Mila's Story: A Race Against Time

Timeline from the initial clinical diagnosis to the initiation of treatment^[1]

In 2016, a 6-year-old girl named Mila began showing signs of a rare and fatal neurodegenerative condition. Her symptoms started subtly at age 3 with an inward-turning foot, progressed to vision problems at 4, and by 5, she was experiencing language regression and clumsiness. As she approached her 6th birthday, Mila's condition rapidly deteriorated, leading to hospitalization due to vision loss, frequent falls, and difficulty speaking and swallowing.

After extensive testing, a skin biopsy revealed abnormal lysosomal inclusions characteristic of Batten's disease. Genetic testing identified one known pathogenic mutation in the MFSD8 gene, but the second mutation remained elusive. Determined to find answers, Mila's family enrolled her in a research study at Boston Children's Hospital.

Using whole-genome sequencing (WGS), researchers discovered a novel mutation: an SVA retrotransposon insertion in MFSD8 intron 6. This insertion caused missplicing of the gene, leading to Mila's condition. With the genetic cause identified, the race was on to develop a treatment.

Inspired by the success of nusinersen, an antisense oligonucleotide (ASO) for spinal muscular atrophy, researchers designed a custom ASO to correct Mila's specific mutation. After testing multiple candidates, they identified the most effective one, naming it "milasen" after Mila.

Milasen Development^[1]

In an unprecedented feat, researchers moved from genetic discovery to clinical treatment in just one year. They conducted rapid toxicology studies, manufactured the drug, and obtained FDA approval for an expanded access investigational new drug application.

Mila began receiving milasen treatments in January 2018, when she was 7 years old. The drug was administered intrathecally, with doses gradually increasing over time. Within the first year of treatment, Mila showed no SAEs, and her seizure frequency and duration decreased significantly.

The dosing schedule of milasen^[1]

The concentration of milasen in cerebrospinal fluid (CSF) before each administration (trough) and at day 174 without concurrent dose administration. ^[1]

The trends in seizure frequency and duration as reported in a seizure diary recorded by the parents^[1]

The trends in seizure activity as detected by electroencephalography (EEG)^[1]

While Mila's story represents a groundbreaking approach to personalized medicine for rare genetic diseases, it also highlights the challenges and ethical considerations in developing patient-specific treatments. Mila's journey offers hope for other patients with rare genetic conditions and paves the way for future advancements in tailored therapies.

Part I：IND Submissions for Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases:  Clinical Recommendations Guidance for Sponsor-Investigators

The guidance provides recommendations for managing administration, dosing, and clinical monitoring of individualized ASO drug products for SDLT genetic diseases with no alternative treatments. It focuses on ASOs targeting unique genetic variants specific to 1-2 patients, not larger patient populations with same disease^[2].

▶The protocol must be reviewed and approved by an institutional review board (IRB) before proceeding, per 21 CFR part 56.

▶Informed consent must be obtained, including risks, potential benefits, and providing updates.

▶If the individualized ASO drug product is intended for use in children, there are some special considerations: 

▶Confirm the patient's clinical and genetic diagnosis through relevant laboratory testing(e.g., gene sequencing, enzymatic analysis, biochemical testing, imaging evaluations, as applicable).

▶Provide evidence linking the targeted gene variant(s) to the patient's disease pathogenesis. If the evidence is insufficient, additional investigation(s) may be needed before initiating use of the ASO drug product.

▶Show the targeted variant(s) are unique to the patient, including: 

▶ Starting dose

▶ Dose escalation approach

Given the limited nonclinical data available when initiating dosing, the sponsor should consider a dose escalation approach. Dosing should be initiated at a low level and escalated to higher doses cautiously based on:

The protocol should clearly outline:

If a loading dose is proposed, the protocol should contain a rationale for using a loading dose(s) and maintenance dose interval(s), providing a rationale based on:

The dose escalation should be done cautiously（e.g.,by no more than a two-fold increment at a time）, allowing sufficient time to observe the response to a dose change before making further dose modifications.

▶ Dose de-escalation or discontinuation

Dose de-escalation or discontinuation may be necessary to manage unacceptable toxicities and maintain an appropriate benefit-risk profile for the individualized ASO drug product.

♦ Administer starting dose and escalations in inpatient (hospital) setting with close monitoring initially.

♦ For intrathecal, use experienced personnel and have sedation/interventions available.

♦ For at least 24 hours after administration, the participant should be closely monitored for acute, serious  adverse events (AEs)  that may be precipitated by:

♦ After the safety and tolerability at a given dose level is adequately characterized and any AEs are identified and can be appropriately monitored, subsequent doses at the same level can generally be administered in an outpatient (clinic) setting, if needed. Appropriate safety monitoring and interventions should be available in the outpatient setting for possible serious AEs like anaphylaxis.

♦ For intrathecal ASO drug products, experienced medical personnel should perform the intrathecal administration and administer sedation and/or analgesics if needed for the procedure. Appropriate medical monitoring, procedural interventions, and therapeutic interventions should be available in case of complications from the intrathecal procedure and/or sedation.

The guidance recommends an inpatient setting for initial doses and dose escalations to closely monitor for serious AEs, with a potential shift to outpatient setting once the safety at a dose level is characterized. It also outlines specific considerations for intrathecal administration.

According to the FDA guidance, the key recommendations for safety assessments of investigational ASO drug products are:

♦ Perform routine safety assessments (e.g. AEs, vital signs, ECG, lab tests) while the ASO is being administered and for a period after stopping, based on the anticipated half-life. 

♦ Safety monitoring should be informed by:

♦ Include a detailed schedule of safety assessments in the protocol.

♦ Conduct safety assessments more frequently during the initial dosing period (e.g. first 2-3 months). At minimum, assess before each dose or more frequently if long dosing intervals.

♦ Based on initial results, the frequency of assessments can then be decreased. Clearly outline this in the protocol.

♦ For phosphorothioate (PS) or mixed-backbone ASOs, perform platelet counts at least every 2 weeks or before each dose, whichever is more frequent, due to thrombocytopenia risk. Closely monitor for abnormal findings/bleeding.

♦ For intrathecally administered ASOs, collect cerebrospinal fluid before each dose to evaluate for inflammation/infection. Use remaining samples for PK or biochemical assessments if feasible.

♦ If ASO administration is discontinued for safety reasons, continue safety monitoring until adverse event resolution and evaluate for potential late-onset toxicities.

Assessing whether the ASO drug product is providing clinical benefit to the participant is an important element throughout the administration period. The guideline emphasizes careful tracking of clinical status, use of relevant assessments/biomarkers, continual benefit-risk evaluation, and having criteria for dosing adjustments or discontinuation based on clinical response.

In summary, the key points cover ethical considerations, diagnostic confirmation, dosing strategy, administration procedures, safety monitoring, and assessing clinical response for these individualized ASO drug products in this guidance. Based on this guidance, valuable experience will be accumulated through practice, providing reference for the development of individualized ASO drug products in the future, and further improving this guidance as well.