The 30th of August 2017 was a truly historic day for science and innovation. In the US, the Food and Drug Administration (FDA) issued approval of Kymriah, a genetically modified cell-therapy treatment. The FDA Commissioner hailed this achievement and its dimension in the following statement: “We’re entering a new frontier in medical innovation with the ability to reprogramme a patient’s own cells to attack a deadly cancer. New technologies such as gene and cell therapies hold out the potential to transform medicine.” Just two days earlier, in an unconventional move, biotechnology company Gilead Sciences swooped down on Kite Pharma in a USD 11.9 billion takeover deal, emphasising its commitment to this space.
New gene, cell and tissue engineering therapies herald a disruptive new phase in our healthcare system, making one-time fixes a reality and replacing trips to the pharmacy or lifelong dependence on medications. With the number of gene therapies in active development at an all-time high, this wave of innovation is approaching with great promise and more quickly than most people realise.
The concept arose during the late 1960s when Marshall Nirenberg, a Nobel Prize laureate, wrote a paper about “programming cells with synthetic messages”. Many diseases are caused by a defective gene that prevents the production of a protein needed by the cell to work properly. Gene therapy is one elegant solution to the problem: it transfers a healthy gene into the cell to replace the unhealthy one. One of the biggest challenges to overcome was how to deliver the gene ‘bullet’ to the appropriate place and, as is so often the case in scientific research, this initially led to more failures than successes. Some patients treated in first clinical trials developed leukaemia because the viruses dropped their genetic payload into the wrong part of the genome, thereby switching on cancer-causing genes. A second big blow occurred in 1999 when an 18-year-old patient with a non-fatal liver disease, Jesse Gelsinger, died in a gene-therapy experiment. In Gelsinger’s case, the virus used for transportation made his immune system go into overdrive, causing multiple organ failure and brain death.
It was this death that caused gene-therapy research and development to grind to a halt for a while, but it also became the critical driving force behind a renewed search for safer and more efficient viral transport vehicles. In work that originated in the Wilson Testing Laboratories at the University of Pennsylvania during the early 2000s, a library of over 100 different adeno-associated virus variations was isolated from natural sources. This next-generation viral technology enabled not only higher levels of precision in the targeting of genes to the desired tissues, but also has to date shown unprecedented safety. During the past five years 70% of the vector types used in clinical programmes have been based on this novel library, underlining its innovative value. Regulatory agencies are soon to put their stamp of approval on them.
Renewed enthusiasm for the space follows eight gene-modified therapy approvals globally. The most recent approval of Kymriah, a chimeric antigen receptor T-cell (CAR-T) therapy, embodies a unique gene modification approach using a patient’s own immune cells to kill the most common type of childhood cancer, acute lymphocytic leukaemia. Each dose is a personalised treatment of extracted white blood cells which are engineered or “armoured” ex-vivo to enable them to recognise the tumour once reinserted into the body. Kymriah patients have a 90% chance of survival overall. Looking ahead, Kite Pharma’s axi-cel CAR-T therapy for aggressive non-Hodgkin lymphoma is next up to the product approval finish line along with Spark Therapeutics’ Luxturna for inherited retinal disease, marking more major milestones for the sector in what could become not just a historic day, but a historic year.
Now, on the verge of curing the first monogenetic (single gene defect) disorders, the general effort has become to leapfrog from ultra-rare diseases to less rare ones. With the caveat of small patient numbers, there has been an intensified ramp-up of positive clinical datasets since the middle of 2015 for indications such as bleeding, and neuromuscular, eye and liver diseases. We foresee a step-up in the rate of clinical newsflow over the coming 12-18 months, in turn solidifying new treatment options. Bluebird Bio has the largest number of gene-therapy programmes in Phase III and will report further data this coming December in beta-thalassemia and sickle-cell disease patients. The hope is that treated patients can continue to live free of burdensome once-a-month, costly and suboptimal blood transfusions. AveXis’ gene therapy for spinal muscular atrophy Type 1, a deadly disease brought on by the degeneration of motor neurons in the spine, showed survival rates of almost double the lifespan of untreated babies and we anticipate updates on continued survival to carry on. Many other rare disease programmes are expected to present first in-human data over the coming months representing what could become a spurt of clinical successes. We are cognisant of the potential for imminent and significant developments at both the clinical and stock level and are positioning our portfolio accordingly.
Mounting interest by big biopharmaceutical companies for pre- and clinical-stage gene-therapy assets intensified in 2016. In one of the earliest moves into the space, Pfizer bought an early-stage company, Bamboo Therapeutics, for a total value of USD 645 million, and with it, announced a mission to “become industry leader in gene therapy”. Allergan followed on its heels with the purchase of gene-therapy company Retrosense Therapeutics, to access a novel development programme in the restoration of vision in blind people. Mid-sized biotechnology company Shire recently announced its debut into the space via an investigational new drug submission in haemophilia A. More long time coming is Biogen’s investment via collaborations with key pioneering players such as University of Pennsylvania. We believe Gilead Science’s most recent decision to acquire Kite for a hefty amount, in a move away from single drug pills to highly complex, niche cell therapies, strongly hints at a value potential far beyond today’s expectations.
Even though first commercial products have not translated into profit makers, the healthcare industry recognises their tremendous platform technology value. This is further evidenced by intensified regulatory support such as accelerated breakthrough therapy, fast-track and orphan drug designations being awarded by the FDA. Investors are willing to finance companies in this risky effort: the Alliance for Regenerative Medicine Quarterly Data Report states that the field raised $4 billion in assets in the first half of 2017 alone.
Clearly regenerative medicine is ready for prime time. The efficacy appears curative and the safety profile clean. With single gene disorders now ‘tackled’, researchers are moving onwards in an attempt to cure more complex, more common, but multi-genetic conditions such as solid cancers, Alzheimer’s, diabetes and heart failure. However, the complexity of curing diseases originating through a mix of genetic mutations and influenced by lifestyle and environmental factors, many of which are not yet fully understood, suggests that this next historical frontier in medical innovation will be for future generations to celebrate. For now we remain passionately convinced of regenerative medicine’s inherent value creation in its ’simplest’ form, one gene at a time.