By Deborah Borfitz 

June 14, 2023 | Stanley T. Crooke, M.D., Ph.D., founder and longtime leader of the company that pioneered RNA-targeted therapeutics, is now chairman and CEO of the n-Lorem Foundation descaling the technology to treat patients helpless before a healthcare system that wasn’t built for “n-of-1” problems. He will be addressing a room of physicians and scientists tomorrow on the campus of Vanderbilt University, closing in on his 900th seminar focused on his novel nonprofit solution providing free-for-life medicine to desperately ill patients with no other alternative. 

The treatments are all highly potent and long-acting antisense oligonucleotide (ASO) medicines, a chemical class first designed by the Ionis Corporation that are being used to target single culprit genes one patient at a time on an industrial scale, says Crooke. Millions of nano-rare patients are thought to exist worldwide, although the vast majority are undiagnosed and only a tiny fraction of those with an identified mutation can be helped currently—largely as a matter of funding and geography. 

Despite the odds, the 3-year-old n-Lorem Foundation now has 90 nano-rare patients, seven of whom are either being treated or ready to be treated pending institutional review board approval. But 200 submissions have been received, says Crooke, noting that the acceptance rate (57%) has been well above what was expected (10% to 20%). 

Discovering, developing and treating one patient for life runs, on average, about $1.3 million and eligibility is limited to those who live in the U.S. both because of the cost and the fact that the Food and Drug Administration (FDA) is firmly on board. The agency’s initial guidance  for ASO use in these types of patients was released in January 2021, quickly followed by more detailed guidance; recommendations around chemistry, manufacturing, and controls; and clinical guidance. 

“It was reasonable to focus on getting the U.S. sorted out as a first step,” Crooke says, since most regulatory authorities around the world follow the FDA’s lead. The guidance documents came two years after he first wrote to senior leaders in the agency’s drug division and was stunned by their immediate and uniformly positive response to his planned pivot from corporate CEO to n-of-1 philanthropist. 

That collective encouragement was all the green light Crooke needed to launch his nonprofit, whose name is borrowed from the Latin word (lorem) for therapy. The FDA’s published recommendations were all predicated on characteristics of ASO technology and apply only to nonprofit efforts. 

Although 77-year-old Crooke has held senior positions for many years, he has always staunchly believed he worked for the patient. “In that sense, nothing has changed,” he says of his late-in-life career transition. “I entered the industry when it was not really popular to mention the patient—it was a business, and I disagreed violently with that.” 

Truthfully, Crooke says, he didn’t want to head up the lifechanging foundation although the work has been unspeakably rewarding for everyone involved. He quickly realized he alone was capable of industrial scale production of personalized ASO medicines. He had only a bit of nonprofit experience with two established players (Philadelphia Orchestra and the Franklin Institute), but he also singlehandedly raised about $10 billion in funding for the Ionis Corporation which was, comparatively speaking, a much harder sell.  

Financially speaking, n-Lorem has been remarkably good at raising money and it is in large part thanks to the generosity of more than 30 industry partners from across drug discovery, development, and manufacturing, he says. This alone has reduced per-patient costs by 40%. 

Efficient Technology 

Definitionally, a nano-rare patient describes someone whose mutation is shared with up to 30 other patients worldwide. Most nano-rare patients have a single gene mutation that causes a cluster of symptoms affecting their health leading to degenerative conditions or death. 

There is no regulatory path to commercial approval for single patients or under-30 patient populations, on whom it would be virtually impossible to conduct a clinical trial, says Crooke. It was this quandary that sparked the idea for n-Lorem. 

In 2017, he was visited by two parents of children with extremely rare mutations asking if the Ionis Corporation could make an ASO medication to treat them. “I had to tell them it simply wasn’t commercially feasible, but it was in that conversation that I realized the technology we had developed was efficient enough to make an ASO for these deviations pretty cheaply,” he continues.  

As described on the foundation’s website, ASO medicines use short strands of modified DNA that are designed to bind precisely to target RNAs and thereby modify the process of creating a disease-causing protein. The advantage of ASO therapies is that they can be developed rapidly, inexpensively, and are highly specific. 

More than a dozen ASO drugs have been commercially approved for use in the U.S., including the first blockbuster drug (Spinraza, marketed by Biogen) of the Ionis Corporation. As a foundation of care in spinal muscular atrophy, many thousands of individuals have now been treated with Spinraza worldwide, says Crooke. “What is unique about nano-rare patients is that there is a single gene cause that can be identified and, in many cases, once we know that then we can make an ASO [to treat them].” 

