FDA to hold a meeting on ALS treatment they previously deemed ineffective.

Pressure from lobbyists and patient advocates may be pushing for expensive, ineffective drugs for the sake of having something, even if safety and efficacy data may be lacking.

It’s been a current mantra of mine to remind readers of the precautionary principle when it comes to the approval of certain drugs. As of now, many drugs are seeing a quicker path towards accelerated approval even if the evidence is lacking in regards to actual effectiveness.

One treatment I have covered often are Alzheimer’s immunotherapies, with Leqembi being the most recent one to gain full FDA approval even though there was limited evidence that it slows down cognitive decline, carries a risk of brain hemorrhages, and comes at a steep cost of nearly $30,000 annually. Despite all of these uncertainties, patient advocates and yearning from the public for any treatment for Alzheimer’s has led to Leqembi’s approval, leading to a lifelong dependency on a medication to which the long-term costs and benefits are unknown.

This is now the current paradigm in healthcare, in which a pharmaceutical giants weaponize the public’s want and need of a treatment in order to push for fast-tracked approvals of medications, especially if there are no current treatments available- a predicament more than likely spurred on by the accelerated approval of COVID vaccines and treatments.

We are also seeing this as well in the case of GLP-1 receptor agonist drugs such as Wegovy, Ozempic, and Mounjaro which are now being touted as weight-loss drugs, and as research investigates the possible use of these drugs for addiction we may see even further incentive for broader prescription labels for these medications, leading to even further medicalization of obesity and other diseases.

We may as well call Ozempic a "miracle drug"...

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This move is making it’s way into the realm of ALS. Also known as 'Lou Gehrig’s disease’, Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons where complications in the extremities in the form of weakness and wasting progresses towards the CNS and the brain. Most deaths related to ALS occurs due to respiratory failure.

Masrori, P., & Van Damme, P.¹ notes the following clinical manifestation:

The clinical presentation of ALS typically consists of adult onset focal muscle weakness and wasting, which has a tendency to spread with disease progression. The weakness most commonly starts in the limb muscles, more often in distal muscles than in proximal muscles. In about 25%–30% of cases there is a bulbar onset of the disease, presenting with dysarthria, dysphagia, dysphonia, or more rarely with masseter weakness. There is a high degree of variability in the age at onset, the site of onset and the disease progression rate of ALS. The disease is relentlessly progressive in most patients, with a median survival of about 3 years after symptom onset, where death is mostly attributed to respiratory failure. About 50% of patients will suffer from extra‐motor manifestations to some degree in addition to their motor problems. In 10%–15% of cases, an additional diagnosis of frontotemporal dementia (FTD) can be made [4], whilst 35%–40% of patients will have mild behavioural and/or cognitive changes. FTD is characterized by the degeneration of frontal and anterior temporal lobes and presents clinically by behavioural changes, impairment of executive functioning and/or language impairment [5]. ALS and FTD are now considered to be two ends of a spectrum due to the overlap in molecular mechanisms underlying both neurodegenerative disorders [6].

The cause of ALS is multifaceted, with most forms being of unknown etiology (Brotman, et al.²):

Although many potential mechanisms have been proposed, a precise, single etiology of sporadic amyotrophic lateral sclerosis is yet unproven. These mechanisms include altered RNA processing leading to prion-like self-aggregation, superoxide dismutase type 1 SOD1 mutations leading to free radical toxicity, cascading inflammatory responses, and excessive concentrations of glutamate, among others.[1][2] The rarer entity of familial ALS has numerous genetic mechanisms, most frequently repeat expansion of the C9ORF72 gene and various mutations of the SOD1 gene.[3] Mutated SOD1 protein misfolds and forms aggregates, leading to cellular injury and eventually apoptosis. Both genetic aberrations are inherited in a mainly autosomal dominant pattern.[4] Ultimately, rather than a single unifying cause, ALS is an etiologically diverse clinical entity, which is the result of a multitude of separate potential preceding aberrations.[5]

As of now there has been no cure for ALS, with many available treatments reducing the symptoms or slowing down the progression of the disease.

However, within the past year two treatments have received fast-tracked approval, along with controversies surrounding their efficacy.

One treatment from Biogen called Tofersen received approval in April.

The drug is an oligonucleotide that targets mRNA which transcribes the superoxide dismutase 1 enzyme. It’s been suggested that some ALS patients carry certain mutations relating to SOD1, leading to a toxic gain-of-function in these patients. Thus, the use of an oligonucleotide such as Torfersen is intended to bind to mRNA encoding SOD1 and prevent its production.

Torfersen saw accelerated approval, although evidence seemed to be lacking as reported by The Associated Press:

Biogen’s 100-person study failed to show that the drug significantly slowed the disease compared with a dummy treatment. Patients were tracked for more than six months using a scale that measures the decline of basic movements, including writing, walking and climbing stairs.

But those who received tofersen showed significant changes in levels of the toxic protein and a second neurological chemical that is considered a key indicator of the disease’s progression.

Bear in mind that Biogen is the same company that brought us Leqembi and Adulhelm along with a partnership with Japanese company Eisai.

ALS patient advocates applauded this approval even though the annual cost of this treatment is likely to be above $150,000, and clinical data appeared to be lacking.

In September 2022 another drug from Amylyx Pharmaceuticals called Relyvrio received accelerated approval based on a small study which appeared to show some benefit in patients who used this treatment, again as reported by The Associated Press:

The Food and Drug Administration approved the drug from Amylyx Pharmaceuticals based on results from one small, mid-stage study in which patients with the debilitating disease appeared to progress more slowly and survive several months longer. Typically, the FDA requires two large studies or one study with “very persuasive” survival results for approval.

