Rare Diseases: A New Purpose

How drug repurposing could help drive orphan drug access if pharma can accept the risks

By Nader Murad, Senior Analyst

Email: [email protected]

The US National Institutes of Health describes drug repurposing as “studying drugs that are already approved to treat one disease or condition to see if they are safe and effective for treating other diseases”.

The investment and time required to repurpose a drug is significantly less when compared to new drug discovery and could, therefore, translate into potentially lower prices and faster access to new treatments.

Government incentives for rare diseases

Historically, orphan drugs and their relatively small target populations have been a particularly risky endeavor for pharmaceutical companies. Considering that getting a drug to market currently takes 13–15 years and between US$2 billion and $3 billion on average, commercially speaking, it makes better sense to aim for a wider pool of customers to maximize the return on investment and ensure sustainability.

In response, regulators have tried to incentivize the development of therapies for rare diseases, with the US introducing the Orphan Drugs Act in 1983 and Europe following in 2000 with EU regulation on orphan medicinal products (Regulation (EC) No 141/2000). Both offer rewards to orphan drug developers such as extended marketing exclusivity, grants, fee reductions and regulatory support. These actions have had a welcomed impact on rare diseases. In the decade prior to the US Orphan Drugs Act, fewer than ten therapies for rare diseases were brought to market, compared to over 200 approved therapies in the following 25 years. Similarly, in the EU, 14 orphan drugs were approved in 2016 compared to only one in 2000.

Still, more needs to be done to improve access to rare disease treatments. By some estimates, almost 95% of rare diseases (over 7000 identified so far) do not have an approved treatment. Drug repurposing can significantly contribute to alleviating the burden of such diseases. So far, most of the effort going into repurposing has come from academia and non-profits.

However, established pharmaceutical companies, with their clinical development experience, financial capabilities, and in-house clinical data are better placed to maximize the potential of drug repurposing. Yet, for them one of the main obstacles to fully embracing this concept stems from threat from generics and off-label prescriptions, and their commercial implications.

Approved and unapproved

To understand these hurdles, it is important to divide drugs into two categories, each fit for repurposing but with different potential commercial potential.

The first category are drugs that have previously been approved for another indication but which have lost market exclusivity. These present significant risks for pharma as the loss of exclusivity opens the door to generics, eroding the price of that therapy.

Theoretically, a manufacturer can obtain market exclusivity for repurposing a known drug for a new indication allowing them to create a commercial opportunity for the asset. However, the availability of a generic version undermines that opportunity. A case in point is the repurposing of sildenafil – previously approved for erectile dysfunction as Viagra – for pulmonary arterial hypertension (PAH), a rare condition. A modified dose of the drug was approved for PAH under the brand name Revatio, but, in the UK, the dose strength of Viagra was considered suitable for PAH, resulting in its use for the condition after its loss of marketing exclusivity.

Although in this case the threat to Revatio came from a drug developed by the same manufacturer, it highlights the risks that a therapy can face from both off-label use and generics.

Despite regulatory guidance aimed at limiting off-label use to situations where no alternative treatments exist, it still happens for purely economic reasons. Failing to rein in such behavior reduces the potential for repurposing. However, with a rare disease, where patient numbers are small and registries are common, it is possible for regulators and payers to track and control prescriptions.

In addition, there are ways for pharmaceutical companies to ringfence repurposed drugs from the off-label threat. A repurposed drug that has been reformulated or is delivered by a novel method that is indispensable to the new indication will most likely be prescribed over the generic.

Alternatively, but not without controversy, pharma companies can use the restrictions imposed by a Risk Evaluation and Mitigation Strategy, often requested by the FDA for drugs with a precarious safety profile, to deny generic manufacturers access to the API (Active Pharmaceutical Ingredient) for generic development.

Greater potential

The second category of drugs as repurposing candidates has greater commercial potential; drugs that have never previously been approved for any indication and so have no generic versions. Here, the rewards are twofold.

The pharmaceutical company can benefit from the reduced development costs, time and risks, while gaining full-duration market exclusivity (for orphan drugs, seven years and 10 years in the US and EU, with an additional six months and two years for a pediatric investigational plan, respectively). One example is thalidomide, used in the 1960s for the treatment of morning sickness but withdrawn due to severe safety issues, and successfully relaunched for the treatment of leprosy in 1998.

The business of repurposing drugs seems to be a win for all, but the collaboration between regulators, payers, HTA agencies and prescribers is integral for the concept to flourish.

There have been recent efforts to reward drug repurposing. The Orphan Product Extensions Now (OPEN) Accelerating Cures and Treatments Act, passed in the US earlier this year, grants companies an additional six months of market exclusivity in an orphan disease. While no similar efforts have been noted Europe, the increased collaboration between the FDA and EMA, especially in the context of rare diseases, holds promise.

Is all of this enough? Rare diseases patients do not have the luxury of time. Fostering a fair playing field for drug developers will ensure faster access to safe and effective treatments.


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Please contact the P4A team at [email protected]

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