Addressing the Needs of Nano-Rare Patients

Recently, a number of articles have been published that identify patients with extremely rare genetic diseases as in need of more effective diagnosis and treatment and have proposed potential solutions.^1–3 Additionally, at least one article suggesting a scheme to pay for the treatment for patients with extremely rare mutations ⁴ has been published. While I applaud the focus and intent of these articles, in my opinion, they have failed to address a number of critical issues. Nor have most of these publications addressed how the desperate needs of patients who suffer from extremely rare diseases today are to be met. In this commentary, I take advantage of the experience at n-Lorem to suggest some approaches that have worked. Obviously, while the experience of n-Lorem is relevant, other approaches may be viable as well.

At n-Lorem, in 5 years, we have processed >350 applications for treatment, accepted >130 patients for treatment, filed >23 investigational new drug applications (INDs) to treat >33 patients in four different divisions of the Food and Drug Administration (FDA), demonstrated clinically significant benefit in all patients treated for a sufficient duration to evaluate benefit, experienced no drug-related severe adverse events (SAEs), and demonstrated excellent safety and tolerability profiles. The processes used and the actual data accumulated with regard to the first 173 patients who applied for treatment have been summarized.^5,6 Such compilations of data provide a broad overview of the performance of personalized ASOs in a diverse group of patients. For example, that analysis shows the urgent need to introduce genomic sequencing into newborn evaluation protocols to reduce nearly 5 years from symptom onset to diagnosis, that to date there have been no ASO-related SAEs or AEs and that significant benefits have been observed in multiple patients with neurodegenerative diseases. Additionally, case reports provide the opportunity to evaluate the performance of each ASO in an individual patient or patients. ⁶ Based on this experience, solutions to several issues have been developed and shown to work. In this commentary, I will share some of those lessons.

How Should Extremely Rare Populations be Defined?

Better defining extremely rare populations is important because, today at least, solutions must be different for diseases of different prevalences. Further, imprecise definitions have led to considerable confusion about what is feasible and what is not, particularly for nano-rare patients. I have defined nano-rare patients as patients expressing pathogenic mutations with a known worldwide prevalence of <30 patients. This number was carefully selected by estimating the fraction of 30 patients that might be available for treatment as, on average, being about 3. This means that a single Good Manufacturing Practice (GMP) manufacturing batch of ASO can be used to treat these patients for many years, facilitating free lifetime treatment. Moreover, today at least there is no path to commercial approval for ASOs for diseases of this prevalence, thus limiting options to pay for treatment.

An important attribute of ASO technology is the mechanistic versatility available. Toxic gain of function (TGOF) mutations are typically treated with ASOs designed to activate RNAse-H1 cleavage of the target RNA. In the event that a heterozygous TGOF mutation is present in an essential gene, one can design an allele-selective RNAse-H1 ASO. On the other hand, if the mutation causes inappropriate RNA splicing, an ASO can be designed to correct the splicing defect. Alternatively, ASOs can be designed to increase translation using several different mechanisms. ⁷

I suggest the term micro-rare for patient populations of 31–1,000 or so. Even at this prevalence, a path to commercialization exists, making a number of financing options possible. These include simply commercializing the ASOs and seeking appropriate pricing, supplementing commercial returns by selling priority vouchers and subscription models. Many of these approaches have been summarized in a previous commentary. ⁴

How Should ASO Safety be Optimized as We Treat Nano-Rare Patients?

Nano-rare patients suffer from severe, progressive, fatal genetic diseases and because of inefficient diagnostic procedures, such patients typically suffer from advanced diseases. Given the frailty of nano-rare patients and the very limited preclinical data on ASOs designed to treat nano-rare patients, it is absolutely essential to minimize the risk of drug-related adverse events by assuring the highest quality in each step in the process that leads to the ASOs to treat these patients.

The minimum experience in ASO technology required

Though superficially, after 35 years of basic research and advances in the technology, ASO technology may seem simple; ASOs are complex biologically active chemicals. As with drugs of other types, the difference between an optimal and sub-optimal ASO can be substantial. Variations in potency, target selectivity, cytotoxicity, innate immune activation, and other properties can greatly influence the clinical outcome. ⁷ To consistently design and discover safe and effective ASOs, meaningful experience with the technology is required. Academic scientists who have made no significant contributions to ASO technology and have limited drug discovery and development expertise should collaborate with organizations with expertise in the technology.

Multiple extramural expert reviews in the process are essential

Even if an organization has significant ASO expertise and experience, nano-rare patients require extremely challenging risk/benefit decisions. To facilitate and audit decision-making at n-Lorem, we have established several expert panels that include extramural members with appropriate skills and experiences to provide advice at critical steps in the process from application to treatment. All applications for treatment are reviewed thoroughly and presented formally to a panel of experts at the Access To Treatment Committee. When the n-Lorem team has identified an ASO that it considers to be appropriate for administration to a patient, all the data on the ASO and updated information on the phenotype of the patient are thoroughly reviewed by an expert panel, the Research Management Committee. The final treatment protocol including treatment goals and clinical measures to be assessed are reviewed by clinical experts who serve on the Study Treatment and Assessment Review committee. Of course, all INDs are reviewed by the FDA and institutional review boards. Additionally, a data safety monitoring board (DSMB), once again comprised of extra- and intramural experts, reviews all safety data quarterly. I believe that these extramural expert panels help assure the very best treatment possible for nano-rare patients.

