White Paper Issue 18: Bringing Patients to Treatments

Updated: May 30

Patient frustration with the lack of ALS treatment options and the progression of compounds through the drug delivery pipeline is evident when talking with ALS patients and reading their comments posted on ALS forums. Clinicians we speak to have the same mindset, more promising drugs need to be available for their patients.


There are issues that delay commercialization of drugs:

  • Regulatory pathways are slow and regimented, often taking 8 years, but necessary to prove safety and efficacy;

  • drug development is expensive. Most novel ideas die in what’s called the pre-clinical “valley of death”;

  • companies have an obligation to know, or have a reasonable expectation based on animal models, that the drug will be beneficial and safe, but lack the ability to identify the patient population that could benefit from the therapy. A model predicting utility in a person doesn’t yet exist;

  • drug companies can’t risk adverse events after millions of dollars of investment by treating an inappropriate group of patients limiting access outside controlled clinical trials.

It will take some imaginative thinking to get potential therapies into the hands of ALS patients. This paper explores some patient options for access to drugs and NDR’s thoughts on the issues.

Here are some of our proposed possibilities:

  • Develop and validate in vitro bioassays that target ALS-related disease mechanisms;

  • shorten the pathway to patients using physician directed precision medicine* to identify patients that could benefit from therapy;

  • use Expanded Access of appropriate therapies based on precision medicine;

  • use the data from Expanded Access and an Orphan Drug Designation to make drug development attractive to entities for commercial development;

  • facilitate multiple therapies by stacking treatments in individual patients.

*precision medicine is identification or optimization of a therapy for a particular group of patients by using genetic or molecular profiling.


Licensed drugs may fall into a “new indication” for treatment of ALS. Off-label use is available to clinicians to use these drugs to treat ALS patients. However, one would want a safety study in ALS patients. No one wants to use a drug that could accelerate disease. A second group of drugs that may be investigated for ALS therapies are those with an existing investigational new drug (IND) application. These drugs have compiled pre-clinical data and are far along in the pipeline with considerable time and financial investments by a company.


Expanded Access (or Compassionate Use) is an available option to get unapproved drugs into the hands of a seriously ill patient when no other treatments are available. Drugs considered for Expanded Access are investigational drugs that are being tested in clinical trials but haven’t been approved by FDA.


The program for a single patient, expanded access request results in permission from FDA to receive an unapproved investigational drug from the manufacturer. The manufacturer must be willing to provide the investigational drug for expanded access. The short form to apply for this use is easily available on line and the content is what you would expect from the government. However, this avenue is limited to drugs with the safety and efficacy clinical trials required for an IND.


There is a difference between Expanded Access and Right to Try, FDA permission for use is not required for the Right-to-Try a drug. As explained above, the Expanded Access is for drugs that are still under clinical investigation, meaning they have to be under clinical investigation. The Right to Try is for patients that can’t enroll in clinical trials for products that have completed an FDA-approved Phase 1 clinical trial, is in a clinical trial, or is in ongoing development, not placed on clinical hold or discontinued by the manufacturer. The take home message is that the drug must be far enough along in the development process to be in a clinical trial or completed Phase 1 clinical trials for a patient to request Right to Try.


The FDA has several caveats for Expanded Access for a drug. The drug needs to have an active IND and the condition must have no alternative therapies, patient enrollment into a trial is not possible, the potential patient benefit justifies the potential risks of treatment, and the big one: providing the investigational medication will not interfere with investigational trials that could support a medical products development or marketing approval for the treatment indication. Perhaps the interfering with enrollment into trials is the biggest hurdle. Are there enough patients to enroll into a safety/effectiveness trial? ALS is a rare disease and the availability of patients to enroll in trials is an issue.


The FDA approved the IND application for the Healey ALS platform trial. This platform is an innovative way to have multiple patients enroll in drug trials at the same time. The first drugs tested on the platform were Zilucoplan, verdiperstat, and nanocrystalline gold. The platform takes place in 54 sites in the Northeast ALS Consortium (NEALS) in conjunction with the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital in Boston. The Healey group decide which new drugs, with IND’s, can go onto the platform. The difficulty in getting a drug onto the Healey Platform is the number of patients available for enrollment into the studies. The Healey web site is quite informative with webinars and updates.