Unlike Tofersen, Relyvrio is a combination of two different treatments already in use called Sodium Phenylbutyrate and Taurursodiol. The combination is intended to provide an anti-apoptotic effect on neurons by reducing ER stress and ameliorating mitochondrial apoptotic processes. Supposedly, some ALS patients may already take these medications in combination to treat their ALS, and so this combination isn’t exactly groundbreaking in its application.

Again, the evidence here was controversial, with the FDA panel originally voting against approval. However, pressure from advocates, patients, and politicians led to another review and eventual backing of the drug (The Associated Press):

The latest approval followed a remarkably turbulent path, including two negative reviews by the FDA’s internal scientists, who called the company’s results “borderline” and “not persuasive.” A panel of outside advisers backed that negative opinion in March, narrowly voting against the drug.

But the FDA has faced intense pressure from ALS patients, advocates and members of Congress. In recent weeks the agency received more than 1,300 written comments from the ALS community supporting the treatment.

That outpouring helped sway the same expert panel when FDA reconvened them earlier this month to revisit Amylyx’s drug. The second time around, they backed the drug, 7-2. The vote was not binding, but it seemed to open the door for FDA approval.

Several panelists said they were also reassured by an extraordinary exchange at the meeting in which FDA’s Dr. Dunn requested — and Amylyx affirmed — that the company would voluntarily pull its drug from the market if a large, ongoing study doesn’t confirm its benefit.

Again, a drug argued to not be compellingly effective saw accelerated approval with pressure from the public. In this case, the cost of Relyvrio is also argued to be expensive as well. The drug saw approval in Canada with a proposed price of around $165,000.

Prior to these approvals only two treatments were available, and so to see a sudden accelerated approval of medications should raise serious concerns with respect to the actual evidence to support such approvals.

This brings us to the current predicament, in which the FDA will hold a meeting this week to review a prior ALS treatment they argued to lack evidence.

In this case, the treatment called NurOwn produced by company Brainstorm is a stem cell treatment utilizing mesenchymal stem cells derived from bone marrow of patients (i.e. personalized stem cells). The argument is that use of these stem cells, which are induced to produce neurotrophic factors, may help to alleviate neuron death.

This may sound fascinating for those interested in all things stem cell related, although it doesn’t appear that Brainstorm was able to meet the goals of their clinical trials, with the evidence the company provided to the FDA appearing to lack some key pieces of information.

All of this is reported in a document released from the FDA ahead of the Wednesday meeting, with the document stating the following [context added]:

On initial receipt of the BLA [Biologics License Application], FDA determined that the submission was scientifically incomplete to demonstrate substantial evidence of effectiveness, and that the manufacturing information was grossly deficient to ensure adequate product quality. Examples of critical information not provided in the BLA submission include missing or inadequate control of materials, validation of methods missing or incomplete, lack of data demonstrating manufacturing consistency, control strategy for prefilled syringe not provided, inadequate manufacturing and testing facility information, and facilities not ready for inspection.

FDA therefore refused to file the submission and detailed these deficiencies in a Refuse to File (RTF) letter to the Applicant. The Applicant elected to request that the BLA to be filed over protest, and subsequently provided further retrospective analyses and biomarker results.

FDA recognizes the urgent unmet need for additional effective treatments for ALS. At the same time, the critical statutory requirements for approval of drugs and biologics include substantial evidence of effectiveness and evidence of safety, and demonstration of adequate product quality. 1 Although the agency has potential issues with the quality and safety of this product, at this advisory committee meeting FDA is seeking to obtain input from the committee as to whether the available data can be considered to constitute substantial evidence of effectiveness to support regulatory approval of MSCNTF for treatment of ALS.

The last paragraph is what’s interesting. The FDA is admitting that Brainstorm has not provided sufficient evidence to argue for approval for NurOwn, and yet is likely kowtowing to public pressure to reevaluate their stance.

This is remarked in an article, again from The Associated Press published today, noting that a 30,000 petition served as the reason for Wednesday’s meeting:

At Wednesday’s meeting, federal advisers will hear from FDA scientists, company researchers and patients before taking a non-binding vote on NurOwn's effectiveness. FDA will make the final decision on the therapy later this year.

The meeting was scheduled after ALS advocates delivered a 30,000-signature petition seeking a public vetting of the treatment.

Brian Wallach, co-founder of the advocacy group I AM ALS, says even if NurOwn only provides a small benefit for some patients, it should be made available. A former Obama White House staffer, Wallach was diagnosed with ALS in 2017.

I haven’t looked through the prior approvals, as well as this stem cell treatment in greater detail so I can’t provide any more details on whether these drugs are safe and effective.

Regardless, the current situation just provides even more evidence that we are no longer in an era in which robust clinical data is needed in order to get a drug approved. So long as the public yearns for a treatment, the FDA and other regulatory bodies are willing to forego evidence if having any treatment is deemed better than having no treatment.

We all want treatment for these debilitating diseases, but our want of a treatment shouldn’t be weaponized to force approval of things to which we have no long-term, or even short-term efficacy data.

We’ll see what comes of NurOwn, but if the current track record of the FDA is anything to consider then it’s likely that NurOwn may end up seeing approval.

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1. Masrori, P., & Van Damme, P. (2020). Amyotrophic lateral sclerosis: a clinical review. European journal of neurology, 27(10), 1918–1929. https://doi.org/10.1111/ene.14393

2. Brotman RG, Moreno-Escobar MC, Joseph J, et al. Amyotrophic Lateral Sclerosis. [Updated 2023 Jun 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556151/