The minimum path to consistent discovery of optimal ASOs

The process we employ at n-Lorem is the product of more than 30 years of ASO experience and data from millions of thoroughly studied ASOs. Though, as more is learned, the current process will doubtless be refined, each step and the number of ASOs studied at each step are considered the minima based on our experience. ⁵ For example, for an RNAse-H1, ASO experience has shown that a minimum of ∼500 ASOs should be screened, that the potential to activate innate immunity needs to be studied in either peripheral blood monocytes or B-lymphocyte derived cells (BJAB) cells. ⁵

Frequent monitoring of clinical treatment

As ASOs are still relatively novel, there is very little experience with nano-rare patients and even less experience with treating nano-rare patients with genetic medicines. We have established processes that support frequent interactions with investigators to answer any ASO technology questions and to assure proper data collection. Such interactions are particularly critical when changes to dose or schedule are contemplated and if there are changes in the phenotype of a patient or changes in concomitant medications. Individuals experienced in monitoring multi-site clinical trials are particularly suited for this task.

Our experience has demonstrated that a modified cross-over design clinical trial in which data are collected during the months required to discover and develop an ASO for a patient and those data are compared with the same measures on treatment is effective.^5,8 Moreover, as we have gained experience, we have developed more sophisticated approaches that support using patient- and caregiver-evaluated outcomes.^5,8

How is Health Equity to be Maintained?

This is simple: treat all patients who are appropriate for ASO therapy irrespective of financial means or the ability to raise money. At n-Lorem, there is no place on our application form for financial disclosure, and we only prioritize patients for more rapid treatment if they are rapidly progressing toward death or loss of an organ. Though it may be challenging to fund a broad effort such as at n-Lorem, I worry that well-intentioned efforts to treat patients who may have access to sufficient funds to discover and develop a personalized ASO may lead to the perception that only wealthy patients or families can be treated and this could lead to a significant backlash.

What Chemical Classes of ASOs are Considered Sufficiently Well Understood to be Subject to the Special Guidance for ASOs for Extremely Rare Patients?

Phosphorothioate 2′-methoxy-ethyl (PS 2′-MOE) ASOs represent the most thoroughly studied class of ASOs and databases incorporating all safety data from non-human primate through all controlled clinical trials have been published and are available to regulatory agency.^9–12 For targets expressed in hepatocytes, PS 2′-MOE ASOs conjugated with N-acetyl-galactosamine (GalNAc) have been thoroughly studied and, once again, a safety database has been published.

What Organs Should be Treated by What Routes of Administration?

Though after systemic administration, PS ASOs are broadly distributed to peripheral tissues, distribution follows blood flow and is uneven with the kidney and liver accumulating most ASO at low doses. At higher doses, the primary tissues saturated and PS ASOs accumulate in other tissues. ¹³ Moreover, the sub-organ pharmacokinetic/pharmacodynamic relationships for these organs are well understood. Consequently, PS 2′-MOE or PS 2′constrained ethyl (PS cEt) PS ASOs may be used for targets expressed in renal tissues. For hepatocyte targets, PS 2′-MOE GalNAc ASOs can be administered subcutaneously monthly. For CNS targets, PS MOE ASOs can be administered intrathecally quarterly. For retinal diseases, PS 2′-MOE or PS 2′-cEt ASOs can be administered intravitreally quarterly or every 6 months.^14,15

What are the Optimal Clinical Study Designs to Evaluate ASO Performance in Single Patients?

At n-Lorem, we have found that a modified cross-over design provides an excellent solution to evaluate ASO performance in single patients. As the duration of action of ASOs is quite long and nano-rare patients are too ill to be treated for any period of time with placebo agents, the standard cross-over design must be modified. We first develop treatment goals and the methods by which potential benefit will be monitored with the treating physician. We then collect detailed baseline data focused on the agreed treatment goals and clinical assessments during the 15–18 months required to prepare the ASO to administer to a patient. Then during treatment, the same clinical assessments are used to determine whether the ASO is resulting in clinically significant benefit.^5,6

How Can the Treatment of Nano-Rare Patients be Effective Today and Scaled to Meet the Need?

Fortunately, ASO technology has been scaled to treat millions, and ASO design and discovery are automated and benefit from artificial intelligence (AI). At n-Lorem, as mentioned we have filed INDs to treat >33 patients and have >100 ASO programs at varying stages of development. However, industrializing a process as complex as ASO discovery and development requires significant ASO and drug discovery experience, investment in automation, and the recruitment of experienced scientists, clinicians, and drug development professionals. Systems sufficient to assure appropriate monitoring of treatment and data collection are required and have been built to meet current and near-future demands. We have sufficient resources at n-Lorem to double the number of patients treated in 2025.

Should Data be Shared?

