Some diseases are rare, in that they are experienced by relatively few people. Others are neglected, in that few, if any, drugs are available to treat them.
Rare and neglected diseases aren’t rare in their prevalence. When taken together, they affect tens of millions of people in the U.S. and more than 1 billion people worldwide. But “neglected” correctly characterizes their levels of research funding, which need to be greatly increased, according to Ramaiah Muthyala, associate director of the Center for Orphan Drug Research at the University of Minnesota, Twin Cities.
To bring more attention to the problem of rare and neglected diseases, Muthyala and drug discovery consultant Clark N. Eid organized and chaired a Division of Medicinal Chemistry symposium on the subject at the American Chemical Society national meeting in San Francisco last month.
“The development of drugs for rare and neglected diseases is slow and too rare,” Muthyala said. “Funding for rare diseases by the National Institutes of Health and other agencies is very low. Rare and neglected diseases all have difficulty attracting commercial interest by mainstream pharmaceutical companies. In most instances, pharma is interested in getting involved only at a very late stage, if at all.”
Henrietta D. Hyatt-Knorr, director of policy and program planning and analysis at NIH’s Office of Rare Diseases Research, agrees that the need for treatments is enormous. A rare disease is one that affects fewer than 200,000 people in the U.S., and about 6,800 rare diseases are known today, Hyatt-Knorr explained at the session. In the U.S., patients with rare diseases number 25 million to 30 million—8 to 10% of the current U.S. population.
Medications available for rare diseases are often classified as “orphan” drugs. An orphan drug is a vaccine, preventive agent, or diagnostic agent that is administered to fewer than 200,000 people in the U.S. each year. “A drug is also considered an orphan if there is no reasonable hope that profit can be made from U.S. sales,” Hyatt-Knorr said. Government incentives to develop orphan products in the U.S. include seven-year marketing exclusivity to the first sponsor that obtains Food & Drug Administration approval of a designated drug and a tax credit equal to 50% of clinical investigation expenses.
Neglected diseases are ailments that tend to be overlooked by drug developers. Examples include sleeping sickness, Chagas disease, and malaria. They are uncommon in the U.S. but endemic in developing countries. The World Health Organization estimates that 1 billion people—one-sixth of the world’s population—are affected by one or more neglected diseases.
NIH’s Office of Rare Diseases Research collaborates with NIH institutes in a network of research consortia for more than 90 rare diseases and promotes translational research on rare diseases. The office also provides governance and oversight for a new congressionally mandated program, Therapeutics for Rare & Neglected Diseases, which facilitates drug development so more drugs get into human clinical trials more quickly. The office’s efforts dovetail with those of nongovernmental organizations such as the Medicines for Malaria Venture and the Global Alliance for TB Drug Development, which help organize public-private partnerships to fight rare and neglected diseases (C&EN, Nov. 9, 2009, page 16).
The session’s mantra was that drug discovery for rare and neglected diseases needs greater emphasis and resources. But symposium speakers also showed that progress is being made.
For example, senior research investigator Fabrizio Gasparini of Novartis, in Basel, Switzerland, discussed his group’s discovery of a possible therapy for fragile X syndrome, the most common inherited cause of mental retardation and autism.
Protein synthesis at brain synapses is promoted by metabotropic glutamate receptor 5 (mGluR5) and inhibited by fragile X mental retardation protein. The fragile X syndrome mutation reduces or knocks out that inhibitory protein, leaving mGluR5 to overstimulate protein synthesis, which is believed to cause a number of fragile X symptoms. One way to restore proper balance is to inhibit mGluR5. Gasparini and coworkers discovered a drug, AFQ056, that does just that. AFQ056 is currently in Phase II clinical trials for fragile X syndrome and for movement disorders in patients with advanced Parkinson’s disease.
Researchers at PTC Therapeutics, in South Plainfield, N.J., are working on a novel compound to treat some cases of Duchenne muscular dystrophy. DMD is a rare disease in which all body muscles, including the heart, weaken progressively. It’s the most common lethal genetic disease in children, primarily boys. No cure exists, and the fatality rate is 100%. Patients die at about 16 years of age, on average.
Some cases of DMD are caused by a mutation in the DMD gene, which codes for dystrophin, a key structural protein in muscle tissue. PTC Senior Vice President Neil Almstead and coworkers screened the firm’s library of compounds to identify molecules that allow the ribosome to read through such mutations, permitting expression of functional dystrophin. They then chemically optimized the hits to improve potency and in vivo activity and reduce toxicity. The result was the small molecule ataluren (PTC124).
