Thursday, 21 April 2016

Drug Repurposing Conference, Part 3, London - 29th Feb 2016

On 29th Feb I had the pleasure of going to the Findacure Drug Repurposing for Rare Diseases conference which was held at the Royal Institution in London.  My notes on this conference will take up a few posts. This is part 3 of 3. Part 1 is here. Part 2 is here.

Dr Jack Scannel of Innogen Institute at the University of Edinburgh talked about the case for user led innovation. Scientists have survivor bias - they over-estimate the performance and nobody hears about the 9 out of 10 failures to get to the success. Nobody knows which drugs will sell well, and nobody knows what new drugs will be used for.

He described a paper by DeMonaco from 2006: The Major Role of Clinicians in the Discovery of Off-Label Drug Therapies This paper describes a study into new uses identified over 5 years for drugs introduced in 1998.

29 new drugs were introduced in 1998, and of these new uses were found for 22 of them. In total 143 new applications for those drugs were identified, 82 of these were field based discoveries based on looking at the reporting of the studies, and 57 were led by the laboratory. The paper looks at the field discoveries and reported that 60% of the applications were as a result of a clinician understanding the mechanism of the drug, some 11% were serendipitous discoveries, with the remaining 29% found some other way.

Drug repurposing can be for both common and rare diseases. Even with trials for common diseases clinical trials often don't tell enough about the real world populations who might use the drugs. The issue is how to sort out a trial for diseases with a small patient population.

Jacks key points were that:

  • User-led innovation should be incentivised
  • The would maximise the amount of safe chemicals available
  •  The process reduces timescales
  • The process reduces the demands for phase 3 clinical trials
  • This should improve the ability to track and manage information. 
He observed that often the 2nd, 3rd or 4th use for drugs can be better than the original use.

People can find out about clinical trials at

The last paper of the day was by Dr Victoria Parker at Addenbrookes Hospital, Cambridge.  She talked about repurposing sirolimus for rare mosaic overgrowth disorders. The elephant man has mosaic overgrowth. There is a protein which is working too much, and the objective is to find a drug to turn off the protein.

The drug sirolimus was one example of a potential drug which was shown to work at low concentrations. They set up an open label, uncontrolled, non-randomised pilot trial with 10 patients from the UK. It took over a year to get the trial set up. Victoria described some of the challenges.

As mosaic overgrowth is a rare disease there is a limited overview, and not enough data to statistically justify a randomised controlled trial. The patients were scattered across the UK, so collaboration was needed in the trial design. NHS trusts have no capacity to undertake blood tests, and GPs need approvals to do so. Therefore the trial had to be designed to minimise the study interventions (blood tests), and private sector involvement was needed. 

Funding was the next challenge. The list of costs included: Staff time, a database for the results, the drug itself (and any placebos), shipping costs for the drug, imaging and blood test costs, insurance and pharmacy fees. Pfizer agreed to provide the drug free of charge, the determined that the database could simply be a spreadsheet, and it was cheaper for them to get insurance for 3 separate trials in single locations than a single policy for a multi-centre trial. Overall, the costs were reduced from an initial estimate of £150k down to £60-70k.

Victorias last points were about a revision to the EU Clinical Trials Directive around "low intervention trials" which have minimal additional risk, and therefore "less stringent rules". These come into play from 2018.

There was also a set of lightning talks - each for 5 miutes.

Ravi Jandhyala (Evidence for Access) described that research into treeatments for rare diseases is difficult. Studies have to trade between; Small number of subjects, requirements of randomised controlled trials, high attrition rates and long study durations. Judgement is needed in trial design, and should make use of real world experience, which involves looking at the evidence in the population, the characteristics of the patients and the identification of the patients. Focus on the patient is key.

Dr Julia Ambler (Sparks) outlined their expertise in awarding and managing grants for childrens medical research. They have the greatest chance of making an effort, researchers know where they money comes from, donors know where their money has gone and progress news is shared. Overall they aim to avoid duplication, save time/money and invest in quality research. They also support fundraising activites.

Dr Alan Rothaul (Re-Pharm) described how it is possible to use a computer model to hunt for rare disease treatment candidates - computer aided chemistry. For any target that is identified it is necessary to understand the biology, and then to look through the database for candidate. They look at the 2D and 3D shapes and the field point representation of the drug and compare it with the target. With a match, a proof of concept is obtained which is the optimised and taken forward for development. He described a case where out of 2500 molecules they had 25 close hits, which resulted in 6 trials, identifying one lead compound, which they are tring to move forwards.

Heather Band (Batten Disease Family Association) described Batten disease and how research into drug repurposing is using zebra fish. She observed that family groups are often the starting point for patient groups.

Jane Reed (Linguamatics) described a text mining tool that uses natural language processing to extract chemical, gene and action information from text. However, she notes that the language used in medical texts if no common and it is difficult to get information out.

Richard Smith (Healx) described an on-line tool which allows people to track rare disease research. There are around 1 million papers published per year, and around 100 thousand mention a rare/orphan disease. The tool aims to understand the hierarchy of the papers, and presents a summary of medical information and allows data to be filtered.

These are my key points from the panel discussion:

The difference between off-label and approved drugs for the patient is often about reimbursement,

Routes to off label drugs in the UK is either through GP or hospital, but varies throughout the UK.

Randomised Controlled Trials are often not representative of the typical population.

Patient groups are often good at making sure that trials are valid/representative. 

Combination therapies (i.e. taking more than one treatment at once) can be effective.

Randomised Controlled Trials are not necessarily required for orphan drugs.

No comments:

Post a Comment