Sarepta Therapeutics also has several ASO therapies FDA-approved for treating patients with Duchenne muscular dystrophy, including Vyondys, which has further familiarized neurologists with the technology. Much education about ASOs and the work of n-Lorem is still needed among academic endocrinologists, hepatologists, nephrologists, and ophthalmologists in the research field, he says.   

Price of Success 

To have a starting point for the nonprofit, the first piece of the puzzle was how to gain access to appropriately characterized patients and qualified investigators. Genomics still being so new, he expected n-Lorem might get a handful of applications its first few years and easily be run with an all-volunteer staff—neither of which turned out to be the case, Crooke says. 

Demand has been 20-fold greater than expected, he reports. The foundation has succeeded in raising enough funds to hit this year’s goal—to file 10 investigator-initiated INDs ($13 million)—but “we’re not catching up with the backlog and that’s really troubling all of us. 

“If we had more money, we could easily file 20 INDs,” he continues. Lifetime treatment costs will come down over time as the nonprofit gets more efficient and grows to the point where ASO medicines on occasion treat more than a single nano-rare patient.  

Lab capacity won’t be an issue. Until recently, n-Lorem was paying for several people at the Ionis Corporation to work on its behalf. But the foundation is now building its own lab facility three times that size where the bulk of treatments for future patients will be made, says Crooke. 

It can be difficult for patients to meet the eligibility criteria, and in some cases to survive long enough for their personalized ASO medicine to be developed, Crooke says. Only certain organs—specifically, the liver, kidney, central nervous system, eye, and lung—can be treated since too little preclinical data exists on manifestations in other organs. “Remember, we are going from in vitro to humans and so we have to assure that every step is as high quality as possible and... we are not adding side effect burdens to these patients.” 

Additionally, ASO medicines cannot be produced for null mutations since the treatment is designed to replace a gene. This automatically eliminates a significant fraction of ultra-rare patients, he notes. 

Some cases need to be put on hold until the investigator has provided sufficient information to be sure n-Lorem scientists understand the causal mutation and its nature. The ASO development process also has a 15- to 18-month timeframe, and several patients have died from their condition during the wait. Those have been “really bad days,” says Crooke. 

For individuals suffering from a nano-rare mutation, “[ASOs] are about the only play right now,” Crooke adds, although he remains hopeful that gene therapy will eventually be a safe and inexpensive option for patients at scale. “We can’t have technologies come on board unless they are capable of being industrialized and scaled and done with high quality, and it is going to be a while before any of the other [technologies] are ready to do what we’re trying to do, and that’s a shame.”  

Expansion Plans 

Only when genome sequencing gets incorporated into more evaluation protocols will the incidence rate of ultrarare mutations start to come into view, says Crooke, who is an advocate of such testing at birth. He also believes gatekeeper physicians need to be alert to the issue of these n-of-1 mutations and trained to refer patients to centers that can make a diagnosis and genetically characterize them. 

Patients and parents still have trouble finding their way to a personalized medicine center for testing, Crooke says. That’s because physicians begin with a differential diagnosis based on a list of similar cases they have seen before. Consequently, most nano-rare patients are either undiagnosed or misdiagnosed and even those who achieve a diagnosis aren’t properly treated. 

A network of 12 tertiary care institutions forms a consortium known as the Undiagnosed Disease Network (UDN) to characterize patients who may have ultra-rare mutations, says Crooke. Data from the first 173 cases taken on by UDN centers suggests how “idiosyncratic” the diagnostic odyssey can be for patients—a journey that can take anywhere from a few months to 36 years. 

Patients face enormous challenges in accessing medical care of any kind because the hospitals capable of providing treatment worry about risk and how they’ll get paid, Crooke continues. To help remedy the situation, n-Lorem has to date established six “partners in excellence” with world-renowned academic medical centers and institutions across the U.S., including Columbia University, and is looking to broaden its network of repeat customers to ensure quality and enable efficiencies.  

Crooke says he is now exploring the options for accommodating n-of-1 patients in other countries, which puts n-Lorem two years ahead of the original expansion timetable. One possibility is to train other organizations to be individualized ASO makers, but only if high quality can be assured since the difference between an optimal and suboptimal ASO treatment can be “life and death.” This will happen only in countries where the medical care is highly advanced and the scientific infrastructure exists to understand the mutations and take care of patients with an experimental medicine, he adds. To do otherwise would be “far too difficult and far too risky to even try.”  

What Crooke most wants people to know is that “these [nano-rare] patients and families exist, are desperate and in need and we can help many of them. Hopelessness is a terrible state for a human being... we need to come together and see what we can do to help them.”