FDA Returns Disappointing News for ALS Stem Cell Therapy

Last week DNA Science covered a setback in a clinical trial of a gene therapy for Duchenne muscular dystrophy (DMD). Also recently, FDA’s Cellular, Tissue, and Gene Therapies Advisory Committe turned down a stem cell treatment for amyotrophic lateral sclerosis, aka ALS, Lou Gehrig’s disease, or motor neuron disease.

The two conditions and the therapeutic approaches differ, but their clinical trials illustrate the importance of selecting patients whose characteristics suggest that they are the most likely to respond.

DMD affects 1 in 3,500 male births, compared to approximately 1 in 400 people who develop ALS during their lifetime.

DMD Recap

In DMD, a mutation on the X chromosome partially or entirely deletes the gene that encodes the protein dystrophin. Both the gene and the protein are gigantic, and critical. The protein dystrophin, although scant, tethers the actin and myosin protein filaments that make up the bulk of skeletal muscle, a little like twine tying up fireplace logs.

The muscle weakness of DMD typically begins in young boyhood, with a wheelchair needed by school age or sooner. Because all cases of DMD are due to mutation in a single gene, adding functional genes – a gene therapy approach – makes sense. It aims to correct the faulty instructions at the DNA level, straightforward, at least conceptually, because mutations are deletions, of part or all of the gene. That’s not the case for ALS.

The Course of ALS

ALS affects motor neurons in the central nervous system (brain and spinal cord) that stimulate skeletal muscles to contract. Symptoms creep up gradually. A teacher I visited for nearly two years as a hospice volunteer first noticed inability to hold a piece of chalk or a pen. A musician couldn’t control his fingers and would trip often as his lower leg muscles weakened. An athlete could no longer run without tripping. Other early symptoms include muscle cramps and twitching, and difficulty speaking or swallowing.

Symptoms progress, as paralysis sets in, but thinking, reasoning, and memory are spared. The person remains aware – my hospice patient dictated two memoirs, the exercise distracting him from what he knew lay ahead. ALS also spares the senses. Which body parts are affected, and how rapidly function wanes, differs greatly.

Most people diagnosed with ALS – after eliminating other possibilities – live up to 5 years after the first symptoms arose, which may have been dismissed as simple clumsiness. Ten percent live 10 years or more, yet many others succumb within a year or two. The great variability is one challenge in treating the condition.

ALS is a disease of adulthood, beginning typically between 40 and 70 years of age. It affects more biological males than females among patients under age 65, but after age 70, ALS affects them at the same rate.

Diagnosis of ALS is one of exclusion, a frightening conclusion after ruling out other explanations for the gradual loss of motor functions – from the feet up, or the head down. Testing reveals the damage to upper or lower motor neurons, as symptoms spread. The journey ends when swallowing and breathing cease.

The Complex Causes of ALS

In contrast to DMD, mutations lie behind only about 10 percent of ALS cases; these are termed familial. Thirty or so mutations that cause ALS pepper 19 of the 24 types of human chromosomes – so there are several ways to inherit it. Most people with familial ALS have mutations in any of four genes (C9orf72, SOD1, TARDBP, or FUS). ALS, therefore, is an extremely heterogeneous disease, with several genetic malfunctions leading to the same phenotype – as well as the majority of cases that aren’t genetic.

Whether a health condition is genetic or not has practical consequences. Being genetic means that an individual’s risk of inheriting the family condition is predictable.

Most ALS cases are sporadic. The disease may develop in response to an environmental factor, such as repeated head injuries. One widely-quoted study that investigated nearly 20,000 professional football players who had participated in at least one game between 1960 and 2019 revealed a four-fold elevated risk of developing ALS compared to the general population. Individuals who served in active duty in the military are also at higher risk. Other explanations include oxidative stress, glutamate toxicity, mitochondrial dysfunction, an overactive immune system, and exposure to certain toxins.

However, the clinical course of ALS is the same, whether the cause is familial or not. The pace though varies quite a lot.

Can a Patient’s Stem Cells Help?

The only treatment for ALS is a drug, Riluzole, taken as a tablet or a film. Considered a “neuroprotective” agent, Riluzole blocks the excitatory neurotransmitter glutamate from crossing synapses, possibly slowing the disease course, particularly after a long time. But extending survival after years of living with ALS is perhaps not the outcome that all patients would seek. Stem cells, theoretically at least, may offer another approach.

Mesenchymal stem (aka stromal) cells (MSCs) offer a tantalizing combination of characteristics for treating several diseases. They can divide and differentiate as any of a number of cell types, and secrete neurotrophic factors, which are biochemicals that promote survival and growth of neurons.

