Empowerment of rare disease patients in modern healthcare delivery



By David Cavalla, Numedicus Limited.

If you’re fond of alliteration you’ll know that you can divide the stakeholders in modern healthcare into three ‘P’s: patients, payers and pharmaceutical companies, with physicians and pharmacists taking additional minor roles. Traditionally the patient has played a passive part, but over recent years the patient community has dramatically increased its involvement and influence in modern healthcare delivery, particularly in the rare disease sector.

Approved drugs do not exist for over 90% of the 7,000-8,000 rare diseases, and the commercialization of niche products for rare and orphan drugs has become the most favored growth opportunity over the conventional mass-market ‘blockbuster’. Repurposing is a common development option, but the development of drugs in these areas is dependent on access to patients in clinical trials.

Patients with rare conditions are increasingly organized into communities with a voice, and they are using their collective power to get what they want, namely access to better medicines.

Social media helps patients organize

Rare disease patients are much more likely to be ill as a child, and from inherited genes, than as an older person. This leads to highly motivated communities consisting of patients and their friends and relatives. Social media makes it possible for self-organizing communities to further the aims of rare disease patients.

Pharma companies are keen to form alliances with patient groups to further their case for payers to reimburse expensive medicines.

A key demand of patient groups is that that healthcare resources are allocated to the patients, even when such resources are scarce. The charity Action Duchenne, recently parked the wheelchairs of over 100 teenage boys outside the UK parliament to campaign for reimbursement of the first approved drug for the condition.

Some of the carers of rare disease patients and the patients themselves go to great lengths to educate themselves about the relevant condition. From this position, it is an easy step for them to ask themselves a simple question – what more can a patient or carer do to improve therapy?

Patient groups founding drug companies

John Crowley has two children with a severe neuromuscular lysosomal storage disease called Pompe Disease. He started a foundation to raise money for the condition, then took a job with Bristol Myers Squibb in order to learn all he could about the pharmaceutical business.

His next step was to found Novazyme Pharmaceuticals to develop an enzyme replacement therapy for his daughters’ condition. This was subsequently acquired by Genzyme corporation and the treatment was brought to market.

Later, John Crowley became CEO of Amicus Therapeutics which is also engaged in lysosomal storage disorder research for Pompe and Fabry diseases. His story featured in a book, and in 2010 was made into a film called Extraordinary Measures starring Harrison Ford.

This story is exceptional, but there are many other examples of patient- and carer-motivated drug development.

Charities taking on drug development

The Cure Parkinson’s Trust is a leading charity aiming to slow the progression, stop or even to reverse Parkinson Disease, the progressive neurodegenerative condition characterised by rigidity, tremor and bradykinesia.

The trust has rapidly acquired interests into the study of a wide range of potential therapeutic interventions, and is currently connected with over 50 pharmaceutical companies and associated with nearly 3,000 investigators. They are carrying out a number of advanced clinical trials, including a Phase III trial of the calcium L-type blocker isradipine; drug repurposing features frequently in the work they do, with studies underway on exenatide and liraglutide (GLP-1 agonists), simvastatin (HMG-CoA inhibitor) and N-acetyl cysteine (antioxidant).

They place particular emphasis on a network of key opinion leaders with interests in investigating novel mechanisms in the condition, and are led by Dr Richard Wyse, a former lecturer in various London hospitals as well as medical director at two biotech companies.

Another example of this is Dr Pan Pantziarka of the ReDO project (Repurposing Drugs in Oncology), which was formed from the AntiCancer Fund and Global Cures. This organization has 5 trials underway, mostly drug repurposing combinations such as metformin (antidiabetic)/zoledronate (anti-osteoporosis)/sirolimus (transplant rejection medicine).

A particular focus is on the treatment of the rare cancer angiosarcoma with propranolol. Dr Pantziarka has a personal reason for his interest in cancer, but is also scientifically trained. ReDO are looking at putting in place a regime of tax incentives from the UK Government for the development of generic repurposed drugs.

