Details on the Glioblastoma Trial and a Black Box Site for Ethical Release of Inside InformationJanuary 8, 2014

The recent press release by CytRx regarding the glioblastoma trial indicated that Aldoxorubicin does indeed cross the blood-brain barrier to attack, and sometimes eradicate, glioblastoma tumors.  There has been some discussion on the Yahoo Finance CytRx board regarding a possible mechanism by which Aldox is able to move across the vascular endothelium, the “skin” which forms the walls of the blood vessels supplying the tumor cells with oxygen and nutrition.

This topic was covered by two top scientists during the Science Day presentation in June 2014: Dr. Dan van Hoff and Dr. Felix Kratz.   Both reported that the vascular endothelium within GBM tumors is defective, apparently due to the rapid growth of the tumor.  They stated that there are numerous holes in the endothelium, ranging in size between 50 and 200 nanometers.  The fact that the scientists gave specific measurements indicates to me that this is pretty well established.  (I did independent research during my undergraduate years for honors in biochemistry.  Coincidentally, my research measured the sizes of macromolecules such as ribonuclease A, by trying to pass them through microscopic holes in a membrane.  The hole sizes were first measured by passing through other molecules of various known sizes.  Presumably, the hole sizes in the endothelium were determined by a similar method, or by scanning electron microscopy.)   These are large enough to let albumin pass through unimpeded, since its size is a mere 15 nm x 3.8 nm.  Doxorubicin is much smaller, and this is the case with other chemotherapeutics as well.  Consequently, they are ALL able to cross the blood-brain barrier at tumor sites, but their success is short-lived.   They are rapidly rinsed away by the hyper efficient lymphatic drainage system of the brain 

So what is so special about Aldox?  Unlike the other chemotherapeutics (except for temazolamide, the current standard of care for GBM), Aldox has a therapeutic benefit because the rapidly multiplying cancer cells are hungry for any food they can get, and albumin is the most available since it is the main protein component of blood plasma.  They gobble it up by a process of macropinocytosis, as discovered by Dr. Daniel van Hoff, and the acidic environment inside the cell (pH reduced from 6 to 4) breaks the linker molecule binding the doxorubicin to albumin, releasing it inside the cell.  The released Dox, both inside and outside the cells, is toxic to them.

Why was the tumor removed from a subject?  Glioblastoma behaves differently than most other tumors in the body.  Instead of being a discrete, well circumscribed mass, it is more diffuse and lace-like.  The tumor is often also surrounded by an area of inflammation, and it can be impossible to distinguish between a region infiltrated by the lace-like extensions and inflammation.  For that reason, the tumor was surgically excised from one patient (or more?), and microscopic evaluation of the specimen revealed no living cancer cells.   This is exciting news, since it proves the effectiveness of Aldox as a potential cure for brain cancer, even in a patient with advanced disease.

Why was this news released now, instead of waiting until all 28 patients had completed therapy?  CytRx is currently in the process of writing an abstract to be submitted to the organizers of ASCO (American Society of Clinical Oncology) 2015, covering these early findings.   The abstract is due by the end of January, and is evaluated by an ASCO committee to determine whether CytRx should be given a spot to present these findings (and any updates) at the June 2016 annual meeting.  Since this information will be made available to ASCO soon, CytRx management wanted to release it to all investors to maintain a level playing field within the investor community.

Does anyone have early access to inside information?  There is another way that CytRx’s clinical results are made available to big pharmaceutical companies, and that is CytRx’s “black box” website.  This website is designed to provide big pharma with inside information, with the objective of interesting them in possible partnerships, which can enhance shareholder value by providing cash to accelerate and/or expand the pipeline without selling more shares.  Big pharma companies who wish to monitor research results as they occur, can sign a nondisclosure agreement, and are then granted access to this restricted site.  There, they can view results at almost the same time that CytRx receives them from the clinical testing centers.  Now, if it is a double-blind study, they will still not know which patients received Aldox, and which received the control drug(s) or placebo.  Still, it is not difficult to calculate the therapeutic benefit of Aldox, using known historical data on the control drug, and the ratio by which patients are assigned to each arm of the trial.   For example, suppose that Aldox is being compared to Dox, and every 3 patients are randomly assigned in a 2:1 ratio Aldox:Dox.  If Dox gives a progression-free survival of 10 months, and the average PFS for all of the patients is 20 months, we can calculate that the PFS for Aldox is 25 months because (25 + 25 + 10) /3 = 20. 

Why is a Japanese pharmaceutical company interested in Aldox? The GBM study is an open label study, so big pharma did not need to do any calculations to see the promising clinical benefits of Aldox in some of the first 12 patients in the GBM trial.   This may be one reason that at least one Japanese pharmaceutical company is currently showing interest in partnering with CytRx.  As Mr. Kriegsman mentioned at a recent investor conference, this partnership, if sealed, would involve CytRx selling the rights to market Aldox in one or more indications within Japan, in exchange for cash payments.  This cash would be mainly used to advance and possibly expand the company’s research programs, without the need to sell more shares, so that share value would not be unduly diluted.  

Other reasons why Japanese pharmaceutical companies might be interested in Aldox relate to the cancer profile of the Japanese population.  Due to still-high smoking rates, lung cancer is a bigger problem in Japan than in the United States.  Other cancers include stomach and intestinal cancers, I believe.  Today’s (1-8-14) results on HIV-related Kaposi’s sarcoma are also very promising particularly, in my view, because HIV is a high profile, politically important disease which could speed approval of this new therapy here at home.  Also, the results showed remarkable success in treating lung tumors in these patients, which may bode well for the results of CytRx’s major small cell lung cancer trial.  My guess is that the Japanese companies have seen the earliest results of the SCLC study, and are most interested in buying the rights to market Aldox in Japan for this particular indication.  It is generally easier to get a drug through Japan’s regulatory process, so early approval there could provide useful ancillary information in support of CytRx’s future new drug applications in the United States and Europe.  

Taken all together, CytRx’s clinical research programs show promise in multiple indications, and the company is confidently preparing to be ready to market Aldox immediately should it win regulatory approval.  I am very confident that it will, and I predict a market value of $5 to $7 billion within four years.  That’s worth waiting for.