So far, there are no treatments that arrest or reverse the disease, but there are treatments for symptoms and for prolonging life and maximizing function.
Sodium Phenylbutyrate–Taurursodiol (Relyvrio) - Approved by the FDA. The combination of Sodium Phenylbutyrate–Taurursodiol (TUDCA) was approved for use in ALS by the FDA in September 2022. The drug is marketed by Amylyx and branded as Relyvrio.
Sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered orally once a day for 3 weeks and then twice a day) was studied by Paganoni and others, and the result of their phase II Centaur study was published in the New England Journal of Medicine in September 2020 (link to N engl j med 383;10 nejm.org September 3, 2020) The multicenter, randomized, double-blind trial compared 89 ALS participants on sodium phenylbutyrate–taurursodiol with 48 who were given placebo. All had onset of ALS symptoms within the previous 18 months, and all had diffuse ALS. In other words, they had fairly rapidly progressive ALS that was of more recent onset. In the drug-treated group, there was slowing (more than 25%) of the rate of functional decline over the 6 months. Adverse events with the active drug were mainly gastrointestinal (diarrhea, nausea, abdominal pain). A larger study was undertaken to better prove efficacy.
The investigators then reported a long-term survival analysis of participants in CENTAUR. These subjects may have initially received drug or placebo and then all went on active drug. With 35-month maximum follow-up, median overall survival was 25.0 months among participants originally randomized to active drug, and 18.5 months among those originally randomized to placebo. Initiation of sodium phenylbutyrate–taurursodiol treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo.
Usually the FDA does not approve drugs based on the results of a single trial that was relatively small, but they did in this case since it was agreed that the drug would be discontinued if the results of an ongoing large study do not show benefit.
On Feb. 2, 2023, Amylyx Pharmaceuticals, Inc. announced the completion of enrollment in that large study called PHOENIX, a global, 48-week, randomized, placebo-controlled Phase 3 clinical trial of AMX0035 (sodium phenylbutyrate and taurursodiol ). Amylyx anticipates topline results in 2024. The study enrolled 664 participants living with ALS.
The drug carries a list price of about $158,000 per year in the U.S. per the company on a conference call, noting that the price is below the latest FDA-approved ALS product. However, Amylyx is “committed to providing financial assistance” for patients with commercial insurance and will provide the drug at no cost for underinsured or uninsured patients who meet “certain financial eligibility criteria” and who have “exhausted all other options,” said Amylyx’s chief commercial officer Margret Olinger.
Rilutek (riluzole) is approved for use in treatment in ALS and has been shown to prolong life by three months on average. Some may benefit more than others. Blood work is required while taking this drug. This drug is expensive.
- Dosage, Adult (usual): 50mg twice daily before morning and evening meals.
- Adverse Effects: fatigue, liver test abnormalities, low white blood count, nausea, and fatigue.
- Drug Interactions: sulfasalazine (azulfidine)
Radicava (edaravone): 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 was initially approved as an intravenous (IV) 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.
The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising and gait disturbance.
Radicava IV 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
- At least 2 affected body regions (arm, leg, bulbar)
- Normal breathing at time of entry
- Progressive Disease (usually at least moderately progressive)
A previous study in which patients had disease for less than 3 years showed no significant benefit.
The majority of our patients who have received IV Radicava do so 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.
The FDA approved oral suspension Radicava in May 2022. The oral form goes into the bloodstream rapidly like the IV form. It is dosed at 105 mg as a liquid and is injected into the mouth or a feeding tube via syringe. It is given on an empty stomach in the morning. The frequency of dosing and cost are the same as the IV formula, but it is more convenient than the IV option. An ongoing study to determine if dosing daily is better than 10 days per month is ongoing, and we have been participating in that study.
The first step in getting the drug is to fill out the benefit investigation form and provide it to your doctor.
Anti-oxidant vitamins: There is theoretical but no proven benefit from antioxidant vitamins. Beta carotene (10,000 IU), vitamin C (1,000 mg daily), and vitaminE (400 IU three times daily) are used by some patients but of unproven benefit. We recommend them.
Coenzyme Q10(CoQ10) is used by some patients, but studies have not shown benefit. 200 mg per day is optional therapy.
L-acetyl carnitine. A small study showed that 1000 mg of acetyl-L-carnitine three times a day may be beneficial in ALS patients. It is not proven therapy, but we consider it optional with a very low risk.