Absolutely! The dissemination of information about the nature of nano-rare patients, the phenotypes of afflicted patients, ASO technology, and the special guidance provided by the FDA is essential. Sharing what is learned in scientific manuscripts and lay presentations is also critical, particularly, as I believe what we learn from nano-rare patients will ramify across all diseases and change the way we think about health and disease altogether. It is also important to share the processes used to decide which patients are treated and detailed processes used to identify optimal ASOs be described. In my view, the appropriate approach to disseminating scientific information is in peer-reviewed scientific publications, presentations at scientific meetings, and in presentations geared to lay audiences.

It is vital to frequently share safety data, first with the DSMB, the FDA, and investigators, then with all interested audiences. In particular, any potentially drug-related SAE must be reported rapidly to all relevant audiences as well as to the FDA. Similarly, as data are developed sufficient to support evaluation for potential benefit, such data should be incorporated into individual case reports and published. Similarly, publications that describe the aggregate data should be published.

Should Data be Pooled?

Yes, under appropriate well-controlled circumstances. To pool data from different ASOs and analyze the data effectively, the provenance of each ASO must be thoroughly documented as there is a significant difference in the performance of ASOs depending on how thorough the preclinical evaluation is. Further, it is essential that detailed information on the patient phenotype prior to treatment and during treatment and the dose and the dose schedule for each ASO must be thoroughly presented. Only if minimum standards are met, should data for different ASOs be pooled.

How is ASO Treatment of Nano-Rare Patients to be Paid for?

As previously indicated, nano-rare patients present unique financing challenges, even when compared with slightly more prevalent disease I refer to as micro-rare disease. For micro-rare diseases, a variety of potential schemes to finance the discovery, development, and provision of ASOs have been proposed, ⁴ but at least today, none of those schemes can be applied to nano-rare. The challenge specific to nano-rare patients is that, at least today, there is no path to commercial approval and therefore no direct course to recoup investments and create sustainable cash flow.

Nevertheless, I am optimistic that the treatment of nano-rare patients can be afforded, and sustainable financing can be achieved using a modification of the approaches that therapeutic biotechnology companies have employed. After all, the only difference between n-Lorem and many commercial biotechnology companies is that n-Lorem is DELIBERATELY not profitable. Financing therapeutic biotechnology enterprises is effected in phases. During the proof-of-concept phase, the sellable assets are the vision and the leadership of the enterprise. Potential supporters during the proof-of-concept phase are early adopters. In n-Lorem’s case that included biotechnology companies, vendors to the oligonucleotide segment of the biotechnology industry, donors moved by the mission, and often those affected directly by nano-rare diseases. The value created during the proof-of-concept phase is the demonstration that the vision is achievable, at least on a small scale.

Once sufficient proof-of-concept has been achieved, the proof-of-value phase begins. In this phase, it is essential to demonstrate that value can be realized and the value of the vision shown repeatedly. In the case of n-Lorem, that meant demonstrating that nano-rare patients could be treated safely and that many could derive significant clinical benefits. Proof-of-value opens new sources of support. In our case, that included new larger individual donors, disease-focused patient advocacy funding authorities, state and federal grants, as well as continued support from earlier donors. In this phase, value to patients and families afflicted with nano-rare diseases has been repeatedly demonstrated and new sellable assets created.

n-Lorem has rapidly progressed through both proof-of-concept and proof-of-value phases. More than $50 million dollars in cash have been raised, and more than $200 million in in-kind support achieved. Importantly, a number of sellable assets that can potentially generate sustainable revenues have been created, and n-Lorem is entering the sustainable financing phase.

The most important sellable assets are a group of ASOs that have been clinically validated, shown to be safe and well tolerated, and evidence of a meaningful beneficial treatment effect obtained. These licensable ASOs arise from several sources. Most frequently, the prevalence of a mutation proves to be much larger than suggested by the literature, once effective treatment has been reported. On occasion, new data suggest that a non-allele-selective RNase H1 ASO can be used safely, meaning an entire patient population can be treated with a single ASO. Occasionally, a splicing mutation can affect many patients such that nano-rare splicing ASO can provide treatment for a population. In any case, such ASOs are attractive potential commercial assets because of the clinical data shown in one or a few patients. Licensing fees, milestones, and royalties can provide sustainable income.

Other sellable assets that are being developed include access to our unique and growing database that couples detailed genotypic data with detailed phenotypic data. This database provides a wealth of information validating therapeutic targets and pathways as well as therapeutic strategies. A third source of sustainable revenues derives from the multiple patents filed that protect novel inventions made in the pursuit of the treatment of our patients.

As n-Lorem has just entered the sustainable financing phase, we cannot claim success yet, but given the initial interest in some of our assets, we are encouraged.

Conclusions

Effectively and safely treating nano-rare patients on a scale requires that many questions be addressed. In this commentary, I have attempted to provide the key questions and the answers developed at n-Lorem and evidence that our solutions are working. Financing the industrialization of the treatment of nano-rare patients is indeed challenging. Nevertheless, the success of n-Lorem to date and initial interest in assets that may support sustainable financing are encouraging for the future while we do our best to deliver therapies in the present.