Further to the discussion on diarrhoea and the pivotal Rett trial
As background, 80% of trial participants on trofinetide experienced diarrhoea; 20% didn’t. Of those on placebo, 20% experienced diarrhoea; 80% didn’t.
Analysts have questioned the potential impact of the diarrhoea on both safety and efficacy.
Firstly, they have questioned whether the diarrhoea issue might cause the FDA to decide that the safety risks of trofinetide outweighs its benefits.
On this question, I think that the following points speak in favour of trofinetide:
Of those in the study who were on trofinetide and experienced diarrhoea, 97.5 % of cases were classified as either mild or moderate.
Normally, 80% of Rett patients suffer from constipation. I heard one Rett mother say that constipation can take control of the whole day. It can lead to pain, irritability and refusal to eat in patients who may also not be able to communicate what they are feeling. Severe cases of constipation can lead to hospitalization. One could well argue that mild diarrhoea is preferable to constipation.
It is likely that diarrhoea in the trofinetide-dosed trial group was exacerbated by concomitant medications. Many Rett patients are routinely treated with laxatives for constipation and also with other medications (such as PPI inhibitors or H-2 receptor antagonists) for reflux, which is suffered by 40% of Rett patients. These medications can also cause diarrhoea.
Dr. Dominique Pritchard, CSO at the International Rett Syndrome Foundation and mother of a girl living with Rett, has said that Rett carers are so used to dealing with GI and other challenges that they are unlikely to be fazed by mild to moderate diarrhoea.
In the unblinded Lilac extension trial which followed the main trial, it was reported that the diarrhoea was able to be controlled through implementation of a management plan. During the blinded Lavender trial, it wasn’t possible to advise adjustment/cessation of routine medications, whereas this could be done during the unblinded extension trial.
95% of those who completed the main Lavender trial elected to enrol in the 9 month extension study, suggesting that the possibility of diarrhoea wasn’t a major deterrent. And as of December 2021, there had been no drop-outs reported from the extension study on account of adverse events, suggesting that diarrhoea management programs implemented during this period had been successful.
Safety data from the Lilac extension trial will be included in the NDA.
Finally, as discussed here before, one could argue that there are many therapeutic drugs that have been previously approved by the FDA, despite having much more serious side effects than mild to moderate diarrhoea.
Secondly, analysts have questioned whether the high rate of diarrhoea in the trofinetide population led to functional unblinding of the study, which could bring the validity of the trial data into question. That is, could patient/carer/physician assumptions about being on the drug, based on whether diarrhoea was experienced or not, have led to bias in reporting of results?
On this question, I think that the following points speak in favour of trofinetide:
The Acadia CEO says that the regulatory body will “automatically” look at this issue. In order to answer this question, the company has done a great deal of analysis and is highly confident that the data proves that there has been no functional unblinding.
Data comparisons have been made between those on trofinetide, with and without diarrhoea, and those on placebo, with and without diarrhoea. No meaningful difference in response was found between those participants who had diarrhoea and those who didn’t.
Should one assume that the carers assumed that trofinetide caused the GI side effects? After all, many patients in both the active or placebo groups were likely to have also been taking laxatives and reflux medications which come with the potential side effects of diarrhoea, nausea and vomiting.
Further to the discussion on whether the FDA would approve a drug with just a “modest” clinical benefit
Consider the FDA's approval of Sarepta’s Exondys 51 and Vyondys 53 for the rare disease, DMD, for which there were no approved therapies
Like Exondys 51, Vyondys 53 was approved based only on dystrophin production “that is reasonably likely to predict clinical benefit” in DMD patients, the FDA said in a statement—not on proven clinical improvements. In a small clinical trial, 25 patients on Vyondys 53 saw 1.02% of normal dystrophin production after 48 weeks of treatment, up from 0.1% at baseline.
By the way, other studies have suggested that a minimum 15 to 20% of normal dystrophin production is needed to improve muscle function.
Consider the FDA’s own words in a document released last year
Therapeutic context plays an important role in FDA’s assessment of the acceptability of uncertainty. For a drug intended to treat a serious disease with unmet needs, FDA may accept greater uncertainties about benefit or risk at the time of approval, for example through the accelerated approval pathway. In other situations, such as in the case of a drug that is intended to treat a non-serious disease and for which other therapeutic options exist, FDA would not be likely to accept as much uncertainty regarding either benefit or risk.
Consider that the FDA has made a committment to listening to the voices of patients and their families during the rare disease drug development and approval process.
Consider the words of Dr Dominique Pritchard ,CSO of the International Rett Syndrome Foundation and mother of a daughter with Rett syndrome, when commenting on the trofinetide pivotal trial results
“A change in just one point would mean change from often to sometime. A seemingly small change can make a big difference to the patient and family.”
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