n-Lorem Foundation has taken on a challenge that many nations consider too great: treating patients with ultra-rare diseases (which affect 30 or fewer people) for free, for life.
n-Lorem Foundation has taken on a challenge that many nations consider too great: treating patients with ultra-rare diseases (which affect 30 or fewer people) for free, for life. It received FDA guidance January 5th and is in the midst of preparing the first package of investigational new drug (IND) applications – usually with an n-of-1, for individual patients. Patient dosing is expected to begin later this year.
“No one has ever done this before,” Stanley Crooke, M.D., Ph.D., founder, CEO, and chairman of the board of n-Lorem Foundation, told BioSpace. “I expected we’d have 5 applications our first year. We had 48, and are moving to treat 23 people.” Experiments are planned for patients at Harvard and 10 at Columbia University for an aggressive mutation of ALS. While forming n-Lorem, “We helped two investigators obtain antisense oligonucleotides for several patients,” he added.
n-Lorem selects patients based on their genetic mutation and the organ affected rather than their specific diseases. “We focus on the organs we really understand,” he emphasized. “It’s the cause of the mutation, not the name of the disease, that matters.”
The treatments all use the antisense technology and automation techniques developed at Ionis Pharmaceuticals, which Crooke founded.
Crooke, who retired from his position as Ionis CEO one year ago while remaining as executive chairman of the Ionis board, pioneered antisense technology. “I’m still involved with the science that we created and continue to advance,” he told BioSpace.
“It’s the efficiency of antisense technology, coupled with its other characteristics, that makes n-Lorem’s approach feasible.”
As Crooke explained, “With small molecules, if you make any chemical change, you have a new ballgame. That’s not the case with RNA-targeted drugs. They’re basically the same,” but each one uses a particular nucleotide to bind to specific genetic sequence. “With antisense, there basically are no undruggable targets and, within a chemical class, they have consistent performance.”
Antisense drugs are versatile, too, he pointed out. “Because they can be delivered by any administration route (oral, aerosol, intrafecal, intramuscular, intravenous, etc.), they can help many patients.”
Safety is critical in all clinical trials, but with ultra-rare diseases, even greater care is taken. Therefore, before administering a drug, he said, “We know in detail what happens in those organs and where the drug goes, the dosage, and the general duration of effect. We’ve created safety databases that begin with non-human primates and extend to controlled clinical trials.” n-Lorem publishes that data and also makes it available to regulatory agencies.
Providing a lifetime of treatment for free is possibly financially because of the limited quantity of doses required. “The potency of modern antisense oligonucleotides is so high and their duration so long that the annual quantity required per patient is very small,” Crooke said. For example, an aerosol treatment for a lung disease may require only 3 grams per year and an intravitreal treatment for an eye disease may need less than 50 mg per year.
“The minimum we can make in a GMP facility is 10 grams. It is stable for years as a powder, so we have enough (from one batch) to treat a patient for 20 years,” he said.
Developing these drugs commercially would have resulted in exorbitant costs for patients, Crooke explained because most drug platform technologies are not well-suited for creating individualized medicines. Traditional companies have neither the technologies nor the financial incentives needed to develop ultra-rare therapies. Crooke, therefore, created n-Lorem Foundation to do that charitably.
Working closely with Ionis, “We connect the need to the drug development engine. We’re the middleman,” he said.
n-Lorem’s role is to “understand exactly what the mutation is, the kind of mutation (splicing, for instance), the function of the gene, the primary and secondary manifestations of the disease, the organs involved, and what’s important to the patients, then to decide whether to make selective or non-selective antisense.” Not surprisingly, “We focus on the organs Ionis know the most about.”
Then, to file an IND, n-Lorem needs an investigator and institution to support that work, as well as patients.
The Undiagnosed Disease Network (a consortium of tertiary care institutions for that purpose) directs a large number of patients to n-Lorem, but most come from physicians. “There are millions of these patients, and the more people we sequence, the more unique mutations we find. Genetic diseases are vastly more common and more complex than we used to think.”
Before filing each IND, n-Lorem defines a patient-specific treatment plan, identifies the primary manifestations most likely to benefit from treatment and obtains as much natural history from the patient or family as possible before preparing the antisense oligonucleotide. “
n-Lorem is a public non-profit foundation, completely independent from Ionis. During its first year it was bootstrapped with approximately $10 million in funds from Crooke and his wife, Ionis (which provided funds and in-kind services), Biogen, Inc., and individual donors and volunteers. It has a three-year runway. “This year we are preparing for formal fundraising,” he said.
The Foundation also is working with contract research organizations to conduct limited preclinical studies, with Illumina and Covance for genomics data, and with Charles River Laboratories and the Korea Institute of Toxicology.
“I spent 2019 discussing this approach with the FDA,” Crooke recalled. The Agency “realizes this is outside the bounds of existing approaches and responds well to the idea of being charitable. We are looking forward to more definitive guidance in the coming months.”
