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The beginning of this year marks the 40th anniversary of the passing of the Orphan Drug Act. While the field of rare diseases has seen much progress both in diagnostics and the development of new therapies since then, there are still significant challenges that need to be overcome to reach the majority of the 300 million people worldwide who are affected by these conditions.

Jim Geraghty has worked in the biotech and pharma industry for many years and has followed the burgeoning orphan drug scene since its inception, including recently publishing a book called Inside the Orphan Drug Revolution.

Jim Geraghty
Jim Geraghty
national director for AI, health, and life sciences, Microsoft

“Many important therapies for hundreds of diseases have been brought to patients. But there are 7,000 identified monogenic diseases, and we have therapies for only a few hundred of them,” he tells Inside Precision Medicine.

The Orphan Drug Act, passed on January 4, 1983, was set up to make developing drugs for rare and neglected diseases easier. Defining orphan diseases as diseases affecting “less than 200,000 persons in the U.S.,” the act also included diseases affecting more than 200,000 people “for which there is no reasonable expectation that the cost of developing and making available in the U.S. a drug for such disease or condition will be recovered.”

Getting treatments to patients

Since the passing of the act, the genetic basis of many orphan diseases has been identified and treatments for over 1,000 orphan indications now have FDA approval.

Matt Brown
Matt Brown
CSO, Genomics England

“Rare disease therapeutics is, I think, a highly exciting area … partly because of better funding and awareness and new approaches by regulatory authorities to allow different clinical trial designs, which previously weren’t allowed,” says Matt Brown, CSO at Genomics England, which is working to improve rare disease diagnostics and encourage research into new therapies in the U.K.

“In addition to just small molecule design, which has clearly been what most therapy’s been about until recent times, there are other areas [including gene therapies and antisense oligonucleotides] which have suddenly hit maturity and where I think we’re going to see an absolute boom in therapies for a whole wide range of rare diseases.”

Geraghty highlights that many of the orphan diseases that remain without treatments are ultra-rare. He believes a multipronged approach is needed to get more therapies to these patients.

In addition to the development of advanced gene and cell therapies to treat these conditions, there needs to be a reason for therapy developers to get involved. “I think the biggest challenge really is around the incentives. There’s been discussion of an ultra-Orphan Drug Act, to provide greater incentives for these extremely rare diseases, perhaps longer market exclusivity, enhanced tax credit benefits,” he explains.

Some of the approved therapies, particularly those that effectively cure the condition they are designed to treat, have received a lot of media attention for the high price they are being marketed at. However, Geraghty emphasizes that this needs to be balanced against the potentially higher cost of treating that condition for many years. Brown agrees, adding that “people just forget about what a big cost these really severe diseases actually have.”

One option to tackle therapy costs is to change the way payments are made. Geraghty is chairman of the boards of Aceragen (formerly Idera Pharmaceuticals), Pieris Pharmaceuticals, and Orchard Therapeutics. He explains that companies such as Orchard, which develops gene therapies including Libmeldy for treatment of metachromatic leukodystrophy (MLD), are saying to payers, “we would prefer not to get one big lump sum payment upfront.… We’re moving toward multi-year annuity kinds of payments, which better balance the reimbursement with the therapeutic benefit.”

Tackling the diagnostic odyssey

Diagnostics for rare diseases have advanced significantly in the last couple of years, primarily linked to better access to good quality genetic sequencing technology. In the U.S., the work of Stephen Kingsmore and colleagues at Rady Children’s Institute for Genomic Medicine in California, as well as that of Robert C. Green, a professor at Harvard Medical School and medical geneticist at Brigham and Women’s Hospital, and his team, have advanced the use of sequencing to diagnose or detect rare diseases in babies and children.

With decreasing costs and increasing speed, using sequencing as a diagnostic tool is becoming more mainstream. Last year, researchers at Stanford University managed to break a record by sequencing a whole human genome in just five hours and two minutes using Oxford Nanopore’s PromethION 48 sequencer. The same team diagnosed a patient with a rare disease in under eight hours from the start of the sequencing process.

In the U.K., Genomics England is pioneering the use of sequencing technology for rare disease diagnosis. “Our model shows that our whole genome sequencing works,” Brown tells Inside Precision Medicine. “The challenge, though, is that only about 25% of rare disease families actually get a diagnosis.”

