Industry-Sponsored N-of-1 Trials in Orphan Drug Development

N-of-1 clinical trial is often mentioned as one of the approaches to address the challenging issues in orphan drug development. at one point, FDA rolled out more guidance on 'N of 1' gene therapies including the guidance on "Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases". AHRQ had a publication "Design and Implementation of N-of-1 Trials: A User’s Guide". Recent "baby KJ's story" was touted by the FDA as a success story for individualized treatment for a N-of-1 disease condition "FDA Cell & Gene Therapy Roundtable: Putting Every Patient Within Reach of Innovation". Nature magazine had an article "A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases"

We would like to check the reality to see how many drugs or biological products were approved by the US FDA based on the evidence from N-of-1 clinical trials. 

We identified a few ultra-rare disease cases in the past decade where industry or institutional sponsors conducted single-patient (“N-of-1”) trials of experimental therapies. Notably, no drug or biologic approved in the last 10 years appears to have relied on N-of-1 clinical trial data for its FDA approval. The only FDA approval historically based in part on N-of-1 evidence was danazol for hereditary angioedema in the 1980s. Below we summarize key examples of N-of-1 trials involving drugs/biologics and rare indications:

Drug/ Biologic	Orphan Indication	Sponsor (Company/Institution)	N-of-1 Trial Design & Results	Regulatory Outcome
Milasen (custom ASO)	CLN7 Batten disease (Infantile neuronal ceroid lipofuscinosis)	Boston Children’s Hospital (Timothy Yu’s lab)	Single-patient, customized antisense oligonucleotide. FDA cleared an IND for Mila in late 2017, and she received serial intrathecal doses. Her seizure frequency fell dramatically (from ~30/day to <10/day) and her neurologic decline stabilized during treatment.	Investigational (IND only; no FDA marketing approval)
Custom ASO for A-T (no trade name)	Ataxia-Telangiectasia	Boston Children’s Hospital / A-T Children’s Project (Dr. Yu)	Personalized splice-modulating ASO for one AT patient. FDA granted an IND in 2020 for an N-of-1 trial. The child began receiving the ASO (via intrathecal delivery) later in 2020; detailed clinical outcomes have not yet been published.	Investigational (IND only; ongoing treatment)
CRD‑TMH‑001 (CRISPR-based gene therapy)	Duchenne muscular dystrophy (specific exon 1/promoter mutation)	Cure Rare Disease (nonprofit biotech)	Single-patient CRISPR/Cas9 gene-editing therapy. FDA cleared an IND in August 2022 for a one-person trial. The only enrolled patient (the sponsor’s founder’s brother) was dosed but later died (cause under review). As a result, efficacy remains unknown.	Investigational (IND only; trial suspended)
Danazol	Hereditary angioedema	Original developer (Searle/Pfizer)	Historical example: A multi-crossover N-of-1 trial (9 patients, 47 treatment periods) was reported in 1976. This small trial of danazol demonstrated reversal of HAE symptoms and formed part of the FDA approval record.	Approved (for HAE; orphan indication) https://www.fda.gov/media/87621/download section 5.2.4

Each case is discussed in more detail below.

Milasen for Batten Disease (CLN7)

• Drug & Sponsor: Milasen is a one-off antisense oligonucleotide (ASO) developed at Boston Children’s Hospital by Dr. Timothy Yu’s team. It was designed for an 8‑year-old patient (“Mila”) with a unique retrotransposon mutation in the CLN7 gene causing Batten disease.
• N-of-1 Design & Results: After rapid sequencing and preclinical work, the FDA granted an IND to trial milasen in late 2017. Mila then received intrathecal milasen injections every 3 months under an N-of-1 protocol. Over ~9 months of treatment, Mila’s seizure frequency fell from ~30/day to under 10/day, and her neurological decline notably stabilized. No significant adverse effects were reported, and her condition improved in several clinical measures. These results were published in the New England Journal of Medicine (2019).
• Regulatory Outcome: Milasen remains an investigational therapy given under an IND. It was not submitted for FDA marketing approval (and Mila later died in early 2021). Thus, no FDA approval was sought or granted for milasen.

Customized ASO for Ataxia-Telangiectasia

• Drug & Sponsor: A patient-specific splice-switching ASO (unnamed) was developed by Dr. Yu’s group (supported by the A-T Children’s Project) for a young girl with ataxia-telangiectasia (AT). The ASO was tailored to correct her particular ATM gene splicing defect.
• N-of-1 Design & Results: The FDA granted IND approval for this one-off ASO treatment in 2020actionforat.org. The affected child began receiving the ASO via intrathecal infusion that year, under a single-patient trial protocol. (To our knowledge, no detailed efficacy data from this N-of-1 trial have yet been published.)
• Regulatory Outcome: This custom AT therapy is in the investigational stage (IND only). No FDA marketing approval has been sought or obtained.