Creatine, a protein supplement, has been used but studies have been negative at 5-10 grams per day. We do not currently recommend it, but it is not harmful.
Research into other drugs to arrest ALS is ongoing. There is no evidence that chelation, other supplements, or alternative medicine is helpful. Empiric use of experimental drugs is not recommended since they could make things worse. Stem cell treatment is not available in the US and is not recommended at this time. Safety studies using stem cells are ongoing, but no treatment studies have started.
We understand that patients often chose unconventional therapies that we do not recommend and our primary message is to avoid treatments that can make you worse, like diets that cause weight loss. Overall, we urge caution. We can discuss these issues with you at clinic visits, but many patients call us about supplements, diets and other therapies that we really have no scientific data about and cannot make any specific recommendations about their use. We strongly encourage you to read the reviews of the publications by neurologists in the ALS Untangled Group (ALSuntangled.com) Most of these reviews are published online and discuss the studies and specifically comment whether or not the proposed mechanism of benefit makes sense and then they grade the evidence as far as preclinical data, case reports, trial data, and then they grade the risks.
Soon after ALS is diagnosed, we recommend maintaining weight or even gaining weight through a generally healthy diet and do not have any particular dietary recommendations during the early stages. In particular, we do not recommend any particular “fad” diets.
Therefore, in the early stages, we recommend the above regimen and mostly suggest trying to maintain as normal of a healthy lifestyle regimen as possible.
Excessive saliva and drooling occur in ALS due to weakness in the muscles in the face and the mouth. Excessive secretions may cause difficulty in speaking, and may lead to aspiration. Anticholinergic medications, such as glycopyrrolate (Robinul) or scopolamine, and medications with anticholinergic side effects, such as tricyclic antidepressants (Elavil- amitriptyline), are often used to reduce the amount of saliva and help to control drooling. The most common side effects of these medications, however, are drowsiness and constipation. As a result of the latter, it is often recommended to increase fluid intake to help maintain the motility of the intestinal tract and to also help maintain some moisture in the mouth. Furthermore, if the mouth becomes too dry, saliva substitutes, such as Salivart, may be used to help maintain moisture in the mouth. If medications are ineffective, botulinum toxin or radiation may be helpful but may not be covered by insurance.
Thick mucus is treated with fluids, guaifenesin (Robitussin or Mucinex), or Mucomyst by nebulizer. Milk products aggravate thickening of mucus. A suction device or cough assist may also help.
Emotional lability, the loss of emotional control, is one of the problems associated with the bulbar symptoms of ALS. We usually treat this symptom if it is embarrassing, bothersome, frustrating, or affects quality of life. Although it is not actually a symptom of depression, it improves with the antidepressant Elavil (amitriptyline) that also helps with all of the following symptoms: increased saliva, depression, and poor sleep. If Elavil does not work, we recommend Neudexta (dextromethorphan and quinidine). Starting dose: One capsule daily by mouth for 7 days. Maintenance dose: After 7 days, 1 capsule every 12 hours.
The most common adverse reactions (incidence of ≥3% and two-fold greater than placebo) in patients taking Nuedexta are:
- peripheral edema
The following central nervous system lability scale (CNS-LS) can be used to determine if there is significant emotional lability causing Pseudobulbar Affect (PBA):
The CNS-LS is a short (seven-item), self-administered questionnaire, designed to be completed by the patient, that provides a quantitative measure of the perceived frequency of PBA episodes. A CNS-LS score of 13 or higher may suggest PBA.
Using the scale below, please note the number that describes the degree to which each item applies to you DURING THE PAST WEEK. Use only 1 number for each item.
|Applies Never||Applies Rarely||Applies Occasionally||Applies Frequently||Applies Most of the Time|
- There are times when I feel fine1 minute, and then all become tearful the next over something small for no reason at all.
- Others have told me that I seemed to become amused very easily or that I seem to become amused about things that aren’t really funny.
- I find myself crying very easily.
- I find that even when I try to control my laughter I am often unable to do so
- There are times when I won’t be thinking of anything happy or funny at all, but then also may be overcome by funny or happy thoughts.
- I find that even when I tried to control my crying, I am unable to do so.
- I find that I am easily overcome by laughter.
Muscle/joint stiffness (spasticity) is treated with stretching, physical therapy, and medications such as baclofen. We find that medications may be less effective than in other conditions such as multiple sclerosis.
- Class: skeletal muscle relaxant, centrally acting
- Dose adjustments: kidney impairment, geriatrics
- Adverse effects: drowsiness, slurred speech, hypotension, weakness, constipation, urinary frequency.