He explains that this is due to a number of different factors. To begin with, the genetic causes of many diseases are still unknown. But new genetic information is being published every day and so regular re-analysis of genomic data can help spot pathogenic mutations that were previously unknown, potentially boosting diagnostic rates.

Another reason some individuals are not picked up when testing for monogenic disorders is that they may have a more severe case of a polygenic condition that has a milder phenotype in most people. “There’s a lot of development in the research world about polygenic risk score approaches to assessing somebody’s risk of common disease that have potential utility in this setting,” explains Brown.

Another key issue is that most whole genome sequencing is done using short-read technology, as it is more established and cheaper to perform. Long-read sequencing is more accurate than short-read sequencing and also has advantages such as being able to more accurately measure the impact of epigenetics.

“Genomics England’s been doing a lot of work with long-read sequencing … which gives us the ability to identify variants that are regularly missed by short-read sequencing,” notes Brown. “For example, insertions/deletions, gene duplications, and copy number variants, these are all things which short read struggles with, but long read is better at.”

Genomics England is also researching combining DNA sequencing with other omics technologies, such as transcriptomics, proteomics, and metabolomics, to assess whether that can also improve diagnostic rates for different rare diseases.

Future challenges

The science being used to target rare diseases in 2023, both on the diagnostic and treatment fronts, is definitely developing at a fast pace. But other challenges remain for those determined to help more patients in this area.

“The Orphan Drug Act was only enacted because patients, families, and advocates really fought for it,” says Geraghty. “Insurance companies fought against it and are still fighting against access to expensive therapies.… No patient or family pays the list price of a drug; no one could afford to. The real issue for patients is not the list price of the drug. It’s the out of pocket costs the insurance programs charge.… Those keep rising, and insurance companies keep trying to point the finger at drug prices, as opposed to recognizing that what matters to patients and families is out of pocket costs.”

On the face of it, regulatory authorities are supporting the development of new advanced gene and cell therapies, but Geraghty cautions that the views of senior officials don’t always match what happens on the ground.

“The FDA and the EMA do wonderful work. They’re remarkable, high-quality organizations. But what is important is to recognize that for these ultra-orphan diseases, greater flexibility is required. Often, if you look at what the senior officials at the FDA and EMA say, they embrace regulatory flexibility. But then when you get into the bureaucracy of these very large organizations, they become inherently conservative and you can get a kind of box checking mentality.”

He cites the case of Orchard’s Libmeldy, which was approved by the EMA in 2020 and in the U.K. in 2021, but has yet to be approved by the FDA. “It’s still at least a year away from U.S. FDA approval, for reasons that I think are really unfortunate. We’re getting traction with the FDA now toward a path to approval. But unfortunately, that’s two years later than it should have been.”

Brown is keen to continue to help develop the U.K. National Health Service’s fledgling Genomic Medicine Service (GMS), set up in 2018, to better serve patients with rare diseases. As part of the new service, Genomics England is planning a pilot project to sequence up to 200,000 newborn genomes to test the feasibility of this kind of large-scale early screening, a key goal of which will be to diagnose rare childhood-onset genetic diseases. After a public consultation in 2021 that revealed a high level of support for the project, Genomics England plans to begin recruiting babies and their families to take part in the study this year.

“I am really keen to see us converting GMS diagnostics into a feeder pipeline for development and identification of patients who would actually benefit from treatments,” emphasizes Brown. “At the moment, it’s very focused on being a diagnostic process. But I’m hopeful over the next few years that we will push it in that direction.”


Helen Albert is senior editor at Inside Precision Medicine and a freelance science journalist. Prior to going freelance, she was editor-in-chief at Labiotech, an English-language, digital publication based in Berlin focusing on the European biotech industry. Before moving to Germany, she worked at a range of different science and health-focused publications in London. She was editor of The Biochemist magazine and blog, but also worked as a senior reporter at Springer Nature’s medwireNews for a number of years, as well as freelancing for various international publications. She has written for New Scientist, Chemistry World, Biodesigned, The BMJ, Forbes, Science Business, Cosmos magazine, and GEN. Helen has academic degrees in genetics and anthropology, and also spent some time early in her career working at the Sanger Institute in Cambridge before deciding to move into journalism.

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