Huntington's disease: Tominersen dosing interruption in Generation HD1 - Questions and Answers

26/03/2021

On Wednesday, 24/03/2021 was held a meeting via zoom between investigators, associations and patients to answer the many questions arising from the unexpected news of the interruption of the dosing of the experimental drug tominersen in the phase III 'Generation HD1" clinical trial.

The investigators of the Italian centers involved in the study, promptly responded to the need for immediate answers, taking into account that the data behind this decision have not yet been made public.

In the following article, we have summarized, for the benefit of all patients, even those who did not have the opportunity to attend the meeting, the questions emerged and answers provided by the investigators.

Questions and answers

Is it a permanent stop?

Yes, the stop is permanent: the experimental drug will no longer be dosed as part of the Generation HD1 clinical trial.

Is tominersen not effective as previously thought or are there other reasons behind its stop? and more, is there any chance that this clinical trial will be resumed by varying some aspects? 

Tominersen turned out to be not effective as thought, based on the evaluation of data conducted by an Independent Commission, to which Roche has not yet had access. We do not know what parameters were evaluated by this Commission. The protocols of the clinical trials indicate 'primary' parameters (which are assessed with specific clinical scales) and secondary parameters. It is possible that, in the following analysis that will be done by Roche, it will come out that some of the parameters gathered (for example, some cognitive or resonance parameters) will be considered significant anyway. To date, however, we do not know anything about what was considered. 

Roche wants to continue monitoring participants for long-term effects: should participants continue to perform daily exercises and keep wearing phone and watch? Should caregivers continue to submit weekly reports?

From what we know to date, yes: Patients and caregivers will need to continue monitoring and thus also exercise from home. The investigators encourage patients to continue the study in order to monitor their health status over the longer term, also from a safety perspective. Especially since we still don't know what the real reason behind the clinical trial's stop is.

What major side effects might the sudden withdrawal of the drug bring?

What we know to date is that no benefits were observed and, theoretically, no disadvantages are expected. For this reason it is important to continue with the followup visits: blood tests, clinical data collected in the upcoming months will make us totally exclude any unexpected side effects. What we know about this drug thanks to basic research is that interruption of dosing should be associated with a regression of all effects. So, the interruption of the dosing should stop both beneficial and adverse effects. To date, no evidence suggests that the dosing of the drug worsens the patient's condition. And anyway, even if this was the case, once the drug's dosing is stopped, everything should return as it was before taking the drug . 

When will the data that led to the halt of the trial be made public?

Roche has the duty to disclose the reasons for this interruption, otherwise it cannot expect patients to be motivated to continue monitoring visits. The company's official press release speaks of "poor efficacy" but also of "unfaverable safety and efficacy trends". There does not seem to be, therefore, a clinical benefit. Right now, Roche does not have all the information. From what we understand, at least one month needs to go by before it can access the data.  

How does this failure fit into the context of other trials? Should we expect other trials with similar approaches to fail as well?

This is a complex disease and the scenario is complex as well. The other emerging treatments, although similar to this one, are not identical. The differences from a biological standpoint may be substantial. The reasons why this therapy may not have worked can be different. From the time of administration, the amount of protein that was lowered, where the protein lowering occured, how the drug was distributed, how it could be better distributed etc. One thing is certain: everything we learn today from this trial is of great benefit to others as well.

This communication came as a cold shower, patients feel like guinea pigs.

The contribution of patients is fundamental because this is the historical era of clinical research, that is to say research done on and with people. For many years, the only form of knowledge came from basic research (in the laboratory). Researchers and patients have the same goal: to find a cure. In this perspective, the concept of guinea pig does not exist.

Is it possible that the starting hypothesis, namely lowering the levels of huntingtin, does not help to fight the progression of the disease in humans, as was shown in animal tests?

Theoretically it is possible: there are aspects related to the reduction of the protein that may not have been captured by this approach. It could be that a part of the protein is more toxic than another part and in any case there should be some considerations on how the drug is distributed, how much the mutated protein is reduced compared to the healthy one, what is the role of each form of the protein in the body. At this stage, however, none of us can hazard any guesses. Certainly, the scientific world will gain information in the upcoming months from this trial. . 

What sense does it make to suddenly stop the trial now, when phase 3 would have shortly ended, at least here in Italy?

The decision was taken at the global level, regardless of the status of the clinical trial in each country.  If an experimental drug is founded to be ineffective, the clinical trial must be stopped immediately. It would not be ethical to the patients themselves to pursue it further. 

My brother was finding benefit from taking the medication. Now I am afraid that the sudden suspension of the drug may cause a relapse. If this occurs, what should we do?

We confirm that there are participants who maintained a stable condition over the course of the clinical trial. At the moment, however, we do not know whether the condition would have remained stable even if they had not taken part in it. On the other hand, we do know that an independent committee has stated that the drug is not effective. We know that the disease is very different from person to person. And, also, we can't exclude a placebo effect. 

We would have had our last lumbar puncture in July: have any unexpected or adverse events emerged that recommended this sudden interruption?

No, no unexpected or abrupt data on the safety profile have emerged; on the contrary, it has been specified that the discontinuation is not related to the safety of the drug, but to a negative benefit-risk ratio.

Are the visits scheduled at the end of the month confirmed? How long should we continue them?  

Yes, the visits already scheduled are confirmed and should be done according to protocol, until the scheduled end of the study, unless we receive different indications later.

Is it possible to know if I have been given Placebo or Drug?

We don't know yet, but we don't think so. 

Wasn't the 45 to 60% efficacy already established?

These percentages referred to the percentage of reduction of the huntingtin protein, not to the efficacy of the drug, which was to be tested and verified during the phase III of the Generation HD1 clinical trial.

How is it that Roche first encouraged the community so much based on information that later turned out to be so vague? Were we wrong to trust it?

Trials evolve in phases. Each phase takes many years and costs a lot of money. First there is a long preclinical phase. Then the clinical phases. Each phase explores different things. When Roche talked about encouraging data, they were referring to encouraging "tolerability" and "hypothetical" clinical efficacy data. Previous studies were conducted in relatively small numbers of patients, so they could not be certainties. They were clear on this and the data are published in the literature. This situation is unfortunately common to the history of most drugs, of any disease, not only of the nervous system. Certainly, there was no lack of scientific rigor: none of the investigators present would have accepted it, and the same company Roche would not have allowed it. What happened, unfortunately, is in the order of things. 

Will those who participated in this, be able to participate in another clinical trials? If so, will they have to 'clean up' their system first?

This will largely depend on the protocols of the other trials. Surely there is a 'wash out' that is a period of pause in which the body is 'cleaned' from the drug (or placebo) taken previously.

Is there any other hope?

In parallel to this, there is another ongoing clinical trial in Italy with another drug (Proof-HD). There are still other trials that are about to begin. Probably, there will be more failures. Right now, there are about 170 trials worldwide on Huntington's disease, both clinical and observational. Numbers that were unthinkable a decade ago. Today we know the disease much better and deal with it also using non-pharmacological strategies, such as speech therapy or physiotherapy.

Hope must not be lost. The investigators ask patients to help and support them, as they will certainly not stop looking for a cure, due to the failure of this tria