Did I get this mostly right?Does the following representative a fair way of portraying what we can take away from the preliminary safety info disclosed last week? Any suggestions for improvement to this summary?
Given the limited amount of safety information THTX shared on their phase 1a cancer trial last week, what conclusions can we draw that will help us understand better what the possibilities and risks for TH-1902 are? Since we did not get a lot of additional info, we cannot draw too many key conclusions but we will take all that we can from this new info given the potential importance of TH-1902 for both patients and shareholders.
To summarize, THTX said they had now safely gotten to the next to last highest dosage level of TH-1902 to be given in the phase 1a trial and that translates into what is twice the normal level of Docetaxel, the chemo drug that is conjugated to THTX’s drug and which is an already approved and commonly used chemo drug used on cancer patients. The higher the amount of Docetaxel they are able to use safely, the greater the chance there is that TH-1902 will be not only safe, but also effective in killing cancer cells better than Docetaxel alone. TH-1902’s method of action is also supposed to result in many more times the drug getting into the cancerous cell than just twice the normal amount, assuming it works in humans as it did in mice. So, since we already know Docetaxel works to destroy cancer cells, and that its key shortcoming as a cancer fighting drug is that it has serious side-effects, TH-1902 could easily prove quite superior to Docetaxel if it is shown to be effective in killing or slowing cancerous tumors while simultaneously avoiding Docetaxel’s side-effects or reaching those side-effect symptoms much later in the treatment cycle. What we now know for sure from what the company announced last week is that TH-1902 is safe at 1.5x the normal Docetaxel dosage, but we don’t know yet if it is effective. Clearly if it is safe but not effective, the safety issue is irrelevant. So, we are awaiting the next update from THTX and hope it will include some preliminary signs of the drug being effective as well as safe.
So, here are some items we can draw from this limited safety information:
- We can now be nearly certain the TH-1902 trial will progress to phase 1b part of the trial, which is supposed to start in early 2022. The main objective of the phase 1a trial is actually to just determine the Maximum Tolerable Dose (MTD) to be used in the phase 1b trial, any other information gleaned from the trial, particularly efficacy, is not going to be statistically significant and is considered a bonus. We now know that the MTD for the phase 1b trial will be at least set at a dosage level of TH-1902 of 1.5x the normal Docetaxel dose. At that level, there were no adverse events seen at all. At the 2x dosage level, where the phase 1a trial is currently at, which is one dosage level lower than the highest planned dosage to be studied in the phase 1a, a patient experienced a grade 4 level of neutropenia, a side effect from Docetaxel. However, that level of neutropenia is not great enough to end the trial as it is only classified as a grade 2 Serious Adverse Event (SAE), which is the measurement system used to determine when the trial must end, and a grade 2 SAE is not judged to be serious enough to stop a trial. So the trial is continuing in its search for the MTD and will undoubtedly progress to phase 1b where the main objective will be to determine if the TH-1902 is effective as well as safe. As long as the trial is moving forward, there is a chance TH-1902 could actually turn out to be a drug that transform the way certain sortilin expressing cancers are treated, as THTX CEO’s has suggested previously. Clearly, if that happens, THTX’s stock price would likely soar.
- The trial will identify the MTD sometime soon since they are already on the next to last dosage level planned to be tested. Since there has been a mild negative reaction to the drug by one patient when the dosage got to this dose, which is twice the level of a normal Docetaxel dose, that is basically an indicator that the trial could be getting close to reaching its conclusion. Now it may turn out to be a one-off event and the trial will continue on to its planned conclusion without stopping early. Basically, the safety results are largely in line with the pre-clinical work and are about as good as we could have hoped for. And they yet may prove to be the best possible results if the trial concludes at the highest level of dosage without any SAE’s. It is also worth noting that TH-1902 already seems much safer than other targeted cancer therapies that have been recently approved, including Troldelvy, the drug that resulted in the company Immunomedics being sold to Gilead for $21 billion. So, TH-1902 is on a very good safety track at the moment.