In preclinical testing in a mouse model of DMD and in a Phase II study of 38 boys with DMD, ataluren caused the production of functional dystrophin in muscle to increase and levels of muscle-derived creatine kinase in blood serum to decrease. Most of the body’s creatine kinase is found in muscle, so a rise in creatine kinase in blood indicates muscle damage.
Tuberculosis is another disease that might benefit from greater research attention. In the U.S., TB is rare. Nevertheless, there is a global pandemic of TB, and every year 1.8 million people die from the disease, according to the World Health Organization.
In recent years, drug-resistant TB strains have developed. Medications for drug-resistant TB must be administered over extended time periods of up to a year, patients must be supervised while taking the drugs to ensure compliance, and some of the drugs are costly and have severe side effects.
New drugs to treat TB “are urgently required to shorten the long treatment regimen and battle drug-resistant strains,” noted professor of medicinal chemistry and pharmacognosy Alan Kozikowski of the University of Illinois, Chicago, at the symposium. Kozikowski, postdoc Marco Pieroni, and coworkers have identified small-molecule agents with potent (submicromolar) activity against drug-resistant TB. They are currently studying the mechanism and structure-activity relationships of the compounds to further enhance activity and reduce toxicity.
Another rare disease, for which no therapy currently exists, is fibrodysplasia ossificans progressiva. The disease causes calcification of muscle and connective tissue. Initial symptoms develop during childhood, and the disease generally leads to premature death. Mutations in the ACVR1 gene that cause overactive signaling by bone morphogenetic proteins (BMPs) give rise to the disease.
Gregory Cuny, a medicinal chemist at Brigham & Women’s Hospital and Harvard Medical School, is part of a team that developed a potential fibrodysplasia ossificans progressiva medication called LDN-193189. The group first identified a lead compound called dorsomorphin in an in vivo screen for BMP-signaling inhibitors and then modified it to improve potency and metabolic stability, yielding LDN-193189. The designed agent showed efficacy in a mouse model of the disease. The team is seeking partnerships with industry and NIH to pursue development of BMP-signaling inhibitors.
Another group focused its drug discovery efforts on spinal muscular atrophy, a form of motor neuron dysfunction. This rare disease is a leading genetic cause of child mortality. The genetic defect reduces the amount of SMN (survival motor neuron) protein in the body to levels that are too low to sustain proper motor neuron function. In severe cases, children never sit or stand, and some die before age two. Currently, no treatment exists.
Jasbir Singh and coworkers at deCode Chemistry, in Woodridge, Ill., used rational drug design to optimize a small molecule that had previously been found to boost levels of SMN protein in cells. They eliminated the compound’s off-target activity, reduced its toxicity, and improved its potency and brain permeability, yielding the clinical candidate D157495.
They found that D157495 dramatically improved survival and alleviated symptoms in a mouse model of the disease. The compound has been designated an orphan drug, and Repligen Corp., in Waltham, Mass., has licensed it for further development.
Work on rare and neglected diseases is of course also being carried out by groups that were not present at the symposium. For example, just one week after the ACS meeting, Paul G. Wyatt, head of the drug discovery unit at the University of Dundee, in Scotland, and coworkers reported validating a new molecular target for sleeping sickness and identifying compounds that could lead to a potential oral medication (Nature 2010, 464, 728). They are currently trying to optimize their lead compounds in an effort to make better drugs available.
Back at the symposium, Christopher A. Lipinski, scientific adviser at Melior Discovery, in Waterford, Conn., emphasized the need to avoid wasting money and effort in drug discovery, especially for rare and neglected diseases. It’s essential that medicinal chemists evaluate screening hits or leads for favorable drug qualities before compounds are moved into the drug discovery pipeline, not after, he said. It’s better if toxicity can be recognized in the initial stage of drug discovery instead of during a clinical trial, when considerably more resources will already have been devoted to a drug, he noted.
Lipinski cited the work of Jonathan B. Baell and Georgina A. Holloway of the medicinal chemistry group at the Walter & Eliza Hall Institute of Medical Research, in Parkville, Australia, as a good example of what researchers can do to catch problems early (J. Med. Chem. 2010, 53, 2719). Baell and Holloway identified a series of chemical substructures that are “frequent hitters”: promiscuous compounds that are selected in a lot of screens and yet typically turn out to be inactive (false positives). They call these compounds PAINS—pan-assay interference compounds. They have disclosed their PAINS filters so others can use them to eliminate these troublemakers from drug screenings.
That approach to removing likely false positives from drug screens could make developing drugs for rare diseases more efficient, Lipinski noted.
The symposium underscored the massive problems rare and neglected diseases pose. “It is my hope that conferences such as this ACS meeting session will bring greater awareness of the problem with rare and neglected diseases and eventually greater private and public research support for these conditions,” Muthyala said.