Pathway to Treatment

Seek a diagnosis

The first step toward a potential personalized experimental ASO medicine is to achieve a diagnosis and full genetic analysis. If the patient is unable to achieve a diagnosis and perform a full genetic analysis, patients should contact research physicians and institutions (tertiary care centers) capable of achieving these essential goals. It is critical that the patient be cared for by a qualified research physician and a qualified institution.

n-Lorem recommends contacting the Undiagnosed Diseases Network (UDN) at https://undiagnosed.hms.harvard.edu/ or 1-844-RING-UDN (1-844-746-4836) or a similar organization. The UDN is a consortium of physicians and institutions focused on using modern genetic methods to characterize difficult to diagnose patients.

Engage research physician

Only research physicians at institutions (tertiary care centers) are able to submit a formal application for treatment to n-Lorem. Once a full genetic analysis has been performed and the patient is diagnosed, patients should engage a research physician to discuss if n-Lorem would be a potential therapeutic opportunity. Both the physician and their institution need to be committed and capable of administering treatment and working with n-Lorem to collect patient data prior to and after treatment begins (See Physician Readiness for more information on expectations of submitting physicians and their institutions).

Application for Treatment is submitted to n-Lorem

Because substantial information concerning the patient and the genetics of the patient must be provided, and because n-Lorem will be working closely with the research physician and his/her institution, only the research physician can submit an application. Submissions can be made through the Application for Treatment Portal. It is critical that the patient be cared for by a qualified research physician at a qualified institution.

Once the research physician completes the application, n-Lorem scientists conduct a comprehensive review of the scientific literature and engage in discussions with key opinion leaders to understand the disease, the gene, the mutation, the patient’s phenotype, the therapeutic landscape, and the worldwide prevalence of the mutation. This review can take several months, and once complete, will be presented to the ATTC for review and recommendation.

The ATTC reviews the application and makes a recommendation

Our Access to Treatment Committee (ATTC) is made up of physicians, geneticists, experts in conducting clinical trials, experts in antisense oligonucleotide (ASO) technology, bioethicists, and patient advocates. This committee reviews applications from research physicians.

Upon completed review, the Access to Treatment Committee makes recommendations to n-Lorem’s executive team. At the Foundation, we understand that there are seriously ill patients with immediate need of treatment for their condition. We are sympathetic to patients and everyone involved. We are committed to doing everything we can to ensure complete transparency. Due to the complex nature of treating patients with nano-rare diseases, unfortunately, not all can be approved for treatment. Once accepted, drug discovery programs are prioritized based on severity and trajectory of disease.

n-Lorem reviews recommendation and makes a decision

Once the ATTC has reviewed an application and made a recommendation to n-Lorem, n-Lorem will make a decision to accept or decline the application based on the ATTC recommendation, physician readiness, institutional support, severity of the disease, and feasibility of n-Lorem to develop a personalized experimental ASO medicine for that patient. If accepted, patients are prioritized based on criteria such as: the severity of the disease, feasibility of developing a personalized experimental ASO medicine for the genetic cause of the disease, degree of potential benefit vs. potential risks, practicality of treatment, availability of physician and institution to treat patient and conduct necessary studies, and other complexities of the condition. n-Lorem notifies all physicians of treatment decisions. It is the research physician’s responsibility to update their patients on the status of the application. n-Lorem will not communicate any information about an ongoing program directly to the patient.

Once accepted

If accepted, whole genome sequencing (WGS) and patient cells (fibroblasts or iPSCs) are needed for most programs and must be available to n-Lorem prior to the initiation of a discovery program. If needed, generating iPSCs can take a substantial amount of time and may delay the initiation of a drug discovery program by 6 – 12 months.

