Since being placed on clinical hold in December, Halo has generated additional data from the HT-100 clinical program and completed several toxicology studies, and provided this information to FDA in a Complete Response filing. Halo expects a decision from FDA regarding lifting the clinical hold by the end of May. At that time, the FDA may lift the clinical hold entirely, allow Halo to continue the clinical program but with some restrictions (a partial clinical hold), or maintain the clinical hold pending additional information.
If FDA does lift the clinical hold, Halo reports that it will immediately resume the active HT-100 clinical program.
Halo has updated its Q&A document in light of this filing (download PDF):
Q. What is the status of the Halo HT-100 clinical program?
A. The program is paused. No patients are taking drug, and we are not screening or enrolling new patients. Patients currently in the program are continuing to visit clinical sites for some scheduled visits. As detailed below, however, Halo is working actively with FDA to resume clinical development of HT-100 for DMD.
Q. Why is the trial not continuing as planned?
A. FDA has placed HT-100 for Duchenne on “clinical hold.” A clinical hold is a legal requirement that no further dosing of patients take place. It is essentially a pause in a clinical program while new data is generated and evaluated, and a decision can be made about the best way to move forward with development. It is not uncommon for products in development to be placed on clinical hold, and many marketed drugs that today are used safely and effectively were at times in their development placed on clinical hold.
Q. Why did FDA place HT-100 on clinical hold?
A. As part of Halo’s efforts to accelerate HT-100 development, Halo was conducting a toxicology study in dogs in parallel with the clinical program. This toxicology study is a prerequisite for future clinical studies, and we were conducting this study to ensure no delays in future clinical development of HT-100. The study included an evaluation of higher oral doses of halofuginone (the active ingredient in HT-100) than had been used in most earlier toxicology studies; the higher doses were made possible because HT- 100, Halo’s proprietary formulation of halofuginone, is better tolerated than previous formulations of the drug candidate. In this study, the dogs got higher exposures (levels of halofuginone in their blood) than in previous studies, and some of the dogs had serious adverse reactions after taking the first or the first few doses. As required by law, Halo quickly reported the available, preliminary findings from this study to FDA. FDA has asked Halo to provide additional information, including the final findings from this toxicology study, to the Agency. Halo has recently provided this data to FDA. Until FDA has a chance to review the relevant data, however, the Agency has required that we not dose patients and the clinical hold remains in place.
Q. Have there been safety issues in the HT-100 clinical program?
A. No. There have been no results in the on-going clinical trials suggesting a safety concern in patients in the HT-100 clinical program. So far in the clinical program, there have been no significant side effects or laboratory value abnormalities of any kind following treatment with the HT-100 medication. No one has dropped out of the study and no one has had to be hospitalized for any reason. The clinical hold is based on findings in the dog study and not on findings in the HT-100 clinical program.
Q. What was Halo’s response to the toxicology study findings? Why didn’t you stop the clinical program?
A. Halo carefully evaluated the findings from the toxicology study, and considered them in the context of other toxicology and human clinical data generated with HT-100 and halofuginone. Until we had additional data, Halo elected not to escalate to higher repeat doses in the clinical program, but concluded that it was appropriate to continue dosing at the levels that were already being studied in the clinical program. At these doses, patients have been taking HT-100 daily for between 1 and 3 months; been carefully monitored on an ongoing basis by their own physicians, Halo’s medical monitor, and a pharmacovigilance (safety review) committee chaired by a clinical investigator; and no data or results in patients were seen indicating a potential safety issue. Therefore, Halo concluded that it was appropriate to continue treatment of patients currently in the study but wait for additional data before escalating to higher doses. FDA, however, has required us to stop dosing all patients.
Q. Is FDA working with you to allow the program to move forward?
A. Yes. We have engaged in an active dialogue with FDA to clarify their issues and a path to address them, and the Agency provided us with written documentation regarding the clinical hold—a process that often takes 30 days—within a day of their decision. We believe this responsiveness is a reflection of FDA’s commitment to work with us to quickly resolve these issues and resume clinical development.
We have subsequently filed a “Complete Response” with FDA addressing their concerns and expect a reply from the Agency by the end of May. At that time, the FDA may lift the clinical hold entirely, allow Halo to continue the clinical program but with some restrictions (a partial clinical hold), or maintain the clinical hold pending additional information.
Q. Haven’t you done other animal studies looking at high-dose toxicity before? Did any of those studies have findings like this?
A. Yes, 4-week toxicity studies have previously been conducted with non-coated oral formulations of halofuginone (the HT-100 active ingredient) in other species, including the dog and the rat. As with the current dog study, higher doses were used in the rat and the no-effect-level (NOEL) was much higher in the rat than in this dog study. This tells us that the dog is likely a more sensitive species with respect to adverse effects of this drug. It would not be unusual for the dog to be a particularly sensitive species. For example, some common anti-inflammatory drugs that are sold over-the-counter cause serious adverse events and even mortality in dogs at the recommended human dose. As part of our effort to answer the questions raised by FDA, Halo completed an additional toxicology study in another species. The results of this study were included in the recently- submitted Complete Response.
Q. If you thought that the dog was particularly sensitive to the side effects of the active ingredient in HT-100, why did you do a study with higher doses in that species?
A. Halo’s HT-100 formulation of halofuginone increases tolerability and allows dosing at higher levels in the dog. The purpose of a toxicology study is to understand the toxicities (negative side effects) of a drug. This allows you to better manage the safety of the drug in humans since you can monitor and manage these known side effects. Once we had addressed the previous dose-limiting toxicity (emesis, or vomiting) of halofuginone with Halo’s proprietary HT-100 formulation, the appropriate next step was to identify the toxicities that would emerge at higher doses.
Q. Do you plan to restart the clinical program? If so, when?
A. Yes, this is our highest priority. Halo intends to resume clinical development of HT- 100 as soon as possible. Since being placed on clinical hold, we have generated additional data from the clinical program and completed several toxicology studies, and provided this information to FDA in a Complete Response filing. Halo expects a decision from FDA regarding lifting the clinical hold by the end of May. If FDA does lift the clinical hold, we will immediately resume the active HT-100 clinical program.