The conundrum for getting drugs to patients early is that a Phase 1 clinical trial must be underway (Extended Access) or completed (Right to try) for a patient to lobby for an unapproved drug.


Possibly precision medicine will be the salvation for an ALS patient’s predicament. Say, for example one developed an in vitro assay to detect an ALS-associated pathway in a patient. If that pathway was diagnosed and the proposed drug rescued the pathway in the individual’s in vitro assay, it is possible that the drug could be used on a patient-by-patient bases for getting the designation as an Orphan Drug.


The FDA Office of Orphan Products Development (OOPD) mission is to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. In fulfilling that task, OOPD evaluates scientific and clinical data submissions from sponsors to identify and designate products as promising for rare diseases and to further advance scientific development of such promising medical products.


The program was initiated in 1983 to promote drug development for rare diseases. A rare disease is a condition that affects less than two hundred thousand people a year. Big pharmaceutical companies are less likely to develop drugs for rare diseases. However, individuals or small companies may have the interest to develop a drug while the expense can be overwhelming.


It is important to note that an orphan drug designation (ODD) and New Drug Applications (NDA) have actions that are pertinent and different. The product can be designated as an Orphan Drug if it prevents, treats, or diagnoses a rare disease. The designation can be obtained in the pre-clinical stage or later development but is requested before the NDA request. A drug in the IND phase of licensing can be designated while the drug with an NDA can not.


There are incentives for sponsors to develop products for rare diseases. There are tax credits, assistance with trial costs, a waiver of marketing application fees and a seven year exclusivity against competitive products.


The components of the application include the identification of the sponsor and the name of the proposed drug. The checklist includes providing the background of the rare disease or condition, why the particular treatment is needed, a description of drug, and the scientific rationale for its use. If the same drug is already approved for the same rare disease, with or without exclusivity, the designation would be inappropriate. In this case, an explanation why the proposed drug is clinically superior is necessary. This Orphan Drug information is useful to the ALS patient because the information is public.


A particularly confusing part of the application is determining if the rare disease is a subset of a common disease, and how would a property of the proposed drug limit its use to a subset of the population afflicted with the disease. FDA explains that in a more common disease, if a disease related subset benefits from the therapy, then the designation may be obtained. Again, useful information from the application for an ALS patient if the drug is an existing therapy. The patient may go after Right to Try.


So far, checking off boxes on the ODD list, there is no denial that amyotrophic lateral sclerosis, ALS, is rare and treatments are sorely needed. Due to the nature of ALS, subsets of clinical presentations have been confounding factors in understanding this complex disease. The diagnosis of ALS is given to patients that share pathologies found in a group of neurodegenerative diseases. That means the ALS population is a heterogeneous population that could be stratified into subsets. Less than 10% of ALS cases are considered inherited with a familial genetic cause underlying the disease.

Non-familial ALS, called sporadic ALS (sALS), comprises the majority of the cases. The cause of sALS are unknown, yet all ALS cases are considered genetic and sALS patients present without a clear family history.


There is little doubt that identifying biomarkers to stratify ALS patients to a disease phenotype would positively impact the ability to treat subsets of ALS patients and for patients to understand why some therapies are individually appropriate and some are not. Patients need therapies, but they need the right therapies. For the majority of ALS patients the right therapy is unknown.


A gold standard argument for subsets in ALS is the positive effect of lithium carbonate to enhance the survival of ALS patients carrying the UNC13A mutation. The drug was not effective in the general ALS population in a clinical effectiveness trial. The efficacy of lithium carbonate was hidden in clinical studies until the association with UNC13A mutation-carrying subset of ALS patients responsive to treatment was made. The biomarker for this subset of ALS patients is revealed in genotyping. Genotyping is important in other treatment-specific patient classifications, clearly, only SOD1-ALS patients would be expected to benefit from SOD1 antisense oligonucleotide therapy.


