far simpler – the system will flag up if a pack should have been withdrawn when the pharmacist tries to dispense it. While this adds extra effort and cost to the manufacturing process, in the long run it should reduce the problem of fakes in the market, and increase patient safety. n