Dormant therapies: hope for the rare disease community

Abstract

At the margins of the orphan drug world are found what have become known as dormant drugs or dormant therapies – drugs that have been abandoned as they failed to meet designated clinical endpoints in their development and for whom patents have expired. There are also literally millions of compounds disclosed in old patents that cannot be patented again and were overlooked in favor of a few. If partial research and/or development has been done on compounds and drugs, whether failed or not, then that experience must be protected to incent firms to mine the wealth of science already completed in the hopes of finding effective therapies for some of the most debilitating and lethal diseases known.

Keywords:

• dormant therapies
• drug re-purposing
• intellectual property
• market exclusivity
• rare diseases

1. Drugs at the margin

For years orphan drugs for rare diseases have been investigated, developed, and regulated at the margin of the pharmaceutical sector. This was to be expected given the numbers involved but over the years, ever since the passing of the Orphan Drug Act over 30 years ago by the US Congress [1], there has been established a credible niche for these life-saving and life-improving drugs. But at the margins of the orphan drug world are found what have become known as dormant drugs or dormant therapies.

Dormant therapies are often drugs that have been abandoned as they failed to meet designated clinical endpoints in their development and for whom patents have expired. Without adequate protection of their intellectual property, pharmaceutical manufacturers are loathe to re-open investigations even though promise may have been shown. As potentially valuable drugs cannot be patented a second time, potentially effective therapies – either for their originally intended use or a new use altogether – may be overlooked as they are shelved. Firms may be incented to re-investigate and/or re-purpose these failed drugs if their efforts and potential rewards from those efforts were protected.

Some drugs take longer to develop than others and, in a typical new product development gate-keeping exercise, many are screened out of development when remaining effective patent life is inadequate for a firm to recoup its investment. There are also literally millions of compounds disclosed in old patents that cannot be patented again and were overlooked in favor of a few. In fact, pharmaceutical firms patented 10 million compounds in drug-patent applications between 1976 and 2011, which produced only 700 new drugs [2]. Yet many of these compounds may provide therapeutic benefits if pursued further. Under current regulatory and patent regimes, re-designing old compounds to make a patentable product is usually cost and time prohibitive.

Precision of definition is currently a challenge. It has been proposed in the US that a dormant therapy be defined as either a small or large molecule drug that meets an unmet medical need and has prospectively ineffective patent protection, that is, 14 years from the date of approval [3]. In the European Union (EU) a dormant product may also be a product, which has not been marketed for a 12 months period and will not be for another 12 months. In this case a product may remain dormant for a maximum of 5 years and can be re-activated anytime. If not re-activated within 5 years approvals are withdrawn [4].

2. Unrealistic and imperfect solutions

Changes to existing patent laws in the very near future to better accommodate the needs of researchers, universities and pharmaceutical manufacturers is highly unlikely. Intellectual property regimes remain to be harmonized globally. Major sticking points in the negotiation of the Comprehensive Economic and Trade Agreement, providing for free trade between Canada and the European Union, and similarly the Trans-Pacific Partnership hinge around the differences in intellectual property protection around the world. Change in this is difficult and time-consuming to reach.

Some academics and social activists call for government funding of the development of unpatentable drugs. In today’s global economic malaise along with the increasing entitlement spending on an aging population in the industrialized world, government funding of dormant drugs is highly unlikely given the huge risk involved. Charitable funding is also an unlikely alternative source of capital for dormant drugs given the high uncertainty of success and the hundreds of millions required for each successful candidate. Half of rare diseases do not even have a charity to raise funds. Prize funding of research, also suggested by some academics and non-government organizations, is based upon some limited success where discoveries are commodities (as in the development of margarine) [5], or where the science involved is applied (as in the development of the canning of vegetables) [6] and not wet bench. There is absolutely no evidence to support the notion that such funding could work in the field of pharmaceuticals where serendipity is as much at play as rational, linear processes [7].

Currently there are two regulatory tools available to help incent the development of dormant therapies: patents and their extension, and market or data exclusivity. Patents and exclusivity ultimately have the same effect but provide different approaches to the same problem. Patents – normally 20 years – are granted anywhere along the development timeline of a drug by a patent and trademark authority and can be extended for various reasons. Exclusivity for selling a product in a market is granted by a drug approval authority, such as the Federal Drug Administration in the US or the European Medicines Agency, upon approval of a drug and can run concurrently or not with a patent. Data exclusivity protects clinical trial data and delays the entry of generics. Market exclusivity guarantees non-competitive sales for a period of time in a marketplace, which is more appropriate in the case of orphan drugs as genericization is most unlikely given the market sizes and costs.

