SODIUM PHENYLBUTYRATE-TAURUSODIOL TRIAL SHOWS BENEFIT IN ALS
The Centaur phase II/III trial funded by Amylyx Pharmaceuticals and others showed that the oral drug combination of sodium phenylbutyrate and the supplement taurusodiol (TUDCA) slowed functional decline in patients with ALS compared to placebo. The difference was around 30% over 6 months. (Paganoni S et al. N Engl J Med 2020;383:919-930.) Following an extension phase, it was found that participants who received the study drug lived a median of 6.5 months longer over 3 years. (https://news.harvard.edu/gazette/story/2020/10/new-drug-prolongs-als-patient-survival-in-trial/).
Presumably, this study is under FDA review.
Clinical Research in our Center
Studies to Advance Understanding of ALS with the goal of developing better treatment: Genetics, other biomarkers, and tissue banking
Patients can undergo a single blood draw to bank DNA and assess for the most common ALS mutation and for discovery of new mutations that cause ALS (in collaboration with Mayo Jacksonville)
Making Stem Cells from Skin
In a select number of patients, skin biopsies are taken to induce formation of stem cells (IPS), and these cells are made into motor neurons by Drs. Donnelly or Carlisle in the Live Like Lou Center for ALS Research. The cell lines can be studied for disease features and potentially future drug screening
Most Recent Drug Approval
On 5/5/17, the U.S. Food and Drug Administration approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS).(www.fda.gov)
Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent monthly treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free. The infusions take 60 minutes
The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined about 1/3 less on a clinical assessment of daily functioning compared to those receiving a placebo. There was no change in breathing function in the treatment or placebo group. Follow-up data that did not include a placebo control, suggest the slowing of functional loss may extend to 12 months.
The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising and gait disturbance. Patients in the study received daily venous punctures for the infusions.
Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.
Patients in the study had:
- ALS for 2 years or less with independent living status
- At least 2 affected body regions (arm, leg, bulbar or trunk)
- Normal breathing (FVC > 80%) at time of entry
- Progressive Disease (usually at least moderately progressive)
- ALSFRS-R score > 2 on each sub-item
- ALSFRS-R < 3 on any breathing sub-item, spinal surgery after onset
The ALSFRS-R is a functional rating scale that measures bulbar function (speech, salivation, and swallowing), fine motor function (handwriting, cutting food/handling utensils, and dressing and hygiene), gross motor function (walking, climbing stairs, and turning in bed), and breathing (shortness of breath, breathing when lying flat, and use of BiPAP). There are 3 items per section graded 0-4 with 4 being normal. The maximum score is 48.
Details about the Results of the Study
Edaravone use was associated with a slower decline in the ALSFRS-R
- Edaravone group declined 2.49 points less than placebo (-5.01 vs -7.50) over 6 months
- Of note, clinicians and researchers previously surveyed rated a 20-25% change in slope “somewhat clinically meaningful” (≥ 4 on a 1-7 scale of effect), and this benefit was about 30%.
- Study patients averaged a relatively rapid rate of decline
- 1.35 points/month for placebo group (usual is about 0.6 points/month in the first yr and 0.34 points/month in the second year)
- 0.90 points/month for edaravone group
A previous study in which patients had disease for up to 3 years showed no significant benefit.
The drug became available in August 2017.
The majority of our patients receive the drug via a port (indwelling catheter) which carries a low but real risk of blood clots and bloodstream infection. Most get infusions at home, while a few go to an infusion center.
There is no data on how long patients should be treated, but insurers are generally approving it for 6 months and then require re-approval. The drug is only approved for ALS and not PLS or other neurologic conditions. The cost of the drug is about $145,000 per year. The drug company has a program to assist financially for commercial insurance but not Medicare or Medicaid.
Commercial insurers typically only cover treatment if patients meet the criteria used in the successful study. Medicare has approved it for all ALS patients, but there is no evidence that it would help patients with more advanced ALS.
Example of Authorization Criteria:
- Must be prescribed by a neurologist
- Must have a diagnosis of definite or probable amyotrophic lateral sclerosis (ALS)
- Must have disease duration of less than 2 years
- Must have a forced vital capacity (FVC) ≥ 80%. Chart documentation of FVC is required
- Must not have a tracheostomy, artificial respirator with intubation or receive tube feedings
If the above criteria are met, edaravone (Radicava) is approved for 6 months.
Aetna Policy http://www.aetna.com/cpb/medical/data/900_999/0918.html (PRECERTIFICATION REQUIRED*)
An oral form of edaravone is being developed. We will participate in a clinical trial examining the safety of the oral form.
