Therapeutic protein degradation by design?
The old problem and the new paradigm Classical small molecule drug paradigms generally involve intervention at a ligand protein binding ...
By David Cavalla, Numedicus Limited.
On 6-7 November 2015, I attended the annual conference of the Action Duchenne charity. One of the key points of debate was the status of Translarna, an expensive new product for the rare muscle disorder Duchenne Muscular Dystrophy, which is currently being considered for reimbursement by the NICE, the UK body that approves NHS treatments. The subject raises substantial ire among Duchenne sufferers and their families, due to the hesitation of NICE to fund the treatment, even though it is not a cure and is not the only highly priced product likely to be reviewed for this condition in the future.
At the same conference we heard about the potential to treat the condition with repurposed compounds like Viagra, tamoxifen and metformin; cheap alternatives that are based on small molecule generic products. These research programs are taken forward with public funds or charitable support, and in consequence are much slower to come to the market. If an alternative pricing structure were available to encourage pharmaceutical companies to pursue repurposing as a development strategy, it could mean that more and better drugs are brought to market faster for rare diseases such as Duchenne.
1 in 17 people will be affected by a rare disease at some point in their life. There are over 6,000 rare diseases, and new rare diseases are documented in the medical literature at a rate of 5 per week. Fewer than 5% of these conditions have an approved therapeutic option.
Despite this large cumulative effect, each rare disease, by EU definition, affects less than 5 in 10,000 of the general population. In order to obtain a return on investment for new medical treatments, companies have to charge very high prices to the few people who have the condition.
It is common for medicines to have multiple uses. Aspirin is a salient example: it was first used for pain, then as an antithrombotic and has recently been found to have important potential cancer preventative properties. We now believe that over 90% of existing drugs can be repurposed, in some cases more than once.
Drug repurposing has become increasingly adopted by charities and some small biotech companies as a means to decrease cost and time to market for drugs for rare diseases. The advantages are clear:
However, the return on investment (ROI) for repurposed compounds is not always clear, even with new use patents. Companies are concerned that generic drugs will be substituted for the branded repurposed medicine and they will be unable to recoup their costs.
This represents a tremendous lost opportunity.
Possible solutions to encourage patient-led research are to:
I have worked in drug repurposing for as long as the strategy has had a name and I have considered this problem deeply. I recently wrote a book called ‘Off-Label Prescribing: Justifying Unapproved Medicine’, where I proposed that there should be an enhanced level of pricing for repurposed products. This would be imposed at the point of prescription and reimbursement, and operated for some years as an incentive to the repurposing innovator. Since the book was published, a very similar proposal was made by Prof Ben Roin, a respected policy strategist at Harvard/MIT, with respect to the US system of medicines.
In the era of electronic prescribing, a dual pricing arrangement would not be difficult to implement. Moreover, it would dovetail with the founding principle of NICE, that therapeutic indication and reimbursement are intertwined.
This simple change, linking prescription to condition on an electronic platform with a dual pricing structure, would strengthen the value of mode-of-use patents for the pharmaceutical industry, thus promoting commercial investment into repurposing research.
In the absence of a balanced framework of incentives for drug repurposing, pharmaceutical research will be slanted towards high-priced products that are ultimately unaffordable. Under the current system, the interests of pharmaceutical companies are not aligned with those of patients and healthcare providers. The need to make a profit currently takes companies towards difficult and lengthy research that can command a high price rather than easier and quicker research that is likely to have more effective patient outcomes, but which might be unprofitable. This is a lose-lose scenario for governments and taxpayers alike.
For the sake of patients, and especially for those with the thousands of rare conditions currently lacking any therapy, implementing a pricing policy to protect revenues from repurposed compounds are an option that should not be ignored.
 Translarna was recommended by NICE on 16 April 2016 in connection with a Managed Access Agreement (MAA) with NHS England for ambulatory patients older than 5 years old.
 Off-label Prescribing: Justifying Unapproved Medicine. David Cavalla. ISBN: 978-1-118-91207-2. 216 pages. March 2015, Wiley-Blackwell.
 Roin, B. Solving the Problem of New Uses http://dash.harvard.edu/bitstream/handle/1/11189865/Solving%20the%20Problem%20of%20New%20Uses%20.pdf Oct 13, 2015.