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Finding the cure: rare diseases

Rare diseases could be very lucrative for the pharma and biotech industry. We look at some of the companies on the hunt for treatments
August 5, 2016

The incidence of rare disease defies what the name suggests. Alone, such illnesses are classified as rare if they affect fewer than five in every 10,000 people, but taken in aggregate rare diseases are not in fact rare at all. There are an estimated 30m sufferers in the US, while roughly 6 per cent of the UK population are afflicted with one of 7,000 so-called rare diseases.

It would be fair to assume that developing treatments for these diseases would not be a terribly lucrative market for a pharmaceutical company, and until the 1980s that was certainly the case. But in 1983 a group of organisations in the US made a plea for more to be done to incentivise pharmaceutical companies to invest in rare diseases. And so came the Orphan Drug Act, which granted regulatory and tax incentives to encourage pharmaceutical groups to get developing. The success of the original orphan drug act stateside led to it being adopted in other key markets, including the EU and Japan.

The result has been a huge increase in the development of rare disease treatments. Over the past 30 years, more than 400 medicines representing 447 separate indications have been approved to treat rare diseases, compared with fewer than 10 in the 1970s. The sector is growing at an annual rate of 12 per cent - more than double the growth rate seen in the wider pharmaceuticals market. But issues still exist.

With 7,000 recognised rare diseases, fewer than 500 official treatments falls dismally short of acceptable. Even with the benefits of the Orphan Drug Act, the quest for cures for rare diseases can often be hampered by difficulties in finding participants to complete a clinical trial - specific rare disease patient populations are very small, geographically dispersed and often include children.

There are also big issues with diagnosis. A recent survey published in the Journal of Rare Diseases found that due to the rarity of the diseases and variance in symptoms, a patient will visit on average 7.3 different physicians before an accurate diagnosis is made, a journey that is expected to take an average of just shy of five years.

 

Stepping up a gear with genetics

This is, however, a time of great progress and hope. Biopharmaceutical research is entering an exciting new era with a growing understanding of the human genome - the building blocks that make each person unique. This, in turn, has increased scientists' understanding of rare diseases, which are often more complex than common ones. Already researchers have found genes associated with illnesses such as myotonic dystrophy, cystic fibrosis, progeria and neurofibromatosis. Just last week it was confirmed that the gene that causes the degenerative neurological disease amyotrophic lateral sclerosis (ALS) - whose most famous sufferer is Stephen Hawking - had been identified. ALS grabbed headlines in 2015 when it became the fundraising target for the 'ice bucket challenge'. The money raised through the collective efforts of people pouring buckets of ice water on their heads has contributed to a major scientific breakthrough.

With the help of breakthroughs such as identifying specific gene targets, scientists are on the cusp of what could be one of the biggest medical discoveries: gene therapy - a treatment that introduces genetic material into human cells to compensate for abnormal, disease-causing genes. During treatment, physicians will extract cells from a patient's body, re-engineer them to correct for the abnormality, and administer them back into the body, normally via a carrier such as a virus.

There have been some wonderful stories of patients who have been cured of rare genetic diseases that previously had no treatment. US-based Spark Therapeutics (US:ONCE) has successfully restored sight to young patients suffering from blindness caused by a genetic mutation, with its proprietary SPK-RPE65 drug. The company is on the verge of commercialising this treatment and is currently undergoing a pivotal phase 3 clinical trial with the US Food and Drug Administration (FDA). AveXis (US:AVXS), which recently listed on Nasdaq, is also due to start pivotal clinical trials into its AVXS-101 gene therapy to treat spinal muscular atrophy - a severe neuromuscular disease characterised by the loss of motor neurons leading to progressive muscle weakness and paralysis.

The UK, too, offers examples of companies inching closer to commercial gene therapy. ReNeuron (RENE) has two stem cell treatments in the early stage of clinical trials that could be used to treat stroke disability and critical limb ischemia, a severe obstruction of the arteries that markedly reduces blood flow to the hands, arms and legs. Oxford BioMedica (OXB) aims to discover and develop novel gene and cell therapies for patients with conditions where either no therapy exists, or where current standards of care have significant limitations. The group's three primary programmes are in Parkinson's Disease, cornea transplant rejection and oncology.

 

Cancer: a rare disease?

One of the most promising areas of development for gene therapy is in searching for a cure for cancer, as we detailed in a previous instalment of Finding the Cure (IC, 14 August 2015). Of course cancer, when taken as a whole, is not a rare disease - one in five people will receive a cancer diagnosis in their lifetime - but some cancers have very small patient populations.

Finding a cure for rare cancers is a top priority for medical researchers and companies. According to industry analysts Evaluate Pharma there are 566 medicines in development for patients with rare diseases and of these 151 are for cancers, with 82 specifically for blood cancer.

Recently, gene therapy to stimulate an immune attack on cancerous cells has come remarkably close to what could be called a cancer cure. US-based Juno Therapeutics (US: JUNO) has been grabbing headlines following the success it had in a clinical trial in which 87 per cent of non-Hodgkins lymphoma and acute lymphoblastic lymphoma patients (two types of rare leukaemia) move into remission. Since then, however, the company was forced to abandon a final-stage trial after three patients died. Although it's not uncommon for cancer patients to die during trials - they are often very unwell - this case was different as the patients died not from the cancer but from the treatment. The new cells administered into the body had attacked the patient's immune system, causing swelling in the brain, which resulted in death.

