n-Lorem Foundation launches to develop individualized therapies for ultra-rare diseases

The nonprofit n-Lorem Foundation has launched with the goal of making it easier, safer, and cheaper to develop individualized antisense oligonucleotide therapies—sometimes called N-of-1 drugs—for people with ultra-rare genetic diseases.

n-Lorem represents a new chapter for Stanley Crooke, stepped down as CEO at the end of 2019 after 3 decades leading Ionis Pharmaceuticals. The antisense pioneer will lead the nonprofit and, with his wife, longtime Ionis researcher Roseanne Crooke, contributed $1.5 million to the effort. n-Lorem received another $1.5 million from Ionis, $1 million from Biogen, and funds from other individual contributions.

The concept of a custom-made oligonucleotide therapy captured the public’s attention in 2018, when Boston Children’s Hospital geneticist Timothy Yu revealed he had, in less than a year, diagnosed, developed a drug for, and treated a girl with a unique form of Batten’s disease. The story of his bespoke therapy—named milasen for his patient, Mila Makovec—caused families affected by rare genetic mutations to flood his in-box with pleas for help.

n-Lorem blossomed from Crooke’s desire to serve that pent-up demand in a way that would be safe, efficient, and free for patients. He ticks off what he thinks is needed to scale N-of-1 treatments: a patient whose genetics have been thoroughly characterized, a clinician who can manage a trial for just one patient, an institution that can submit an investigational new drug application (IND), and a therapeutic modality that is efficient enough to allow the drug to be provided for free, for life.

“I conceived of n-Lorem as sort of the middle man—the broker of the genetics, the patients, the needs, and one solution to bring therapeutic options for these patients who have ultra, ultra-rare mutations,” Crooke says.

The queue of families likely to reach out to n-Lorem is long. For now, the foundation will only consider treating US-based patients who come through the Undiagnosed Disease Network, a group of National Institutes of Health–funded academic sites with clinical and research expertise in ultra-rare diseases.

An “access to treatment” committee composed of academic researchers, patient advocates, and executives from Ionis and Biogen will determine which cases n-Lorem should take on. The team will weigh both need and the therapeutic feasibility of each case.

Knowing the regulatory morass that N-of-1 therapies have created, Crooke is reluctant say how many people he thinks the foundation could help in the near term. Although milasen carved out a path for a custom-made drug to go from lab to patient, it’s not necessarily one that can be followed for every disease.

To create n-Lorem, Crooke talked with the US Food and Drug Administration about a swath of issues. One of the first that needs tackling is clarity on the safety data the agency will need to move individualized therapies from the lab into a human.

Although antisense experts have developed screens to weed out toxic sequences of nucleic acids, none are 100% accurate. With researchers hoping to trim the typical safety tests required to give a drug to a human, questions arise over the agency’s risk tolerance in these most urgent cases.

Another issue is that different INDs could be reviewed by different FDA divisions, which could mean shifting goalposts. Crooke has asked the agency to consider consolidating the review of personalized therapies into a single division and to develop general guidance for academics and foundations.

“The challenge for FDA is how far they go with this,” says Art Krieg, chief scientific officer at Checkmate Pharmaceuticals. Krieg, who has spent his career working on oligonucleotides, is organizing a workshop on N-of-1 drugs in April on behalf of the Oligonucleotide Therapeutics Society. He points out that the need is growing: in addition to individual academic researchers and n-Lorem, several other groups are considering ways to systematize the creation of N-of-1 therapies.

Even as the agency is “showing a real willingness to consider streamlining these development programs” for individual patients, regulators must also weigh the reality that all drugs carry risk, Krieg says.

For its part, the FDA is holding a workshop in March to bring together stakeholders—patient advocates, clinicians, manufacturers, regulatory authorities—to explore ways to ease the development of the bespoke treatments.

The FDA’s stance will directly influence the cost of creating the drugs. As Krieg points out, manufacturing the oligo itself is the cheap part. More expensive are the animal safety tests, which can vary widely in cost depending on the type of study the agency requires.

An important goal for Crooke as he sets out on his new venture is to devise ways of measuring the benefits of the new therapies. That’s a difficult proposition for the FDA when a drug might be for just one person.

“We were raising some very fundamental policy issues that will take some time for them to answer, but they’re working on it,” Crooke says. “I think we have a path that can work—a path that’s fast and efficient enough that we can meet the needs of patients.”