Valproate and levocarnitine for SMA

Last updated Sept. 5, 2024, by Margarida Maia, PhD
Fact-checked by Ana de Barros, PhD

What is valproate and levocarnitine for SMA?

Valproate, also known as valproate sodium or valproic acid, is approved in various forms to treat seizures, bipolar disorder, and migraine headaches. In combination with levocarnitine, it was being tested in a Phase 3 clinical trial as an oral medication to improve motor function in people with spinal muscular atrophy (SMA), but the status of that study, which was due to conclude in 2016, is not known.

Therapy snapshot

How does valproate and levocarnitine work?

SMA is caused by mutations in the SMN1 gene, which provides instructions for producing the survival motor neuron (SMN) protein that motor neurons need to survive. Motor neurons are the nerve cells that control the voluntary actions of skeletal muscles — those that allow the body to move. Without enough SMN protein, motor neurons lose function and die. As a result, disease symptoms are marked by muscle weakness, with patients failing to acquire or losing motor milestones.

The SMN1 gene has a backup gene called SMN2. When SMN1 is compromised, SMN2 produces about 10% of the essential SMN protein. SMA patients with more SMN2 gene copies typically experience milder disease symptoms.

Histones play a crucial role in gene regulation by binding to DNA and maintaining its structure. Their interaction with DNA is controlled by enzymes such as histone deacetylases.

Valproate is a histone deacetylase inhibitor, meaning it targets these enzymes to prevent histones from wrapping tightly around DNA. By blocking histone deacetylases, valproate loosens the interaction between histones and DNA, allowing for better gene accessibility to genes like SMN2

This enhanced accessibility can help to increase SMN protein production, potentially easing SMA symptoms.

Treatment with valproate, however, decreases available carnitine, a nutrient that helps the body break down fatty acids and turn them into the energy needed by cells.

Carnitine deficiency can lead to severe complications, including those affecting the heart and liver. To counteract such side effects, valproate is often prescribed alongside levocarnitine, or L-carnitine, the biologically active form of carnitine that the body can readily use.

How was valproate and levocarnitine administered?

In clinical studies with SMA patients, valproate and levocarnitine were administered as a liquid solution or syrup, tablet, or sprinkle capsule, given by mouth two to three times daily.

Valproate and levocarnitine in clinical trials

Valproate has been tested in three clinical studies involving people with SMA.

In pediatric and adult patients, Phase 2 study results showed the treatment was generally well tolerated, but it failed to provide significant benefits in muscle function or strength.

A Phase 3 study opened to investigate valproate and levocarnitine in children with SMA, however its status is uncertain and no published results are known.

SMA CARNI-VAL

The two-part Phase 2 SMA CARNI-VAL (NCT00227266) trial tested the safety, tolerability, and potential efficacy of valproic acid plus levocarnitine against a placebo in 94 children and adolescents with SMA type 2 or type 3. Treatment efficacy was assessed by changes in gross motor skills using Modified Hammersmith Functional Motor Scale (MHFMS) scores, a measure of motor function where higher scores indicate better motor skills.

In the trial’s first part, 61 children, ages 2 to 8 and unable to walk, were randomly assigned to Depakote (divalproex sodium), a sprinkle capsule formulation of 125 mg valproic acid, in combination with Carnitor, a levocarnitine syrup — or to a placebo combination — given two to three times daily for six months. After those months, the placebo group also moved to active treatment for another six months.

Results showed no significant difference between the two groups in MHFMS score changes over the trial’s initial six months.

A post-study analysis, however, found that 2- to 3-year-olds treated for one year showed significantly better MHFMS scores after accounting for initial weight, compared with those given the placebo. A separate analysis focusing solely on age showed that younger age (ages 2 to 3) significantly contributed to rising MHFMS scores.

Side effects were reported in both patient groups, but more common in those given Depakote/Carnitor. The most frequent side effects among these children were pneumonia (inflammation of the lungs), vomiting, and fever. Excessive weight gain also was noted in treated children compared with those on a placebo.

The trial’s second part was open label, enrolling 33 SMA type 3 patients, ages 3 to 17, able to stand independently for up to two seconds. All were treated with Depakote and Carnitor for one year. The combination was generally well tolerated, with side effects mostly reported to be mild and transient.

No significant MHFMS score changes, however, were recorded over six or 12 months of treatment. Other measures of motor function, such as the time to walk 30 feet, time to climb four stairs, and time to rise from the floor, also remained unchanged. No gains were noted in SMN protein levels.

A measure called CMAP, which provides information about the number of functioning motor neurons and muscle fibers, showed significant improvement. But, as the researchers noted, this change “suggested a minor biological effect” that was “not clinically meaningful.”

SMA VALIANT

The Phase 2 SMA VALIANT (NCT00481013) trial tested Depakote and levocarnitine, initially against a placebo, in 33 adults, ages 20 to 55, with SMA type 3. All were able to walk at least 30 feet without assistance. Like the SMA CARNI-VAL study, SMA VALIANT was sponsored by the University of Utah.

The trial’s main goal was improvements in the maximum strength of voluntary muscle contractions after six months. Secondary outcomes related to changes lung function, electrical activity in muscles, and overall physical abilities with the goal of better understanding treatment effects on the body.

Patients were assigned to a 250 mg Depakote capsule or to a placebo capsule, given in divided doses two to three times daily for six months. The placebo group then also moved to treatment for another six months.

While the treatment was reported to be generally well tolerated without troubling weight gain across adults, it did not improve their muscle strength or function.

Blood samples were used to evaluate SMN protein levels throughout the treatment period. No evidence suggested a rise in these levels in patients’ cells.

Phase 3 trial

A Phase 3 clinical trial (NCT01671384) was launched in India in 2013 to test the safety of Valprol (sodium valproate) plus levocarnitine in children with SMA, and its efficacy in improving muscle strength and function, including lung function. It planned to enroll up to 60 patients, ages 2 to 15, with symptom onset after 6 months of age.

Children were to be randomly assigned for 52 weeks to either a combination of Valprol, as a liquid solution for those weighing less than 20 kg (about 44 pounds) and as a tablet for those weighing more, and levocarnitine, or to a placebo combination.

Its main goal was to assess changes in muscle strength through manual muscle testing at intervals across the trial’s year. Additional goals included changes in motor function as seen in MHFMS scores measured at the intervals, reported side effects, and changes in lung function.

Sponsored by the All India Institute of Medical Sciences, in New Delhi, the study’s status is unknown. It was due to conclude in December 2016, but no results are known to have been posted or published.

Common side effects of valproate and levocarnitine

The most common side effects reported with valproate plus levocarnitine during clinical testing in SMA patients include:

• pneumonia
• vomiting
• fever
• excessive weight gain
• headache
• fatigue
• nausea

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