 

Finding the cure for the cure

A fundamental problem with some new treatments is that they may cause an illness that is a more aggressive killer than the original disease. When it comes to gene and immunotherapy, that rejection or reaction to new cells is not uncommon - in fact it occurs so often in cell transplant patients that it has been identified as its own disease: graft-versus-host.

This will effect approximately 50 per cent of people who undergo cell therapies such as gene therapy, immunotherapy or bone marrow transplants, and finding treatments could be crucial to solving the problems that come hand-in-hand with other disease treatments. Graft-versus-host treatment options do exist, but as cell therapies become more advanced, with more indications, so does the problem. It has been suggested that the key to solving the issue for good will be in improving the delivery method in getting the cells into the body. At present, re-engineered cells in gene therapy are commonly administered into the body via a virus, as this can deliver the new gene directly into the heart of the body.s cells by infecting them. However, it is this method that often causes rejection.

Two of Oxford BioMedica's key pipeline assets, corneal graft rejection and oncology, are focused on improving the outcome of gene therapy by improving that delivery method. The group's LentiVector platform technology is a gene delivery system designed to overcome the safety and delivery problems associated with earlier generation gene therapy delivery methods. According to the company, the technology can deliver genes into cells with up to 100 per cent efficiency.

The symptoms and side-effects of chemotherapy and radiotherapy are also sometimes more aggressive than the illness they are trying to cure. Aim-traded MidaTech (MTPH) aims to improve cancer therapy outcomes based on combining current treatments with drug carriers that specifically target tumours. At present, Midatech is focusing on chemotherapy drug candidates to treat rare cancers of the liver and brain. Using the group's new technology, these drugs will be delivered via gold casing directly to the tumour - thus omitting the nasty side effects associated with traditional methods of delivery.

 

Rare illness in children

The National Institute of Health estimates that 50 per cent of people affected by rare diseases are children. These illnesses are responsible for 35 per cent of deaths in the first year of life and 30 per cent of children with a rare disease will not live to see their fifth birthday. Encouragingly, one in three of the orphan drugs currently in development are for children. In addition to the Orphan Drug Act, two other US laws have made a significant impact on paediatric research. The Best Pharmaceuticals for Children Act and the Paediatric Research Equity Act have resulted in a wealth of useful information about dosing, safety and efficacy.

Duchene Muscular Dystrophy (DMD) is an example of an illness diagnosed at birth that hugely shortens life expectancy and reduces quality of life. It is characterised by a severe weakening and wasting of the muscles and is caused by a genetic mutation in the X chromosome, meaning it almost exclusively effects boys. It is incredibly rare - only 1 in every 20,000 people will be diagnosed - but for those afflicted that is one too many.

There is hope for DMD sufferers - it is one of the most highly sought-after cures, with no fewer than 26 products in development in the EU. Summit Therapeutics (SUMM) is working on a novel, small-molecule drug that aims to increase the production of a protein called utrophin, a naturally occurring protein produced during the early stages of muscle fibre development and is switched off when the muscle is mature to make way for the protein dystrophin. However in DMD sufferers dystrophin is absent, which causes the muscle wastage. Summit believes that by stimulating the protein utrophin to act in place of dystrophin, it will have the potential to treat 100 per cent of DMD patients.

Another disease that has seen huge levels of investment is cystic fibrosis, an illness that causes mucus in the lungs and digestive system, making normal body functions more difficult. Currently there is no cure, but medical advances mean that patients now have a better knowledge of symptoms management and babies born with the condition today will probably live beyond the current average life expectancy of 41. But for the sufferers it is a life filled with constant drug taking, physiotherapy and care. The discovery of the gene CFTR, whose mutations cause the illness, has made researchers a lot more optimistic that a cure might be within reach.

 

Fleet-footed biotech vs well-armed big pharma

All the companies mentioned above are small or mid-caps - innovative companies that have the agility to develop new treatments quickly. But is this crucial to being a successful orphan drug developer?

Under normal circumstances the ability to move quickly in drug development is a serious advantage, but when it comes to rare diseases the fast-track designation granted to orphan drugs negates the benefit of being small and fast. For big pharma, fast-tracked drugs can be hugely beneficial, while the long-term exclusivity licences granted to rare diseases treatments means that quite often large pharma groups will see these drugs become some of their top sellers. Of the top 10 rare disease companies by pipeline opportunity, seven are considered pharmaceutical global majors.

In terms of sales pipeline for the next four years, US-group Celgene (US:CELG) has recently knocked Novartis (CH: NOVN) off its perch as the biggest orphan drug company. But both companies had better watch out for the newly created rare-disease giant, Shire (SHP). Through the recent $32bn acquisition of Baxalta, the company now boasts best-in-class treatments worth more than $1bn each in annual sales and a development pipeline of rare disease therapies containing more than 30 new drugs ready to launch over the next four years.

Despite some recent victories, research into treatments for rare diseases is a daunting quest. Scientists face an uphill battle not only in developing cures but also in identifying and rapidly diagnosing new illnesses. But breakthroughs are coming faster than ever before and the ongoing innovation and the hundreds of new medicines in development now offer hope that physicians will have new treatment options for patients confronting a rare disease.

Flemming Ornskov, chief executive of Shire, which has a development pipeline of rare disease therapies containing more than 30 new drugs ready to launch over the next four years