Live Like Lou Center for ALS Research at the University of Pittsburgh Brain Institute. The Live-Like-Lou Center for ALS Research was created in February, 2015 following a $2.5 million dollar pledge by LiveLikeLou.org via the Pittsburgh Foundation. Live Like Lou was founded by Neil and Suzanne Alexander. The University of Pittsburgh matched the contribution as part of an effort to raise $10 million dollars for this new research center. The former University of Pittsburgh Center for ALS Research has been folded into the Live Like Lou Center for ALS Research, and the MDA/ALS Center is a clinical arm of this extensive research effort.
In particular, we work closely with Christopher Donnelly, PhD whose laboratory https://www.isb.pitt.edu/people/faculty/christopher-donnelly-phd is focused on RNA metabolism, protein trafficking in motor neurons, and abnormal protein collections in ALS.
New Gene Discoveries. Mutations in at least 33 genes are known to cause ALS. The most important remains the one due to a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on chromosome 9p. This mutation is associated with up to 40% of cases of familial ALS (fALS). In some families, children developed onset of symptoms 7 years earlier than their parents. Either frontotemporal dementia (FTD) or motor neuron disease (MND) occurs in affected families. Some patients had psychosis with prominent delusions and hallucinations. It is still not certain as to how the C9ORF72 mutation causes motor neuron degeneration. There have been numerous reports of this gene and its presence in various populations. In the US, it is seen in about 10% of patients with "sporadic" ALS.
C9ORF72 and SOD1 mutations account for about half of all cases of familial ALS.
The genetic causes of ALS are shown in the table below:
|ALS Type||Chromosome Location||Gene||% of familial ALS|
|ALS 2 (AR) juvenile||2q33.1||Alsin|
|ALS 4 juvenile||9q||SETX||Rare (motor neuropathy +)|
|ALS 5 (AR)||15q15.1-q21.1||SPG11||Rare|
|ALS 12 (AR)||10p||OPTN||Rare|
|ALS 15 (X)||Xp11.21||UBQLN2||Rare|
|ALS 20||12q13.1||HNRNPA 1||Rare|
See http://alsod.iop.kcl.ac.uk/ for details.
There are other mutation in the genes NEK1, C21ORF72, TBK1, and SCFD that appear to cause or increase the risk of getting ALS. (N Engl J Med 2017;377:162-172). Last, we were part of a team that discovered a mutation in TIA1 as a cause of ALS. (Neuron. 2017 Aug 16;95(4):808-816. e9. doi: 10.1016/j.neuron.2017.07.025)
What else is new in ALS? It is now apparent that cognitive problems are much more common in ALS than was known previously. Although only 10% have full-blown dementia, many patients have milder cognitive problems. In advanced ALS, the vast majority of patients will have cognitive changes (Neurology 2018). Caregivers need to be aware that these changes can affect decision-making and patient-caregiver interactions.
There is also a higher (3-10X) incidence of psychiatric disorders in families of ALS patients. The disorders include schizophrenia, obsessive compulsive disorder, and autism. (JAMA Neurol Dec 2017).
In one genetic form of ALS (C9ORF72), it was shown that a blood and spinal fluid biomarker, neurofilament light, starts to rise 1-3 years before patients become symptomatic. (Ann Neurol 2018;84:130-139)
We also now know that about 13% of patients with ALS have other “atypical features” suggesting involvement of other parts of the nervous system and explaining some of these unusual occurrences. These abnormalities could include problems with eye movement, coordination, tremor, slow limb movement, rigidity, excessive sweating, loss of taste and/or smell. Emotional lability (pseudobulbar affect) is more common in this group of patients as well. (McCluskey L et al. ALS-Plus syndrome: non-pyramidal features in a large ALS cohort. J Neurol Sci 2014;345:118-124).
Urinary disturbances may be more common than previously thought in patients with ALS. In one study, up to 40% of patients with ALS had symptomatic urinary disorders. Although some of these problems may be related to ALS, the use of medications could also predispose patients. Medications such as those used to treat spasticity or depression can lead to urinary symptoms. (Lopes de Carvalho ML et al. Urinary disorders in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2011;12:352-355. Nübling GS et al. Increased prevalence of bladder and intestinal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:174-179).
Deep venous thrombosis (blood clots) in the legs leading to pulmonary embolism or clots in the lungs has been a concern in patients with ALS. In one study, 4 of 50 patients developed blood clots in the legs over a year. One of these developed pulmonary emboli. Patients at the greatest risk appear to have onset of disease in the legs and being wheelchair bound. Unfortunately, we do not know how to prevent blood clots safely in ALS patients and whether or not patients should be routinely screened for blood clots. (Glad M et al. Venous thromboembolism in amyotrophic lateral sclerosis. Neurology 2014;82:1674-1677).