Dr Leonard Saltz, chief of gastrointestinal oncology at Sloan-Kettering, co authored a 2012 NY Times Op-Ed article which contributed to Sloan-Kettering's decision to drop the Sanofi colon cancer drug Zaltrap due to its high cost benefit ratio. His efforts led Sanofi to halve the cost of the drug. His current cost-effect target is Abraxane. He has recently written in the New England Journal of Medicine that the added 1.8 mos in median overall survival it brings to its combination with Gemcitabine does not justify its $6000-$8000/month additional cost. Justify to whom? This is not an easy judgment. The patient, if they could, would likely pay $11,000 for an extra 7 weeks with their family However, since most patients are not paying their own medical bills, the question becomes: is worth $11,000 to keep a terminal cancer patient alive and how much does this end of life care add to the burden of the health care system? Is that amount justified in a society struggling to increase the scope of insurance coverage? From Dr. Saltz's perspective, there must be some amount of added survival which would justify the additional expense. Certainly a complete response would justify the cost. So, to paraphrase Bernard Shaw, we've established that cost benefit analysis would dictate that it's worth paying for a cure-so we're just haggling over how much less than total life expectancy is "worth"reimbursing?
Gemcitabine has been the chemotherapeutic standard of care in pancreatic cancer. In Metastatic Stage 4b, it yields a median overall survival (NYSE:MOS) of 6.5months. When Abraxane is added, that becomes 8.5 months. The combination of Abraxane and Gemcitabine is relatively well tolerated. Folfirinox is a less well tolerated generic combination of
|FOL||= Leucovorin Calcium (Folinic Acid)|
|IRIN||= Irinotecan Hydrochloride|
In the same setting of Pancreatic Stage 4b, this combination yields an MOS of 11.1 months. However adverse effects of Folfirinox have led many oncologists to first employ Abraxane-Gemcitabine, despite the difference in MOS.
So the chemotherapeutic treatment of metastatic pancreatic cancer poses two dilemmas: The most effective agent is least tolerated, and the agent which adds moderate effect to the best tolerated combination therapy is most costly.
This is where pegpH20 fits in like sunscreen at a nudist colony. In the usual (85%) setting of high hyaluron pancreatic cancer, pegpH20 infused with Gemcitabine in a Ph1b study has extended MOS from the 6.5 mos seen with Gem alone to roughly 18 mos- as reported by Halozyme at ESMO in September 2013. This effect is more than double the added MOS achieved with Abraxane. This would be impressive enough taken at face value, however since 4 of the patients were still alive at ESMO, that value will continue to grow for as long as at least three remains so. Since one of the 1b patients experienced a complete biochemical response, having their tumor marker CA19-9 level normalized, the likelihood of additional MOS seems high.
If pegpH20 does for Abraxane-Gem what it did for Gem alone, Celgene will have its answer to Dr Saltz's letter- 2 year survival, an improvement no practitioner of cost-benefit analysis could criticize. In this way Halozyme technology may very well rescue Celgene from the fate of Sanofi, or worse.
PegpH20 actually promises to do more than just extend the MOS of Abraxane-Gem. It is also being studied by Halozyme and the NCI in combination with a version of fofirinox modified by the elimination of a 5FU infusion in order to improve its tolerability. This is being done under a CRADA, meaning Halozyme is awarded full patent rights for the combination, granting a license to the US government on those patents. If pegpH20 triples mFolfirinox's MOS- the number of patients who will be able tolerate the strongest combination will increase, and we may see more 5 year survivors of metastatic pancreatic cancer. This combination would also be very promising for at least 1/4 of all colorectal tumors also found to contain high hyaluron concentrations. Fortunately, Halozyme is planning to market a Diagnostic Hyaluron Tool to identify from biopsy samples which tumors contain high hyaluron content.
Both combinations are currently being studied in Phase 2 trials. The mFolfirinox trial is being funded by Halozyme's co Collaborator- NCI. It is being performed by SWOG, an NCI supported consortium of oncologists. Given the likelihood that the Ph1b results will be proven out in one or both trials, an early halt and the treatment of the control group is quite possible. This would lead Halozyme to file its BLA with the FDA, based on Ph2 data and simultaneously apply for Breakthrough status.
Halozyme also plans to initiate a Ph2 pegpH20 study at a second anatomical site by year end. My educated guess is that it will be done in the site with the second highest- 56%- percentage of high hyaluron tumors- the breast. Abraxane is also approved for breast cancer treatment. Recently insurers have been adding obstacles to its use over generic paclitaxel due to, yes, it's added cost. Halozyme's recent secondary offer was in part justified by the needed acceleration of the pegpH20 program. Adding breast cancer as a target makes Halozyme a bigger player in the chemoenhancement market and a more valuable asset to whoever profits from the sale of Abraxane. It seems Celgene's in that nudist colony with Halozyme selling the lotion.
Disclosure: I am long HALO.