- PBT2 is safe.
- One serious adverse event occurred secondary to PBT2. A worsening of Huntington's disease symptoms upon its cessation.
- PBT2 may improve cognition.
- Efficacy of PBT2 required for approval in Huntington's disease is very low.
- Approval of PBT2 for Huntington's disease will speed up approval for the larger Alzheimer's dementia indication.
- IMAGINE trial results for Alzheimer's dementia due to report by the end of March significantly de-risked by the REACH2HD trial.
I have previously written about PBT2 more generally, whereas the focus of this article is to address some issues people have raised about the trial.
The REACH2HD trial should have recruited more patients.
Biotech investors may be more familiar with other clinical trials, such as cardiology registration trials. The number of patients recruited for these can be in the range of 10-20k. To recruit that many patients for Huntington's disease, you would be testing 12%-25% of people with the disease.
PRAN conducted the REACH2HD trial because it could not afford to fund a large Phase 3 trial in Alzheimer's dementia. Prior to the run-up in the share price, its market cap was <$100m, and targeting Huntington's disease as an orphan drug indication provided an easier way to get PBT2 to market.
Trials in Huntington's disease are small, as there are only about 80,000 patients worldwide with this disease. The registration trial for the only drug approved for Huntington's disease, Tetrabenazine, recruited 74 patients for 12 weeks. REACH2HD, in comparison, recruited 109 patients for 26 weeks.
The REACH2HD trial executive function efficacy was not sufficient.
That the REACH2HD trial showed efficacy in any marker is a significant positive. The fact that it was in the Trail Marking Test Part B, which is a component of the Executive Function Composite z-score, is an added bonus.
PBT2 also improved executive function; the fact that this was also positive in its Phase 2a trial in Alzheimer's dementia is an added kicker. PBT2 did this in only 6 months, in a trial with limited power due to it having 3 arms and only 109 patients. If you are familiar with statistical analysis, you will know that more you divide patient groups up, the harder it is to prove statistical significance.
This also bodes well for the upcoming IMAGINE trial to be reported in March, as it indicates that PBT2 might be working through the same mechanism of action.
Figure 1. Phase 2a results for PBT2 in Alzheimer's Dementia
Figure 2. Results of the Trail Marking Test B in the REACH2HD trial at 26 weeks
PBT2 did not show benefit in motor function.
The REACH2HD trial was always going to be less likely to show improvements in motor function, as they did not specifically look to enroll patients with Huntington's chorea.
They enrolled patients with a total functional capacity of between 6 and 13, inclusive with an average score of 9.2. A score of 7-10 indicates stage 2 disease, and patients at this level are unlikely to have significant motor problems.
Table 1. Demographics of the REACH2HD patients
Figure 3. Components of Total Functional Capacity
Motor problems do not develop rapidly, so with 109 patients the trial would not have been powered to notice the subtle difference in the progression of motor symptoms in only 6 months.
Finally, the REACH2HD trial was a Phase 2 trial. Phase 2 trials are designed to test the safety of the drug in the target population; efficacy markers are there to see which groups the company should target in Phase 3 trials.
On the conference call, management indicated other clinical markers were heading in the right direction but did not achieve statistical significance.
The results were not corrected for multiple analyses.
This is a fairly legitimate point, especially as the more sub-groups you look at, the more likely you are to find something that is significant.
That executive function was significant in both trials, however, makes it less likely that the result was positive due to random error.
Will PBT2 get approved for use in patients with Huntington's disease?
Tetrabenazine is the only FDA-approved drug for Huntington's disease. It improves Huntington's-related chorea, part of the motor symptoms associated with Huntington's disease. It has no benefit in cognition.
The FDA approved it when its main registration trial recruited 84 patients in a trial lasting 12 weeks. That was 7 weeks of dose adjustment, and 5 weeks of maintenance, and follow-up for a week after coming off Tetrabenazine or placebo.
Tetrabenazine reduced chorea, but missed the mark on safety. PBT2, in comparison, improved a marker of executive function, and in terms of safety, was not significantly different to placebo.
The only serious adverse event in the REACH2HD trial occurred in the follow-up period. One patient who had received PBT2 had a significant worsening of his Huntington's disease symptoms after its cessation.
There were five study withdrawals in the Tetrabenazine group and five serious adverse events in four subjects (drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer), compared with one withdrawal and no serious adverse events in the placebo group.
The FDA was willing to approve Tetrabenazine because Huntington's disease is such a serious condition and there were no treatments at that time.
PBT2 is targeting the cognitive impairment that patients with Huntington's disease suffer from. There are even subtle changes in people who do not suffer from Huntington's disease but are carriers for the disease.
The FDA will likely not demand a large degree of efficacy for PBT2 in Huntington's disease, as PBT2 appears to be a safe drug and there are still no treatments that improve cognition.
There are many risks when investing in early biotechnology companies, but PRAN has been significantly de-risked after its REACH2HD trial. PBT2 is now the only drug that has shown a statistically significant improvement in executive function for people who suffer from Huntington's disease and Alzheimer's dementia. These results significantly increase the chances that PBT2 will be successful in the IMAGINE trial due to report in March.
At a current market capitalisation of $336 million, I believe that the risk-reward ratio for PRAN would be favourable, as FDA approval for the use of PBT2 in Huntington's disease and Alzheimer's dementia could eventually see PRAN's share price increase 100-fold.