The existing 5 year data exclusivity in the US for small molecule drugs, which protects only clinical trial data, is inadequate for the time, cost, and risk involved in investigating a dormant therapy in a competitive marketplace. The EU provides 10 year data exclusivity for small molecule drugs and 12 years for biologics, which is somewhat better. In 2011, building upon the market exclusivity given orphan drugs (7 years in the USA and 10 years in the EU) the MODDERN Cures Act was introduced in the US Congress. If passed, the Act would allow a firm to apply for data exclusivity for a drug or biologic, whose patent had expired, so as to re-investigate a dormant therapy to determine if it can prevent, slow the progression of, or cure a disease, meet an unmet medical need, improve outcomes, or reduce risk compared to existing therapy [8]. Under MODDERN, new drugs would receive 15 years of market exclusivity if they contained no active moiety previously approved by the FDA and had < 14 years of patent life left. In exchange, firms would waive their previous patent rights. As of the time of writing, the bill was still before the House of Representatives.

Although a good beginning, MODDERN would still preclude the re-investigation of new uses for existing drugs, which, of course, generally is not pursued by research-based pharmaceutical companies as genericization lurks around the corner of the patent cliff making a whole new round of clinical trials unprofitable. This is unfortunate as often there is already early indication of efficacy for another treatment, the drug’s safety profile is already understood, and mass production has made the cost of raw materials for the potential new trials inexpensive.

3. Why all the fuss?

Two words: rare diseases – diseases that affect very small populations, usually < 1 in 2000, many of which are life-threatening, seriously debilitating, or serious chronic conditions [9,10]. Rare diseases, their signs and symptoms are uncommon to most primary care practitioners making diagnosis difficult and often too late. Globally, ∼ 6800 rare diseases and disorders have been identified affecting 300 million people with > 80% of them being genetically based, which makes the discovery of effective treatments very costly and complicated. Only 350 rare diseases account for ∼ 80% of patient cases making the remainder of rare diseases very rare indeed. Over half of known rare diseases start in early childhood with about one-third of children, affected by a rare disease, dying before the age of five. Rare diseases account for 35% of all deaths in the first year of life.

However, just over 400 orphan drugs designated to treat rare diseases have come onto the American market over the past 30 years. The low-hanging fruit has been plucked. The search for new therapies for yet untreated rare diseases (beyond just palliation) becomes ever more challenging both intellectually and economically.

Given the very small patient population sizes in any one country, which make a Phase III clinical trial of a 1000 patients to demonstrate efficacy very difficult if not impossible to achieve, and the preponderance of rare diseases starting in early childhood where patient pathology is less understood than in adult males, the hurdles in discovering usable orphan drugs are huge. Traditional patents would expire long before sufficient data was ever accumulated for approval. Anything to help science overcome these hurdles would be most welcome by patients, their families and caregivers.

4. Est tempus

Discovery and commercialization of orphan drugs for rare diseases is a very difficult challenge for the pharmaceutical industry. If partial research and/or development has been done on compounds and drugs, whether failed or not, then that experience must be protected to incent firms to mine the wealth of science already completed in the hopes of finding effective therapies for some of the most debilitating and lethal diseases known.

Scientific discovery and the marketplace must drive the development of new therapies, not arbitrary laws and regulations with no evidence to support them other than convention. Potential therapies that could save lives, or at least provide better quality of lives, are currently not being developed or are being dropped by the wayside during research and development due to intellectual property protection designed for widgets and hairpins. But the patent system is not irrelevant. Every drug on the market owes its success to the protection of intellectual property. Patents are an integral part of markets working efficiently. It is in everyone’s interests that antiquated, one-size-fits-all patent laws be revised and augmented so that the proper incentives are created to incent the development of dormant therapies for rare diseases. There is a virtual treasure trove of orphan drugs for rare diseases to be discovered amongst the millions of compounds relegated to the shelf because of effective patent expiration. The social benefit of the development of dormant therapies for rare diseases will outweigh the efforts needed to reform the patent system.

Declaration of Interest

No funding was received from any source by any means to write this article. The author is a retired professor from McMaster University in Canada and currently works part-time as the Executive Director of The Cameron Institute, a health policy think tank. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.