The wider scope for development models

These examples point out the complex ways in which charities are becoming integrated into the drug R&D landscape, far beyond their original role in fundraising and care support for their conditions, patients can be medical experts, drug developers and clinical investigators. This is particularly the case for rare diseases, but in the future the changes will almost certainly extend into more common diseases too.

For the larger charities, this is not an entirely new phenomenon: Cancer Research UK supports a lot of research activity already – in 2015/6, amounting to £376 million, including nearly £120 million into the biology of cancer. The British Heart Foundation, too, spends over £100 million per annum, mostly on basic research. The focus on drug repurposing as a more efficient translational strategy is likely to grow, however, because of the cost and time advantages which characterise this approach, and it will be interesting to see what changes accrue when some of the larger charities adopt it to the same degree as some of the examples cited above.

Link prescriptions to medical conditions to pave the way for more repurposed drugs


By David Cavalla, Numedicus Limited.


Repurposed drugs are often subject to off-label generic substitution, making them an unattractive development route for some pharmaceutical companies. Dave Cavalla argues that linking prescriptions to medical conditions would make it easier for companies to re-coup costs and open the way to market for repurposed compounds for rare diseases.

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.[1] 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.

Rare diseases are relatively common

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.

Drug repurposing makes development faster and cheaper

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:

  • drug discovery time is reduced by two-thirds
  • the chance of developmental success is increased by 250%
  • the cost of R&D for new medicines is reduced by five-sixths.

Pharmaceutical companies still prefer NCEs

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:

  • incentivise the pharmaceutical industry to invest in drug repurposing
  • facilitate the involvement of the not-for-profit sector
  • create a new pricing structure that links electronic prescriptions and pricing to medical condition.

An alternative pricing structure

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’[2], 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.[3]

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.

Support repurposing through pricing

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.


[1] 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.

[2] Off-label Prescribing: Justifying Unapproved Medicine. David Cavalla. ISBN: 978-1-118-91207-2. 216 pages. March 2015, Wiley-Blackwell.

[3] 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.

Rapidly identifying profitable new indications for existing drugs

Profitable reprofiling opportunities are often created by the publication of new biological targets. When new targets are identified, Blaze can be used to make a rapid assessment of whether any existing drugs are likely to be active against the new target.

In traditional development cycles compounds are usually narrowly tested against one disease indication. This means that a compound may make it all the way to market for a particular medical need without ever having been tested for other indications, often for good economic and ethical reasons.

However, such marketed drugs do represent an excellent source of medications for other indications due to their having well-known safety profiles. Such changes of use are referred to as reprofiling or repurposing.

Recent months have seen a steady news flow about reprofiling successes. Examples include PsiOxus’ reprofiling of s-pindolol for treatment of cachexia in cancer patients and Noven Pharmaceuticals’ launch of reprofiled paroxetine for menopausal ‘hot flashes’. These results highlight the scientific, economic and health benefits of reprofiling.

Reprofiling typically will not lead to a substance of matter (SOM) patent, but it can lead to a new use patent for the existing compound. New use patents offer the same 20 years of patent protection, and due to shorter development paths, usually have a much longer marketable life than a typical substance of matter patent. The comparison is typically 15 years for a new use compared to perhaps only 7 years for an SOM patent. This means that there is an economic benefit as well as a medical benefit to finding new uses.

However, one issue with reprofiled compounds has always been the existence of the original compound, usually available as a generic product, licensed for the original indication. Now there is an increasing trend to litigation of off-label use of medicines and, particularly in the US, a reluctance for reimbursers (typically the large HMO’s and insurance companies) to pay for off-label use. These factors result in an increasingly attractive environment for reprofiled compounds.

Reprofiling opportunities are often created by the publication of new biological targets. When such new targets are identified it is advantageous to be able to rapidly assess whether any existing drugs may thus find an alternative use.

