Huntington's disease trials: update on Vibrant-HD (Novartis) and AMT-130 (uniQure).

As always, we are closely following the developments of the HD ongoing trials. Unfortunately, not too encouraging news arrives on the Novartis (with branaplam) and uniQure (gene therapy with AMT-130) studies.  Both of them pursue the strategy of lowering both mutated and normal length huntingtin to counter Huntington's disease, although with different tools.

The facts:

On August 5, 2022, Novartis announced the temporary suspension of the investigational drug branaplam administration for all participants in the Vibrant-HD study (phase II).

Reason: Some participants treated with the higher dosage would have found peripheral neurotoxicity profiles (peripheral neuropathy). The peripheral nerves conduct electrical impulses to the muscles of the limbs and allow us to move, walk, write etc ... as well as feel the sensitivity of the fingers to the touch.

Branaplam is a drug that is distributed in the brain and also in peripheral tissues.It is administered orally in the Vibrant-HD trial.

Temporary suspension does not imply complete interruption of the study - as Novartis explains - but it is appropriate to acquire information on the reversibility of the neuropathic effects of the drug, to understand whether it is appropriate to resume the study with lower doses of the drug.

In Italy, to date 6 patients have been included in the study, three at the IRCCS Casa Sollievo della Sofevole (Squitieri) and three at the IRCCS Carlo Besta (Mariotti) with a screening visit, for which none of them have yet received the drug (or placebo). We look forward to understanding how this will proceed and whether there will be convincing and prudent elements to continue.

On August 8, 2022, uniQure issued a statement informing that adverse reactions, severe and unexpected, occurred in 3 of the 14 study participants with AMT-130 treated with the highest dosage. All three have now recovered and are fine. They experienced localized inflammatory reactions, severe headaches, and related symptoms. The External Drug Safety Monitoring Committee did not find toxicity profiles such as to propose the interruption of the experimental phase.

However, the company has decided, as a precaution, to temporarily delay the administration of the higher dosages (the lower ones will continue to be administered), until the next report of the Committee, expected in the last quarter of the year.

AMT-130 is a drug delivered through the use of an adenoviral vector directly into the brain with a neurosurgical procedure. It induces a continuous reduction of huntingtin conditioning its degradation. Compared to Vibrant-HD, once administered, it cannot be stopped and lasts forever.

“Critical situations can occur during clinical trials,” says Ferdinando Squitieri. “What worries me is the common denominator among the studies by Roche (Generation-HD1 discontinued months ago), Novartis and UniQure, that is, all three interfere with both the healthy and the mutated protein. Some - fortunately few - participants in all three studies found inflammatory changes at high doses. We must hope that similar situations do not occur, in the long term, even for the lowest dosages and that the lowest dosages are capable of producing concrete clinical advantages ”.

"We are aware that this news will bring some despair in the patient community, but we must not forget to look on the bright side: firstly, the studies have not been stopped, but are continuing with greater caution; secondly, a supplement of data analysis can only help to direct research efforts in the right direction. Remember that this is the first time that we have tried to directly target the cause of Huntington's disease (the huntingtin protein) and therefore several attempts are needed. So please, do not lose hope and trust in science. ", comments Barbara D'Alessio, President of the LIRH Foundation.

You can read more on the Vibrant-HD temporary suspension HERE