Valium (diazepam) is another option, as is Zanaflex (tizanidine)
Constipation - treatments
Constipation can mean different things to different people. It can mean the difficult or infrequent passage of stools or can refer to the hardness of stools. Some people feel "constipated" if they do not pass a stool daily, while others may go two to three days before feeling constipated.
It is first important to note that it is not necessary for every person to move his or her bowels every day. A regular bowel routine is individual from person to person. Some people may move their bowels more than once a day, while others may move their bowels every other day. Both instances are perfectly normal. To determine what your normal bowel routine is, think back to a time before you noticed a problem, and make that your goal to return to a similar schedule. A person should move their bowels at least once every three days.
Constipation can be caused by many factors. Amyotrophic Lateral Sclerosis increases the likelihood of developing constipation in many people because of decreased activity. Diet, medications, delay of transit time through the colon, incomplete bowel emptying, lack of fluids, and lack of exercise are a few other causes of constipation.
How do we prevent constipation? First, we should look at our personal habits, and see where we can improve them. Some tips to follow to ensure regular bowel habits are:
- Increase your fluid intake! Eight glasses of water or juices per day are essential. Adding prune juice daily may also help. (Prune juice maybe more appetizing if you drink it warm.)
- Increase fiber in your diet. Vegetable fiber is largely indigestible and non-absorbable and increases the bulk in our stools. Bran and other sources of fiber may be found in cereals. Read the labels to find the highest fiber sources.
- Attempt a bowel movement at a regularly scheduled time each day and be sure that you are not rushed in any way. Establishing a routine often helps to "retrain" our bowels.
- Add some form of exercise to your daily routine. Inactivity may add to your problem.
- Bulking agents such as bran, psyllium, and methylcellulose may be added to your routine. Although they are considered laxatives, they act slowly and gently and are the safest agents for promoting elimination. Be sure to increase your fluids along with these agents.
- Daily stool softeners such as Colace (sodium docusate) may be added.
If constipation still occurs you may need to add a laxative to correct the situation. There are many over-the-counter laxatives available today, such as Senekot or Dulcolax pills or Dulcolax suppositories. Miralax is often helpful too. Ask your family doctor or pharmacist to help you select the appropriate medication for you.
Cramps may occur in patients with ALS. For Charley horse-type cramping symptoms, it is important that you are well hydrated and do not have any electrolyte imbalances. If the cramping is a significant problem, we may try mexiletine 150 mg twice a day or possibly gabapentin (Neurontin). If the cramping is due to spasms or spasticity, then we would utilize baclofen. Prior to starting these therapies, stretching is important. Sometimes quinine in tonic water also helps with cramps.
Pain is fairly common in the later stages of ALS for a number of reasons. Joints may become stiff and patients may have musculoskeletal back pain due to decreased mobility. We recommend starting pain treatment with simple measures such as acetaminophen, ibuprofen or Naproxen (Aleve) along with moist heat and massage. For moderately severe pain, we may recommend Tramadol and severe pain may require narcotic usage sometimes in conjunction with a pain physician or palliative care doctor.
Bladder problems are relatively uncommon in ALS, but sometimes they occur. If you are having problems with urination such as incontinence or difficulty voiding, we do recommend an evaluation by a urologist first to rule out other causes and to help guide treatment which would generally be “symptomatic”.
Swelling/Edema – This problem is common in weak limbs due to muscle weakness and decreased lymphatic drainage. It is not usually necessary to treat except by intermittent limb elevation. TED hose can also be used. We generally do not recommend water pills. If there is pain, redness or fever, call your PCP to be assessed for cellulitis or a blood clot.
Blood clots – Patients with significant leg weakness and immobility are at increased risk for getting blood clots. Symptoms and signs can include local tenderness, redness, and swelling. There is no consensus on how to reduce the risk of blood clots in ALS patients. Thigh high TED stockings may be a consideration. There may or may not be some benefit from taking a baby aspirin every day. Long term anticoagulation has not been studied in ALS. Notify your physician immediately if you have symptoms of a blood clot.
Pressure ulcers are relatively uncommon in patients with ALS and occur in those who are unable to turn. Such patients should be turned frequently and have pressure points padded.
Falls- Falls are a significant concern in patients with ALS and leg weakness or imbalance. Patients should take special precautions and use assistive devices, rails, and be pro-active in avoiding situations that can lead to falling.