Computational reprofiling is a very efficient way of identifying these new opportunities. It proceeds by comparing existing drug molecules against compounds active against a particular disease in order to look for similarities that will indicate potential for activity against that new indication. Blaze from Cresset is an ideal means of doing this. Blaze utilizes 3D properties of molecules, not just 2D structures; and our innovation for 2013, BlazeGPU, makes it possible to do this faster than ever before, utilizing affordable computer hardware. In combination with strong clinical and pharmacological knowledge, BlazeGPU is an excellent means of finding the possibilities hidden among existing drug compounds.

Using scaffold hopping to search nearby chemical space

How Can Computational Chemistry Help Find New Drugs from Old?

In this series of blogs, Dr Robert Scoffin, CEO of Cresset, explores how computational chemistry is being applied to the field of reprofiling to help find new drugs from old.

As R&D budgets are cut and blockbusters come off patent, drug discovery is becoming more conservative.  Many companies are taking existing drugs or drug-like compounds as the starting point for the discovery of new chemical entities (NCEs) because they know that this is the most likely root to success.  In my last post I discussed Using Pharmacophores to Find New Targets for Existing Drugs.  This month I’m taking a look at the technique of scaffold hopping that makes changes to existing drugs.

Scaffold hopping involves a computational search of the chemical space around existing compounds by making structural changes to known drugs.  The aim is to find a new compound that not only retains the activity of the parent compound, but also shows some improvement, either in terms of improved activity or a reduction of side effects.  The fact that the resulting compound will have a similar chemistry to a known active significantly increases the likelihood of activity and, therefore, return on R&D spend.

This approach is well validated.  Bayer’s Levitra was created by altering Pfizer’s Viagra molecule.  The small chemical change involved a substitution of the nitrogen positions in a fused ring, which was not covered by Pfizer’s patent.  Computational analysis of the field patterns of the two compounds shows that this structural change had only a subtle effect on the molecule’s field pattern: computational analysis shows that Levitra and Viagra share a very similar pharmacophore template.

Scaffold hopping using Spark is an ideal approach to finding NCEs from existing compounds.  Spark uses Cresset’s field technology to find biologically equivalent replacements for key moieties.  The activity profile of the new compound is compared to the starting point or to a pharmacophore.  It is an extremely effective method of exploring new chemical space.  Our recent poster: Rapid Technique for New Scaffold Generation highlights the power of scaffold hopping to both explore new chemical space and to provide enhanced protection for NCEs.

Viagra Levitra Unknown

Above left: Sildenafil (Viagra) from pdb code 1udt; Above center: Vardenafil (Levitra) found by scaffold hopping in Spark; Above right: Potential PDE5 active that mimics both Sildenafil and Vardenafil but lies outside of both patent landscapes.

When I left a trial copy of Spark with a customer at a major pharma company he used it to run a scaffold hopping experiment on some of his current leads.  The results blew him away.  Yes,Spark returned some bioisosteres that he had been expecting and had already thought of.  It also returned some that weren’t viable for patent or ADME reasons.  But it also came up with some gold – new, bioisosteric structures that he had not thought of, that were completely ‘out of the box’.  Needless to say, he bought the software.

In the next post I’ll talk about a recent collaboration between Cresset and RedX that focuses on discovering NCEs by switching the oxidation state of known drugs.

Previous posts in this series:

Dr Robert Scoffin,

Using pharmacophores to find new targets for existing drugs

How Can Computational Chemistry Help Find New Drugs from Old?

In this series of blogs, Dr Robert Scoffin, CEO of Cresset, explores how computational chemistry is being applied to the field of reprofiling.

In my last post I talked about the straightforward ways companies can exploit their existing drugs – by reformulating, recombining and repositioning them. I briefly discussed that repositioning targets may become obvious through literature searches for side effects or off-license prescription. In this post I’ll talk about how computational chemistry can point the way to new targets for existing drugs through the use of pharmacophores.

Pharmacophores are a computational method of expressing the activity profile of a molecule. This activity profile can be used to search for other compounds with similar profiles. When you find a match you can compare the known targets for the two compounds. When two compounds with a similar profile are known to be active against different targets then you have found a promising place to focus your research.

