When Dr. Michael Collins started treating patients with rare bone diseases 20 years ago, “Most of the time I had little to offer them, and that was frustrating for me,” he told journalists on a National Press Foundation program on rare diseases. “But within the last five to 10 years, there’s just been an explosion in advancement… absolutely think we’re at an inflection point. And I think there’s great promise for patients with rare diseases and reporting is absolutely essential for that progress to continue. [Transcript | Video]
Collins briefed on the pathway from rare disease discovery to treatment using case studies from three diseases studied in his lab at NIH. In the case of one disease, researchers were able to repurpose a drug that was still under development for another disorder. In another case, they were able to repurpose an existing drug. Treatment for a third disease remains elusive.
Multiple factors are driving the rapid advancement of medical research. These include advances in genetic diagnoses, increases in speed, decreases in cost – and vast libraries of molecules, Collins said. Molecules used to be identified “in vitro” — in test tubes – are now identified “in siico” – or by computers.
“And now, these libraries are up to trillions of molecules to discover drugs for patients. These are in silico, that is they’re done in computers, which is really much less expensive than those that we had to do in dishes in the past. These molecules eventually need to be tested in preclinical models, primarily mice, and the CRISPR mice advances have made this a much more rapid development than it used to be in the past,” Collins said. Business incentives have also changed, with small biopharmaceutical companies getting into the market and legislative incentives for companies to get involved. And patient support groups have multiplied.
In the past 10 years these factors have combined “to change the whole map of rare disease treatment, much to the benefit of the patients,” Collins said.
Two cases studies illustrate the changes:
Tumor-Induced Osteomalacia (TIO)
The first case study discussed involved a TV journalist whose FGF23 gene was malfunctioning, Collins said. FGF23 provides instructions for making a protein called fibroblast growth factor 23, which is produced in bone cells. This protein is needed to regulate the phosphate levels within the body, a condition called phosphate homeostasis. FGF23 lowers blood phosphate, and patients with too much suffer weakened bones and horrible fractures, Collins said.
TIO is caused by very small and difficult-to-find tumors. For some, just removing those masses is the cure. But in the case of the journalist, those tumors metastasized. In a 2014 study, the genetic defect that causes those tumors was identified through advances in RNA sequencing, revealing a mutation known as “translocation.” “This is where one part of one gene now is broken off and connects to another part of another gene. And in the case of TIO, the one gene was this sort of structural protein called fibronectin one, and it is now hooked up at this signaling protein called FGFR1, fibroblast growth factor receptor one.”
But what if the FGFR1 signal was the source of the overall problem? Collins said researchers concluded that an FGFR receptor blocker might help the patient. They were able to start a compassionate use (Expanded Access) study in a molecule that was available with Novartis at the time called BGJ 398 that went on to become the drug infigratinib, which Collins described as an FGF receptor inhibitor drug. (These were first approved by the FDA in 2019.)
The journalist had an almost immediate and dramatic response to the drug. He resumed playing tennis and saw his daughter graduate from high school.
Unfortunately, the side effects became so severe that the patient decided to end treatment and died five years after starting treatment.
“But nonetheless, he was able to get five years of, for the most part, fairly decent quality of life out of this,” Collins said. “So this was really quite a success story for him and for the field.”
Autosomal Dominant Hypocalcemia Type One
A patient Collins referred to as “Mr. B” had a condition caused by a germline genetic mutation. As a child, he experienced cramping and abnormal tingling in his limbs known as paresthesias. By age six, he was evaluated for learning difficulties and found to have low calcium, low blood calcium, and hypoparathyroidism.
Mr. B’s family history showed that his father also had low blood calcium, which confirmed the genetic source of his condition. And Collins learned he had two siblings who died in infancy, which may have been linked to hypocalcemic seizures. Once diagnosed, Mr. B was treated with calcium and vitamin D, which can keep the blood calcium up. But that can lead to high levels of blood calcium in the urine, which can cause kidney damage or require transplantation.
Collins said research into alcohol dehydrogenase 1 (ADH1) yielded some answers. ADH1 is caused by low levels of parathyroid hormone, which is needed to maintain blood calcium levels. They’re regulated by the calcium-sensing receptor, located on the parathyroid gland. ADH1 occurs when there’s a mutation in that receptor that switches it on, causing parathyroid hormone levels to drop.
Researchers needed to find a way to turn that receptor off, and ultimately one of the compounds used to treat osteoporosis, calcilytics, was identified as a potential solution. In 2005, GlaxoSmithKline licensed a group of calcilytics from a company called NPS Pharmaceuticals to develop drugs for treating osteoporosis. NIH researchers negotiated a contract with GlaxoSmithKline in 2007 to use their calcilytic ronacaleret to treat patients with ADH1. Unfortunately, the treatment failed, and GSK abandoned the drug. “One of the phenomena in this area is that when a drug company is developing a drug for a disease, and especially if it’s developing a drug for a common disease that has a potentially big payoff, they’re really careful. They’re really afraid of doing other studies with that drug, for example, in rare diseases,” Collins said because any negative outcomes could mean a big financial loss for the company.
In 2011, NPS Pharmaceuticals retrieved the license for these calcilytics from GSK, and researchers negotiated another ADH1 study in 2014. The initial proof of concept looked very promising. But just as researchers were about to move on to a larger study, in 2015, Shire Pharmaceuticals acquired NPS and had no interest in the ADH1 research. When Takeda acquired Shire, they too weren’t interested.
In 2020, Collins approached a California biotechnology company called BridgeBio about the potential to treat patients with calcilytics. Their officials contacted a tobacco company in Japan that had developed a calcilytic treatment for osteoporosis.
“It ends up, it was a really lousy drug for osteoporosis, but it ended up being a great drug for ADH1,” Collins said. In just two years, the studies have reached the Phase 2 Clinical Trial stage and yielded some impressive results.
“So rare disease treatment is challenging, but the barriers are falling,” Collins said. “The genetic causes are identified much sooner.”
However, data, information and treatment options are lagging badly in many parts of the world, a huge problem,” he noted. Journalists and others can help move the need through informed reporting, “but it’s a big problem.”
This program was sponsored by Fondation Ipsen. NPF is solely responsible for the content.