CRD‑TMH‑001: CRISPR Therapy for Duchenne Muscular Dystrophy

• Drug & Sponsor: CRD‑TMH‑001 is a one-time, custom CRISPR/Cas9 gene-editing therapy developed by Cure Rare Disease (a nonprofit “n=1” biotech) to target a specific exon 1/promoter mutation in the DMD gene. Cure Rare Disease’s founder (motivated by his brother’s illness) sponsored the program.
• N-of-1 Design & Results: In mid-2022, the FDA cleared a first-in-human IND for CRD-TMH-001. The trial was explicitly a single-patient study: one eligible DMD patient (age 27, the sponsor’s brother) was treated. The therapy was infused intrathecally as planned. Tragically, the patient died several months later; a causality review is ongoing. To date, no efficacy data (or definitive safety findings) from this N-of-1 trial have been published.
• Regulatory Outcome: CRD-TMH-001 remains purely investigational under the IND. No further patients have been treated and no FDA approval has been pursued.

Historical FDA Approval: Danazol for Hereditary Angioedema

• Drug & Indication: Danazol is a synthetic steroid used to prevent attacks of hereditary angioedema (HAE), a rare genetic edema disorder.
• N-of-1 Trial Evidence: In 1976, a classic FDA review noted that the approval of danazol for HAE was supported in part by an N-of-1 multiple-crossover trial of nine patients (47 treatment periods). In that study, each subject alternated between danazol and placebo in random sequence, demonstrating clear reversal of clinical and biochemical abnormalities on danazol. This case was cited in section 5.2.4 of the FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications
• Regulatory Outcome: Danazol was approved for HAE prevention (an orphan indication) and remains an approved drug (marketed as DANOCRINE). This case shows that the FDA has historically accepted single-subject crossover data in rare diseases. However, it is an older example; no similar approvals based on N-of-1 data have emerged in the past decade. The N-of-1 study of Danazol in HAE was published in New England Journal of Medicine in 1976 "Treatment of Hereditary Angioedema with Danazol — Reversal of Clinical and Biochemical Abnormalities"

Summary

In summary, we found only a handful of “N-of-1” clinical trials over the past 10 years involving investigational drugs for very rare diseases. These include two custom antisense oligonucleotides (Mila’s milasen for Batten disease, and an ASO for one AT patient) and one CRISPR gene therapy for Duchenne MD. All were “approved” only under individual INDs and have shown promising signals but remain experimental; none has led to FDA marketing approval. Apart from the historical example of danazol (approved via N-of-1 data in the 1970s), our searches of FDA databases, ClinicalTrials.gov, and published literature did not identify any new orphan drugs approved based on N-of-1 trial evidence. Thus, while N-of-1 trials are an emerging tool for ultra-rare diseases, they have not yet changed the landscape of FDA approvals in the last decade.

Steroid Tapering Design in Action - Failed

In a previous post, I discussed steroid tapering design clinical trials. In these trials, the primary efficacy endpoint is the reduction in steroid dose. Efficacy is demonstrated if patients receiving the experimental treatment are able to reduce their steroid dose significantly more than those in the placebo group.

Steroids remain highly effective for many conditions, particularly those involving chronic inflammation or an overactive immune system. However, long-term or high-dose steroid use is associated with numerous side effects. Therefore, it is highly desirable to develop therapies that allow for steroid dose reduction—or even complete steroid sparing—while maintaining disease control.

One of these diseases is sarcoidosis or lung sarcoidosis. Sarcoidosis is an inflammatory disease in which the immune system overreacts, causing groups of cells to form clusters of inflamed tissue called "granulomas" in one or more organs of the body. The most affected organ is lung. Sarcoidosis symptoms can be treated using corticosteroids, or prednisone, which turn down the immune system's activity to reduce inflammation.

A sponsor, aTyr Pharma, conducted a phase 3, confirmatory trial to investigate if their experimental drug efzofitimod is effective in treating the pulmonary sarcoidosis. The study "Efficacy and Safety of Intravenous Efzofitimod in Patients With Pulmonary Sarcoidosis" was designed as steroid tapering with the primary efficacy endpoint being "Change from baseline in mean daily oral corticosteroid (OCS) dose at Week 48".

This morning, the sponsor issued a press release announcing Topline Results from Phase 3 EFZO-FIT™ Study of Efzofitimod in Pulmonary Sarcoidosis. Study did not meet primary endpoint in change from baseline in mean daily oral corticosteroid (OCS) dose at week 48, although clinical benefit for efzofitimod observed across multiple study parameters.

The change from baseline in mean daily OCS dose reduced to an average of 2.79 mg for the high dose of efzofitimod versus 3.52 mg for placebo, resulting in an insignificant treatment difference. The sponsor blames the unexpected placebo response.

aTyr flunks phase 3 lung disease trial, deflating stock, but still plans talks with FDA

The steroid tapering design offers important clinical advantages by directly addressing the need to reduce long-term steroid exposure, a major source of morbidity in many chronic inflammatory and immune-mediated diseases. The steroid tapering design and the change from baseline in steroid dose is accepted by the regulatory agencies. It provides a patient-centered and easily quantifiable endpoint that demonstrates whether an investigational treatment can maintain disease control while allowing for a lower steroid dose. 

However, this design also has limitations. Variability in tapering schedules, risk of disease flares, and ethical concerns regarding aggressive tapering in placebo groups can complicate interpretation. In addition, results may be less generalizable to steroid-naïve patients, and regulatory acceptance of steroid-sparing endpoints as stand-alone primary outcomes remains uncertain. Careful planning and standardization are therefore essential to balance the scientific value with patient safety and trial credibility.