Treatment Evaluation Agreement

A Treatment Evaluation Agreement is a contract made between n-Lorem and the research physician/institution in which they both agree to the terms for providing treatment to accepted patients. The agreement outlines the responsibilities of the research physician, institution, and n-Lorem. The agreement also outlines that the research physician will conduct and supervise the study in accordance with the protocol and all applicable laws, regulations (including FDA regulations), and conditions of approval imposed by the Institutional Review Board (IRB) and the FDA. An agreement is required to be executed prior to any patient treatments. Because the agreements require several parties at the institution to review, n-Lorem begins the process while the ASO candidate is in early-stage development, thereby expediting the process. n-Lorem will work with each institution to ensure an agreement is reached prior to any patient treatments.

Optimal ASO discovery starts

Once accepted, and with patient genomic information and cell material in hand, the n-Lorem Foundation works to discover an optimized experimental ASO medicine to move into development. The discovery process includes the synthesis and robust screening of approximately 500 ASO candidates to different sites within the target RNA. Small scale manufacturing is next to support tolerability studies for the most promising ASO candidates from the initial screening. Further evaluation leads to the selection of an optimal ASO(s) to move into development. n-Lorem is committed to quality at each step and to the pursuit of an optimal ASO candidate. Depending upon the complexity of the ASO mechanism and the specific genetic mutations in the patient’s gene, the amount of time required for this step can range significantly. Unfortunately, in some cases, n-Lorem may not be able to identify an ASO to move into development.

Data Collection to define the baseline and symptom trajectory begins

In conjunction with ASO discovery, n-Lorem works closely with the research physician to define treatment goals and to collect baseline data on each patient. The baseline data collection will help assess the performance of the ASO in the context of the treatment goals.

ASO development and manufacturing begins

Through n-Lorem’s discovery process, optimal ASO(s) are identified and moved into development. In these studies, n-Lorem evaluates tolerability and potential toxicity of each experimental ASO medicine candidate(s) using the preclinical guidance provided by the FDA. In parallel, GMP manufacturing of the ASO drug substance begins and will yield enough material for many years of treatment.

Sterile fill and finish

In this step, the optimized ASO candidate undergoes sterile fill and finish. This means that the lyophilized ASO powder, which was GMP manufactured, gets formulated and aliquoted in sterile vials. The final product is tested for various attributes to ensure maximal quality. The finished product is then ready to be administered to a nano-rare patient.

IND preparation and filing begins

In this step, n-Lorem works closely with research physicians to generate and submit a Research Investigational New Drug (IND) application to the FDA and other applicable regulatory authorities. IND applications generally consist of 1200 pages of information on the gene mutation, the patient phenotype, all of the preclinical data generated by n-Lorem, and the proposed treatment protocol that carefully balances risk/benefit of the medicine. Because INDs are large documents requiring significant resources and manpower, n-Lorem and the research physician start generating the application while the ASO candidate is in late-stage development, thereby expediting the process.

Institutional Review Board

An Institutional Review Board (IRB) is a group that has been formally designated to review and monitor research involving human subjects. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. This group review serves as an important role in the protection of the rights and welfare of human research subjects.

Once the FDA has provided approval of the Research IND, the research physician will submit the protocol and informed consent to the IRB for review and approval. IRB approval is required prior to the patient receiving the personalized experimental ASO medicine.

Patient receives personalized experimental ASO medicine

Upon regulatory permission and IRB approval, an investigator-led clinical study is initiated and then a patient may receive their personalized experimental ASO medicine. Once study begins, n-Lorem continues to work closely with the patient’s research physician to collect data to measure treatment goals. This process will continue throughout the length of treatment, which could be the life of the patient. As a part of its commitment to patients, n-Lorem will provide the personalized experimental ASO medicine for free, for life.

As an open-access foundation, n-Lorem will work closely with the physician to publish preclinical and clinical data in peer-reviewed and scientific forums. We believe that these data could impact how the medical community thinks about disease, the link between genotype and phenotype, and how disease phenotypes shift throughout a patient’s lifetime.

Data Collection to assess effect in patients on treatment

Once treatment starts, data collection continues to assess the performance of the ASO in the context of ASO treatment. These data are collected by the research physician, the patient and their healthcare providers. This would also be the time during which if there were any adverse or severe adverse events observed, these events would be reported promptly to the regulatory agencies.