#apaperaday: Givinostat: First Approval

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Givinostat: First Approval

Today’s pick is from the journal Drugs by Lamb on the approval of givinostat for Duchenne muscular dystrophy DOI: 10.1007/s40265-024-02052-1

Givinostat was approved by the USA FDA this spring for patients 6 and older. It is an HDAC inhibitor (histone deacetylase). HDAC enzymes remove acetyl groups from proteins, while their counterparts HATs (histone acetylates) add acetyl groups.

As the H in both names suggests, this happens primarily on histone proteins. Histones are proteins around which DNA is wrapped to prevent that the very long, very thin thread of DNA is damaged or gets tangled. Like a thread. However, DNA also needs to be ‘read’ to make proteins.

This reading happens by the RNA polymerase enzyme, which makes an RNA transcript of a gene, which is then processed and translated into protein. When DNA is tightly wrapped, RNA polymerase cannot access the DNA, and genes cannot be expressed –> no protein.

Adding an acetyl group to a histone will open up the DNA so the polymerase can access it. This is a way to locally allow genes to be expressed or not. HATs add the acetyl group (more open DNA), while HDACs remove them (more closed DNA).

This means that HDAC inhibitors like givinostat should allow genes to be more active. How does this work for Duchenne? –> back to the paper. Lack of dystrophin causes muscle damage, leading to inflammation and fibrosis (and impaired muscle repair).

Steroid treatment slows down these processes to some extent, but not enough to prevent disease progression in Duchenne. Due to the lack of dystrophin, HDAC enzymes are more active, which makes the pathology worse: inflammation is more damaging and repair is inhibited.

Furthermore, the FAP cells (fibro-adipogenic stem cells) that should support muscle stem cells to repair damaged muscle, will instead start making too much fibrosis and fat tissue. Thus the pathology is in a negative spiral towards scar tissue formation.

As too much HDAC activity makes the pathology worse, inhibiting HDAC should make the pathology less bad. Indeed in mouse models without dystrophin, treatment with HDAC inhibitors improved muscle mass and a trial in Duchenne patients met its primary endpoint (more later on that).

The author first introduces givinostat as a drug. Below the chemical structure. Givinostat is given as an oral suspension. It can lead to decreased platelets and increased triglyceride levels, so before treatment, one needs to assess baseline levels and patients need monitoring.

When platelet or triglyceride levels are too low/high, dose adjustments may be needed. The author explains givinostat is also tested in trials for cancers – note this is because also there HDACs are disregulated. Givinostat is not chemotherapy and does not cause cancer.

Givinostat is developed by Italfarmaco and for Duchenne the development was done in collaboration with Telethon Italia and Parent Project. The author then outlines the mouse and human studies in more detail. Givinostat was tested in both d2/mdx and regular mdx mice.

In mice, it resulted in less fibrosis, less inflammation, and improved muscle function. In an open-label study in Duchenne patients, the levels of fibrosis and necrosis were significantly reduced after 12 months of treatment compared to baseline.

In a study in Becker patients, no difference in functional decline was observed between treated and placebo. HOWEVER, as this disease progresses very slowly, a decline would be difficult to detect, as there was little decline compared to baseline in untreated.

In other words: it is difficult to show a slower decline if patients barely decline. The treated Becker patients did show less fat infiltration measured by MRI compared to placebo. Then the phase 3 placebo-controlled trial in Duchenne, where patients were treated for 18 months.

Treated patients showed significantly less decline in the velocity of climbing 4 stairs at a level previously reported to be clinically meaningful. Also here, treated Duchenne patients had less fat infiltration and secondary endpoints were improved (not always significantly).

The author explains what is known about the pharmacokinetics of the drug (i.e., what the body does to the drug). It is mainly protein-bound and cleared from plasma with a half-life of 6 hours. It is metabolized, and the metabolites are excreted via feces (and a little via urine).

Then the author goes back to trials again – I’ve already outlined results, but will only add that the trials were done with givinostat treatment in steroid-treated patients. Furthermore, milestone analysis (loss of functions) also showed improvement in the givinostat treated group.

Givinostat is also in development for polycythemia vera (a disease where too many red blood cells are formed) and for other malignancies. The author describes them if you are interested (I’ll focus on Duchenne).

The side effect profile of givinostat is described, including the already mentioned reduction in platelets and increase in triglycerides. Most common side effects in Duchenne were diarrhea and vomiting, and reductions in platelets.

Side effects resulted in 6% of patients stopping or withdrawing from the trial, 36% had a dose reduction, and 14% had a dose interruption. Finally, the author outlines the ongoing trial in non-ambulant Duchenne patients and polycythemia vera.

Also, givinostat is currently under evaluation with EMA for Duchenne. The paper order is strange. I suspect the journal has prespecified article structures for approved drugs, but I get a bit confused with premonitions of trial results & mouse studies early on and details later.