Might MSCs introduced into a patient’s spinal fluid somehow “know” to divide and develop into the needed motor neurons? Or secrete neurotrophic factors right where they’re needed? If MSCs come from the patient (autologous), then an immune response shouldn’t be a hindrance.

That’s the thinking behind Brainstorm Cell Therapeutics’ randomized double-blind, placebo-controlled clinical trial of NurOwn cells, which are MSCs that secrete neurotrophic factors. Remove MSCs from a person with ALS, stimulate them to release the correct brew of neurotrophic factors, then return the doctored cells into the patients spinal fluid, where they should bathe neurons and their supportive glial cells with the nurturing factors. 

Patients were randomized to receive their own treated cells or their own untreated cells as a control, with three bimonthly infusions into the spinal cord. Participants had a clinical ALS diagnosis – they were not stratified by familial versus sporadic, and not by specific mutation. So the experimental group may have been somewhat heterogeneous. Being a geneticist, I’d prefer a clinical trial design in which the participants are as similar as possible.

The investigators assessed outcomes using the ALS functional rating scale as well as analysis of biomarkers in blood serum and cerebrospinal fluid. The biomarker analysis can identify and quantify neurotrophic factors and detect rising levels of inflammatory indicators, such as cytokines. ‘

Back to the Drawing Board After FDA Thumbs Down

Results from the 263 participants were submitted to FDA three years ago, with the last update at ClinicalTrials.gov two years ago. But it took until this September 27, 2023, for FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee to finally vote.

Seventeen of the nineteen members concluded that NurOwn cells had not been shown to be effective, while one voted for them and another abstained. FDA’s own scientists a week earlier had responded similarly, calling Brainstorm’s application “scientifically incomplete” and “grossly deficient,” according to several news sources.

However all is not lost. Continuing biomarker analysis and following the patients may reveal that a subgroup of them does respond, even if it is only in delaying one particular stage of the disease. And so the company is reevaluating data considering only patients with mild to moderate ALS. I wonder what stratification by mutation might reveal.

The ALS Association responded to news of FDA’s ruling:

“We are grateful to everyone who shared their perspectives on NurOwn with the FDA and we thank all the people living with ALS who participated in the NurOwn trials and expanded access program. We call on BrainStorm to immediately unblind the participants in its Phase 3 trial, which concluded over three years ago, so that participants and their family members can know if they were on NurOwn or placebo.”

The ALS Association had previously stated “Our Position on NurOwn”:

“After BrainStorm shared that its Phase 3 trial of NurOwn did not meet its primary or secondary endpoints, we have consistently requested access to the full data package so we could try to better understand its effect on people living with ALS. The amazing testimonials we have seen online do not align with the data that BrainStorm has shared with us or has been published in peer-reviewed publications.

We have an obligation to the community we serve to be vigilant and data-driven, and our approach has served the ALS community well in recent FDA reviews. Until we have the opportunity to conduct an independent review, we cannot take a position for or against approval of NurOwn.”

Eclectic Applications of MSCs

The idea to deploy mesenchymal stem cells to treat a variety of conditions was first described in a 1991 publication. The versatility of the cells to divide and give rise to a variety of “daughter” cell types immediately suggests diverse clinical applications. Clinicaltrials.gov currently lists 1,500+, for everything from cancers to liposuction to knee pain, diabetes, radiation lung injury, rotator cuff repair, diabetic foot ulcers and retinitis pigmentosa. Nor is the BrainStorm trial the only one to deploy MSCs to tackle ALS. An investigation in Israel study used four infusions of the cells, three months apart, and another, from Iran, grew MSCs from fat samples from 19 patients with sporadic ALS. This review from a team in Iran discusses use of MSCs in treating ALS, which has been ongoing for “many years.”

But the ability of MSCs to do so much makes me uneasy, especially compared to the exquisite specificity of a molecular genetic intervention that actually alters instructions, rather than introducing a multifunctional cellular patch of sorts.

Using stem cells makes sense if they secrete something that compensates for a biochemical that a patient’s body can’t produce, or replaces destroyed cells. Perhaps not all people with ALS have the same disease, even though they share symptoms and outcome. For some conditions, stratifying patients by mutation might provide clinical meaningful granularity. Preclinical studies in mouse models of ALS are critical, such as this SOD1 mouse.

But even when patients are matched to interventions considering genotype, such as in the less-than-efficacious gene therapy for DMD, the sheer complexity of a human body, with its trillions upon trillions of cells, can present a daunting challenge.