- While we do not have any information on tumor shrinkage yet, the amount of Docetaxel being put into the patients right now is so great that we should reasonably expect to see some tumor shrinkage when THTX announces those results sometime soon (hopefully before the end of the year). Since we know Docetaxel works, the only issue now is whether THT-1902 is attaching to the cancerous cells sortilin receptors, being assimilated into those cancerous cells via that receptor and is remaining inside the cell long enough to damage the cancer cells. Since this all worked in the pre-clinical tests on mice, we have good reason to believe it will work in humans as well. But until we see the actual data, we are still just counting on these things to work as we expect. And the human body is different from mice so there may be reasons why it does not work as the pre-clinical work indicated. If it did not work as expected, that might lead to some adjustments in the phase 1b trial to obtain the desired efficacy.
- Getting tumor shrinkage that is measurable in the phase 1a patients will, however, unfortunately be complicated by how sick these patients are when they are enrolled in the test. As you may recall, these are cancer patients who are out of other options and are basically very close to death. They are courageously offering their bodies as a testing ground for cancer research in the hope of helping to find a cure or effective treatment before they pass. In some cases, they may unfortunately die before enough TH-1902 treatments can be administered to cause shrinkage of their tumor. In other cases, these patients do not even have tumors that overexpress sortilin receptors, so we do not even expect such patients to have any evidence of tumor shrinkage under any circumstances – they are just helping to determine if TH-1902 is safe for humans. The total number of patients in the trial is supposed to be 15 if the trial goes all the way to its planned conclusion, which it might not, and the early patients were likely not even given a high enough dosage to have shown any impact on the tumor, even if they lived long enough to get several treatments. As you may recall, the first patient in the trial died about 10 weeks into the trial from his cancer and likely did not live long enough or get a high enough dosage of Docetaxel into his system to have an impact on his tumor (dosage levels were low at the start of the trial). So, when considering all of these factors, the number of patients who received a high enough dose to have an impact, had a tumor that overexpressed sortilin and lived long enough for tumor shrinkage to be observed is likely quite a small number. As a result, the odds are stacked pretty high against seeing evidence of tumor shrinkage simply because it is likely only several patients will even be good candidates for tumor shrinkage due to the structure of the phase 1a test and it may be just a matter of chance as to whether any of those patients react to the drug as we hope. In most cancer drug trials the percentage of patients who see a benefit can be quite low with even 30% of patients receiving a benefit from a cancer drug being considered a very good number. So, if THTX’s cancer phase 1a trial ended up with only three patients that might be suitable for seeing some tumor shrinkage, we will be lucky if even one of them actually sees that happen in the phase 1a trial. Still, THTX spoke optimistically about seeing some tumor shrinkage last week and we hope that optimism is justified. Any preliminary sign of tumor shrinkage will indicate that the drug is behaving as expected, and it does not even have to be a lot of shrinkage to confirm that TH-1902 has been able to successfully put Docetaxel into cancerous cells. So, we are hoping to see even a minor sign of shrinkage as that would qualify as what is known as Proof of Concept (PoC) – that the drug is working as designed.
- Even if no tumor shrinkage is seen, there may still be some other evidence gathered from this trial that would help encourage us that the chances of seeing tumor shrinkage in the phase 1b trial is high. That trial will actually be aiming to identify such tumor shrinkage and will be using patients with sortilin overexpressing tumors and who likely are not quite as close to death’s door as the patients in phase 1a.
- The phase 1a trial is taking longer than expected yet the company did not change their estimate of the trial ending by the end of the year. If the MTD is found before the trial proceeds to the last planned dose, then that should be true. Perhaps THTX expect this to be the case given what they are seeing in the current trial participants. In fact it might end sooner than the end of the year if that is the case. But if they are able to safely proceed to the last dose, then it will certainly go to the end of the year and perhaps even beyond. Still, the company has so far stuck to its year-end time frame for the end of the phase 1a. What happens on this timing is likely highly dependent on if the patients that are being treated now generally move smoothly through the dosing process without a lot of safety issues cropping up like the relatively minor one that already has at the current level of dosing. The longer the trial goes, the more it means that TH-1902 is allowing larger amounts of Docetaxel to safely enter the human body and the more Docetaxel that is able to be safely administered, the chances of seeing clinically meaningful tumor regression rise sharply. So, while we want the efficacy info as soon as possible, it is really in our best long term interests for the trial to go to its planned conclusion.