Keytruda: a first-in-class cancer therapy

Continuing our celebration of UK bioscience success, adapted from our report Celebrating UK bioscience which was launched in June, today's blog tells the story of Keytruda and the pivotal role of UK science as we enter a new frontier of cancer treatment.

Harnessing the immune system to target cancer offers a new, powerful approach to tackling the disease, beyond the traditional methods of directly destroying cancer cells. One of the most promising recent advances in cancer immunotherapy, and indeed in cancer drug development more broadly, has been the emergence of “checkpoint inhibitors”.

These therapies are designed to scupper cancer cells’ clever methods of hiding from the body’s immune system. Cancer cells exploit checkpoints within the immune system that are designed to prevent it from going into overdrive, effectively dampening the immune response. Checkpoint inhibitors release these immune system “brakes”, allowing the body’s defence network to spot and attack invasive tumour cells.

Keytruda, recently approved for the treatment of life threatening forms of skin cancer, is a leading example of this new class of therapies. Not only does UK science and its exploitation form a key part of its development, but it is one example of a number of emerging therapies coming out of UK bioscience that are changing the face of future cancer treatment. Accelerated approval for first-in-class drug In September 2014, Keytruda (pembrolizumab) became the first in a new class of checkpoint inhibitors to receive US regulatory approval. This antibody targets the programmed death-1 (PD-1) pathway – a checkpoint normally involved in preventing tissue damage during chronic inflammation. Keytruda was shown in trials to shrink tumours, sometimes for six months or more, in almost a quarter of patients suffering from advanced, life threatening forms of skin cancer.

The benefits Keytruda offers for these patients, who have few other treatment options, prompted the US regulator, the Food and Drug Administration (FDA) to approve the drug almost two months earlier than expected, via an accelerated review process reserved for breakthrough therapies. European approval followed in May 2015, though the drug was made available to UK patients two months earlier. It was the first product to receive a “positive Scientific Opinion” from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK’s Early Access to Medicines (EAMS) scheme. 

A patient receiving immunotherapy cancer treatment[/caption] The pivotal role of UK science in Keytruda's development Keytruda is sold by Merck & Co. Inc., and has changed hands several times during its path to market. But a key step in the drug’s early development occurred at the UK medical research charity MRC Technology (MRCT). In 2006, MRCT applied an antibody humanisation technology, conceived by Sir Greg Winter and his team at the MRC’s Laboratory of Molecular Biology, to a compound belonging to Dutch pharmaceuticals group Organon.

The technique, known as CDR grafting, involved identifying and then inserting the coding sequences responsible for the antibody’s desired binding properties – e.g. to PD-1 in this case – into a human antibody scaffold. CDR grafting has now been used to humanise over 55 antibodies, including three further marketed therapies. Multiple sclerosis treatment Tysabri (natalizumab), rheumatoid arthritis drug Actemra (tocilizumab) and Entyvio (vedolizumab), sold for ulcerative colitis and Crohn’s disease, are all examples of treatments that are available thanks in part to UK bioscience. Organon was attracted to MRCT’s technology and to what was already a highly experienced and well established antibody engineering group. Under a licensing contract signed in 2006, the Dutch group agreed to pay milestones, as well as small royalties on sales of any resulting therapy. In 2008, MRCT delivered to its partner the humanised antibody that would become Keytruda. By then, though, the first of the two multi-billion dollar deals on Keytruda’s path to market had already occurred.

Organon was acquired by Schering Plough in March 2007 for $14.4 billion. Two years later, in November 2009, Merck bought Schering Plough for $41.1 billion. Both deals were driven in part by the buyers’ need to access biotechnology expertise, as big drug firms (until then focused on chemistry-based, small molecule pharmaceutical drugs) began to wake up to the promise of large molecule biological therapies like antibodies and other proteins. A new frontier of cancer treatment Keytruda’s story is only just beginning. Its contribution to the fight against cancer – like that of checkpoint inhibitors more broadly – has much further to go. Cancer treatment is increasingly about combining a variety of therapeutic approaches in what amounts to a multipronged attack. Checkpoint inhibition and other immunotherapies may offer more potent and durable effects than older therapies that block cancer cell growth or kill cells directly, but both contribute to the growing toolbox available to fight the disease.

The UK biotech sector continues to contribute to cutting edge research around checkpoint inhibition and other novel approaches to fighting cancer. One example is Oxford-based PsiOxus Therapeutics Ltd. This company is using an oncolytic (cancer destroying) vaccine technology platform to design and develop cancer-targeting viruses. A recent funding round will allow the start-up to test whether its oncolytic virus, in combination with a checkpoint inhibitor, may provide some hope for patients with metastatic colorectal cancer. As we head into a new frontier of cancer treatment, UK bioscience is helping drive game-changing cancer treatments. Like to find out more? The full version of the Keytruda story, along with five other case studies, can be found in our report, “Celebrating UK bioscience: unravelling the stories behind UK bioscience success”.