Evrysdi can affect sperm generation in males, animal studies find

Changes at high doses seen in rats and monkeys 'reverse' after therapy stops

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by Steve Bryson, PhD |

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High doses of Evrysdi (risdiplam), an approved daily therapy for spinal muscular atrophy (SMA), affected the development of sperm in rats and monkeys, a review of 14 preclinical safety studies reported.

No damage was evident in immature sperm derived from stem cells, and changes affecting sperm ended after treatment was discontinued. Doses given the animals also were higher than those approved for SMA patients.

“The effect is expected to be reversible in humans after cessation of treatment,” the researchers wrote, adding that further studies are needed to better determine how Evrysdi might affect the reproductive health of male SMA patients.

The study, “Reproductive findings in male animals exposed to selective survival of motor neuron-2 (SMN2) gene splicing modifying agents,” was published in the journal Reproductive Toxicology.

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Changes in reproductive tissue seen with high daily doses of 2.5-9 mg/kg

SMA is caused by mutations in the SMN1 gene, which leads to little or no production of SMN, a protein essential for the health of the nerve cells responsible for controlling voluntary movements.

Although there is another gene, called SMN2, that also provides instructions for making the SMN protein, a slight difference in its DNA sequence results in an event called alternative splicing. This causes a portion of the genetic sequence to be removed from its messenger RNA (mRNA), the molecule that carries instructions from the SMN2 gene to make the protein.

As a result, most of the SMN protein produced from this gene is shortened and unstable.

Evrysdi, marketed by Roche and its subsidiary Genentech, is an oral daily SMA therapy designed to target SMN2 mRNA and prevent the removal of that sequence, such that more SMN protein is made from the gene.

Because Evrysdi changes how genes are read to produce proteins, targeting genes other than SMN2 could cause side effects. Preclinical studies of Evrysdi and its developmental precursor RG7800 showed good selectivity toward the SMN2 target. Most off-target splicing events were weak or undetectable at the equivalent doses given to patients.

However, in toxicological animal studies, Evrysdi and RG7800 showed changes in the development of sperm in male animals.

Scientists at Roche reviewed the findings of 14 studies in male rats and monkeys assessing their reproductive tissues after exposure to Evrysdi or RG7800.

Their goal was to “to better understand potential risdiplam secondary splicing effects in males … in more detail,” the scientists wrote.

Six of the studies with Evrysdi were performed in rats, with exposure ranging from two to 26 weeks (about six months). Changes in male reproductive tissues were seen at high daily doses of 2.5-9 mg/kg, which are considerably higher than the maximum patient doses of 5 mg for children and adults, and 0.25 mg/kg for toddlers up to age 2 weighing up to 20 kg (about 44 lbs).

Such changes included sperm concentration, motility, and structure, as well as more “degenerated” spermatocytes, precursor cells that give rise to sperm cells. Degeneration of seminiferous tubules, the location within the testes where sperm are made, was also observed.

Four to eight weeks after treatment stopped, about half of the rats showed a complete return to normal sperm generation. Mating treated males with untreated females during the recovery period did not show any lasting fertility problems, one study showed.

Three studies were performed with Evrysdi in monkeys, with exposures ranging from five days to nine months.

In one study, a single male monkey given increasing daily doses up to 20 mg/kg showed seminiferous tubular degeneration, but this was not observed at lower doses in other animals. Another study observed similar findings in two-thirds of monkeys treated with 6 mg/kg.

The third study showed no testicular effects, but the team noted these monkeys were sexually immature, meaning they had not reached puberty.

No testicular or splicing changes evident weeks after dosing stopped

Five safety studies of RG7800 were conducted in monkeys with twice daily exposures to ensure high blood levels, ranging from nine days to nine months.

One study showed degeneration in sperm cells at specific stages of development at 6 mg/kg each day. Changes were also seen in the activity of genes associated with the cell cycle and programmed cell death, which are known to be sensitive to alternative splicing.

After 55 days or more of recovery, no testicular findings or alternative splice changes were noted. Similar results were observed in other studies in mature animals.

Researchers noted that monkeys given RG7800 showed no damage to spermatogonia — a very early form of immature sperm cells derived from stem cells.

“The testicular findings observed in these studies were stage-specific with no evidence for damage to spermatogonia and demonstrated reversibility following the end of treatment,” the team concluded.

“Further clinical research is warranted to understand both how SMA itself might impact fertility and the effects of disease modifying therapies for SMA on the male reproductive system,” the researchers added.