Opinion: Ultra-rare but not forgotten: New drug development paradigms to treat the rarest of diseases

In addition to the most visible effects of Covid-19 — tragic deaths, lingering illness, economic turmoil, and more — the pandemic is affecting much that is out of the spotlight. One is research on the so-called rare and ultra-rare diseases that affect an estimated 300 million people around the world.

One of us (S.K.R.) has a 2-year-old boy, Raghav, with an ultra-rare disease. He is just one of nine kids in the world identified so far with a disease caused by a mutation in the glutathione peroxidase 4 (GPX4) gene. It causes extremely low muscle tone, difficulty eating, problems seeing and hearing, and abnormalities in the spine, pelvis, and long bones. But Raghav is lucky: Most babies born with this disease die shortly after birth.

In less than 10 months after his diagnosis, a research team had been assembled and repurposed FDA-approved drugs were identified that proved to be incredibly effective at rectifying certain skeletal abnormalities caused by the GPX4 mutation. Sadly they did not improve his quality of life. Raghav still cannot hold up his head, sit, stand, talk, chew, or swallow.

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His story is like that of millions of others with rare and ultra-rare diseases who live — and suffer — without treatments.

The technology to find treatments for nearly every one of them exists today. Gene replacement therapies make it possible to deliver working copies of a gene or protein to compensate for a loss of function. Antisense oligonucleotides can silence harmful mutations. Gene editing with CRISPR-Cas9 can correct faulty mutations at their source. Small molecules that have been approved by the FDA for common diseases can be repurposed to treat rare and ultra-rare conditions.

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Yet more than 95% of rare diseases do not have a single FDA-approved treatment.

The world needs a drug development paradigm that serves all patients regardless of rarity. We propose three strategies for getting there.

Promote early-stage, patient-focused drug development

Treatments for spinal muscular atrophy, cystic fibrosis, and many other rare diseases were created because patients and their families challenged the “death sentence” diagnosis and decided to dive head first into research. In these cases, patients and families led the charge by starting foundations, raising money, and funding research.

Doing that successfully means navigating the complex and risky maze of drug development without a proper road map, skills, or infrastructure, on a shoestring budget, while racing against time.

Some national patient organizations and private foundations offer resources to aid rare disease patients and families on the journey toward a treatment. These resources do an excellent job of empowering people, but bringing treatments to all rare diseases requires scaling up funding to support thousands of organizations around the world.

Platform approach to therapies for ultra-rare diseases

The Bespoke Gene Therapy Consortium, launched by the Foundation for the National Institutes of Health and with visionary leadership from Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, is focused on developing an operational playbook using streamlined templates, master regulatory files, and uniform production processes to lower the cost of developing gene therapy for ultra-rare diseases.

The n-Lorem Foundation aims to create individual treatments for patients with ultra-rare diseases using antisense oligonucleotide technology. The Columbus Children’s Foundation (which one of us, R.J.S., chairs), uses a nonprofit approach to deploy essentially plug-and-play manufacturing to make drug purification and production more efficient and affordable for ultra-rare disease programs that are scientifically promising but aren’t likely to be commercially viable.

These strategies were developed to tackle the unique challenges of ultra-rare diseases, but will also greatly benefit more common diseases by lowering costs and improving the speed of development. We need to systematically invest in creating and formalizing such strategies so they are part of every drug developer’s toolbox.

Enhance public policy to incentivize and scale investment

Incentives and regulatory innovation must be part of the solution for speeding the development of new therapies for rare and ultra-rare diseases.

The Orphan Drug Act of 1983 has helped usher in more than 900 innovative, FDA-approved treatments for rare diseases. The Pediatric Priority Review Voucher program, valuable vouchers to reward successful drug approvals for rare pediatric diseases, has been important in creating additional economic incentives for companies to work on rare diseases. While these incentives are helpful, they are simply not sufficient to create treatments for ultra-rare diseases with 100, or 50, or just 10 patients worldwide. We need Congress to deploy other incentives to further capitalize development in the ultra-rare space.

A path to commercialization for ultra-rare diseases is needed to ensure therapies will be available for all patients in the years to come. Every aspect of clinical development, diagnosis, and regulatory science must be rethought to accommodate diseases that affect only a few patients.

History has shown that patient organizations can play critical roles in drug development and, in some cases, dramatically de-risk steps leading to the clinic and beyond. What’s needed now are novel and unique partnership models for drug development that take a patient-centric approach. Only then will we be able to create a drug development ecosystem that works for every patient, no matter how rare the disease.

Sanath Kumar Ramesh is the founder and CEO of the OpenTreatments Foundation, cofounder of the RisingRare Podcast, and a software manager at Amazon. Max G. Bronstein is the founder of the Journal of Science Policy & Governance and principal at MGB Consulting. He was formerly the chief policy officer at the EveryLife Foundation for Rare Diseases and a senior director of health policy at Audentes Therapeutics. R. Jude Samulski is a pioneer in adeno-associated virus gene therapy and chairman and chief scientific officer of the Columbus Children’s Foundation, an international childhood rare disease fund.

Source: STAT