Of course, the key to success in this area is to have built an effective and reliable pharmacophore. Firstly, it needs to be based on good science, and at Cresset we rely on field technology for this. You can read more about field patterns and Cresset’s field points here. Secondly, computational searches inevitably require simplified search times to make searching large amounts of data possible in finite time, so we need to be sure that our search criteria retain the relevant information.

When a number of compounds are known to be active against a particular target, you can look at the consistent patterns of interaction to determine the most important active sites for the protein. This is the best method for building up a field based pharmacophore that focuses on the likely active sites.

Forge is Cresset’s computational chemistry tool for building pharmacophores and screening them against compound databases. Forge takes advantage of Cresset’s ligand comparison method to align, score and compare molecules from a biological viewpoint. As you can see from the diagram below, it can lead to impressive results.

FieldAlign example

This CCK-2 pharmacophore was derived in Forge from three structurally diverse ligands. The graph shows the tight correlation between field similarity value and CCK-2 activity for seven other diverse molecules with a range of activities.

Of course, pharmacophores are also very useful for evaluating drug candidates that result from a literature search or other discovery methods.

In the next post I’ll discuss approaches to finding new chemical entities using existing drugs as the starting point for research.

Other blogs in this series:

Dr Robert Scoffin,

How can computational chemistry help find new drugs from old?

In this series of blogs, Dr Robert Scoffin, CEO of Cresset, explores how computational chemistry is being applied to the field of reprofiling.

Sir James Black, winner of the 1988 Nobel Prize in Physiology and Medicine, famously stated that “The most fruitful basis for the discovery of a new drug is to start with an old drug”. Disillusioned with HTS, and struggling to bring new chemical entities to market, many companies are turning back to Sir James’ wisdom. They are finding unexploited potential in the chemical space around existing drugs, and this is leading to real therapeutic and business returns.

Re-using existing drugs is the lowest risk approach a company can take to developing their drug portfolio and exploiting their existing intellectual property. At the simplest level, this means reformulation, and of course pharmaceutical companies are continually reformulating. New formulations can lead to better patient convenience by improving the delivery method or by increasing the half-life so that less frequent doses are required.

AstraZeneca developed Nexium by making process changes to the production of their existing drug Omeprazole and selecting only the structure with a single enantiomer. Nexium was the second highest selling pharmaceutical in the US in 2011.

Another straightforward way to re-use an existing drug is to combine it with another drug to find synergies. GlaxoSmithKline’s Advair, with US sales of $4.7 billion in 2010, was the result of combining the two pre-existing asthma treatments Salmeterol and Fluticasone.

The third main way to re-use an existing drug is to repurpose it in a new therapeutic area. Many companies look for alternative indications for their own drugs in order to extend the market and the patent life for a compound. Literature searches can reveal side effects or off label usage of drugs that point to applications against a new target.

For example, Johnson and Johnson’s anticonvulsant drug Topiramate was originally approved by the FDA in 1996 as a treatment for epilepsy. It is now most frequently prescribed as a treatment for migraine, for which it was approved in 2004.

In my next posts I’ll focus on how computational chemistry can help find new drugs by taking an existing drug as the starting point for research. This is variously called reprofiling, repurposing, re-using, or new drugs from old. Sometimes it’s even called patent busting. At the Cresset 2012 EU UGM in Cambridge, UK, Dr Alan Rothaul gave an overview of structure and non-structure based methods of drug repositioning and showed how structure based re-profiling through fragment swapping can feed into new compound discovery.

I’ll explore how Cresset software is helping researchers to take advantage of this profitable approach by:

Dr Robert Scoffin,

New Drugs from Old

In this article, published in the autumn 2012 issue of Innovations in Pharmaceutical Technology, Rob Scoffin (Cresset’s CEO) explores the chemical space around existing drug molecules to provide a lower-risk, lower-cost strategy for the discovery of new chemical entities.

Click below to read full article.

New Drugs from Old