The identification of more insidious biomarkers to identify disease etiologies in sALS patients may require using precision medicine in an in vitro approach. It is NDR’s opinion that it isn’t a shortage of therapies but perhaps a shortage of biomarkers to identify drugable targets in an individual ALS patient.


The literature shows ALS-associated phenotypes such as dysregulated lipid metabolism or pathologic states of increased extracellular ATP that act as cytotoxic factors or pro-inflammatory mediators in neurodegenerative diseases, but these pathways aren’t the etiology in all neuroinflammation, in all ALS patients. For example, pro-inflammatory mediators acting through P2X(7) receptors in astrocyte-mediated motor neuron death are observed in animal models of ALS in a gender-specific mechanism, thus in P2X(7)-ALS, gender must be a factor when stratifying this and possibly other ALS etiologies. No one knows if this is true in people, as it is in mice.


Most neurodegenerative diseases are associated with the accumulation of specific misfolded proteins in different areas of the nervous system. Misfolded proteins are facilitated by other common features of neurodegenerative pathology including poor energy homeostasis and mitochondrial dysfunction. Dysregulated purine metabolism and mitochondrial dysfunction are associated with protein misfolding diseases. Some adenosine receptors are dynamically regulated in murine models of ALS, however, treatments targeting these receptors produce inconsistent model-dependent effects. Despite inconsistent model effects, is hard to argue against purinergic signaling as a common pathology in neurodegenerative disease and in maintaining homeostasis.


It is apparent from the literature that targeting adenosine receptors can be neuroprotective and neurodegenerative. Treating neuroinflammatory disease by regulating adenosine homeostasis is interesting because adenosine is recognized as an endogenous potent anti-inflammatory agent.

Can we convince FDA office of ODD that there is a scientific rationale demonstrating promise for treating some ALS patients to restore purinergic signaling? ALS is a rare disease. How common is purinergic signaling dysregulated in ALS? It may be a common ALS pathology.


The bar for scientific rational is that the proposed orphan drug treatment holds promise in human trials, an animal model specific for the disease, or in vitro pre-clinical data. Uncontrolled trials with efficacy in patients with no response to other available treatments can be submitted as supporting evidence. Is Expanded Access a possible avenue to get data to support the ODD? It’s almost a Catch 22.


The pathogenesis of ALS consists of two stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system, through glial and T cell activities, provides anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a rapidly succeeding neurotoxic phase develops. A well-orchestrated purine-mediated dialog among motor neurons, surrounding glia and immune cells control the beneficial and detrimental activities occurring in the nervous system. Given the complex cellular cross-talk occurring in ALS and the recognized function of extracellular nucleotides and adenosine in neuroglia communication, restoring purinome dynamics might provide efficient treatment to slow the progression of disease. Or nudge the disease into a more treatable dynamic.


A well-known regulator of purinome dynamics is thymopentin, the active pentapeptide of the homeostatic hormone thymopoietin. As people age, thymopoietin decreases; the half-life of exogenous thymopentin is very short, limiting its use as a therapy. NDR proposes to decrease inflammation and rescue cells with dysregulated energy metabolism, both conditions found in some ALS patients, with a novel therapy. The ability of a patients cells to respond to the therapy are testable before and after treatment, hopefully with a blood test.


We expect our therapy to regulate multiple pathways and restore homeostasis in disease with few side effects. Our goal is to get enough target engagement in the dysregulated pathways and leave the normal pathways untouched.


Normally, the development timeline of our treatment to ALS patients would be 8 to 10 years. However, if precision medicine can predict a possible benefit for a patient, or identify 10 patients, and the drug was available under Expanded Access, from a pharmacy that had access from a manufacturer, perhaps safety data could be collected. This is bringing patients to treatments. The benefit of the ODD program is to entice a commercial entity to take the drug forward to more patients after initial safety and effectiveness is shown.


There is a brand new program, CDER ARC, launched in May of 2022. The CDER’s vision is speeding and increasing the development of effective and safe treatment options addressing the unmet needs of patients with rare diseases. We are checking it out, especially their Rare Disease Cures Accelerator.



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