Richard Daifuku

Event-driven, long only
Richard Daifuku
Event-driven, long only
Contributor since: 2012
Company: Phase 1two3
I have not had the time to follow-up on this, but I consider the announcement by DVAX that it had completed enrollment in the follow-up Phase 3 on September 22, 2014 to be good news. Recall that the original Phase 3 trial was put on hold by the FDA after the occurrence of a single case of Wegener's granulomatosis in the treatment arm and presumably would have done so had an significant autoimmune event been reported in the Heplisav arm of the current trial. Thus, the fact that virtually all patients should have completed their second and final injection at 4 weeks following enrollment by now, without the report such an adverse event, virtually eliminates the possibility of a clinical hold and suggests that there is a reasonable likelihood that Heplisav will meet its safety goal in this Phase 3, though of course it is always possible that some unexpected outcome could occur in the follow-up period.
Fortunately, I have not had too much experience with clinical holds. But removal of a hold less than a month after the submission of the amendment by HALO, strikes me as quite rapid. I would have thought the FDA would have taken 2-3 months. Hence, the FDA must have been reassured that HALO has properly addressed the issue of VTEs and that the benefit/risk of PEGPH20 warrants rapid resumption of the clinical trial.
It is gratifying to note that the amendment submitted to the FDA by Halozyme Therapeutics petitioning for removal of the clinical hold includes the administration of LMWH. Per the 12 May 2014 Earnings Call transcript, Helen Torrey, the CEO, stated: "The original trial had excluded some patients, but in consultation with investigators, we are excluding some other patients who may be at higher risk of events. And we did add in the recommendation that low molecular weight heparin be used as prophylaxis for patients."
Thank you for the thoughtful comments. First of all I would like to correct an erratum. In the third paragraph the sentence "The DMC probably evaluated a data set from a pre-specified cut-off and presumably now will totally review the available data." should read : "The DMC probably evaluated a data set from a pre-specified cut-off and presumably now will review the totality of the available data."
In regards to the issue of the pathogenesis of hypercoagulability in this setting, should it be confirmed, it is most likely quite complex. I agree with fezziwig2008 that mucin has been associated with platelet aggregation, however whether this is causative in this setting is unknown. There is a growing body of data supporting the use of LMWH in the context of chemotherapy of pancreatic cancer. In some published series of VTE, associations have been made of increased risk with specific chemotherapeutic agents, although I am uncertain whether the pathogenic basis for such associations is clear. There is also preliminary evidence that 2-O, 3-O desulfated heparin may interfere with pancreatic cancer invasion, metastasis and help reduce chemotherapy resistance by inhibiting P and L selectins, heparanase and the HMGB1-RAGE axis, which could be another reason to consider the addition of a heparin, though these results need to be confirmed in a proper RCT.
You are incorrect. In the referenced study, three phosphate binders where used, only one of which was calcium based, namely: "5.9 g/d calcium acetate (1.5 g elemental calcium), 2.7 g/d lanthanum carbonate, and 6.3 g/d sevelamer carbonate."
In the discussion section of the article the following is stated: "However, progression of vascular calcification was evident not only in patients receiving calcium acetate, suggesting that use of other phosphate binders in CKD might also have unexpected and potentially, adverse consequences. It is possible that noncalcium-containing phosphate binders also enhance the availability of free intestinal calcium and result in a positive calcium balance."
It is important when evaluating scientific information to be guided by the data not prejudice.
Thank you for your thoughtful comments. While I did not review the Japanese data, I did mention them twice in the article and assume that they may act as confirmatory of the US data for the FDA, as KERX's own database is rather small. While I mentioned the Phase 2 you are referencing, I did not further include it in the discussion because it is not currently the subject of an NDA. It certainly is possible that ferric citrate will be approved, result in both correction of iron deficiency anemia and hyperphosphatemia, and be commercially succesful, but other scenarios are also possible. As I mentioned there is some evidence that use of phosphate binders in the US is declining and use of ESAs in anything but severe anemia is quite controversial because of the risk of higher mortality, in particular cardiovascular mortality. Decrease use of ESAs would in turn decrease the need for iron supplementation. Ultimately, it may come down to a matter of cost. How will ferric citrate be priced relative to the combination of other phosphate binders and IV iron? In a setting a lesser ESA use it is also possible that oral iron might be sufficient, in which case the cost comparison would be to a phosphate binder and oral iron.
Perhaps the simplest answer to the above comments, is to refer readers to the Q2 2012 earnings call transcript were AVEO management states: "In the course of our discussions with the FDA, the agency has expressed concern regarding this OS trend and has said that it will review the findings at the time of the NDA filing, as well as during the review of the NDA."
While it is important to be caution in comparing the value of different companies, the market capitalization [MC] of ALXA, currently at $78M, is strikingly lower than what could be considered peer companies. If one considers as peers two companies seeking approval for devices for drug inhalation currently without marketed products:
• MannKind Corporation (MNKD): MNKD [MC of $439M] has no approved products and it is not clear when its lead product AFREZZA (dry powder inhaled insulin) will be approved. Indeed when Exubera, another inhaled insulin, was withdrawn by Pfizer from the marketplace it was reported that there was an increased incidence of lung cancer among former smokers who were treated with Exubera. As a consequence, should AFREZZA be approved, it is likely that the FDA will limit the use of inhaled insulin to individuals who have never smoked and require extensive postmarketing studies to address issues related to carcinogenicity risk.
• MAP Pharmaceuticals (MAPP): MAPP [MC of $544M] has no approved products. Under development is Levadex, an inhaled dihydroergotamine for the treatment of migraine in adults. Levadex has a PDUFA date of April 13, 2013 and no other drugs in the clinic.
While the FDA will review the totality of the data, particularly with regards to safety, it would be unusual for the Agency to consider a Phase II as anything but supportive for efficacy. It is not unusual for trial designs to have a crossover component after completion of the randomized controlled trial. In this instance, the double blind is not preserved and various biases can be introduced, hence such studies are most helpful to add long term safety data not to judge efficacy.
Presumably, DVAX and the FDA had interactions around the design of the two Phase 3 trials. Amongst issues discussed, it would be common to cover sample size. Hence, it is not surprising that the overall safety database is comparable in size to that of Engerix. I made that point to further illustrate that there is no significant difference in the known safety profile of the two vaccines, one of which is approved.
No easy answer. I would certainly follow closely company communications, in particular management conference calls.