Nexavar misses. But did it really?

News today that Nexavar flunked its' Phase III trial in lung cancer. (NSCLC)

I'll be curious to see the data present at ASCO, because I'm not sure that they really failed. While Nexavar missed the primary endpoint (overall survival (OS)), there was an improvement in the secondary endpoint (progression-free survival(PFS.))

(I've yet to see the relevant figures. All I can go on are news reports.)

Also: every patient in the Nexavar trials had failed at least two previous (standard) therapies, with some having failed three. For NSCLC, you're talking about surgery, radiation, and chemo (2 or 3 of the 3 therapies) before being treated with the experimental targeted drug.

NSCLC is a huge market (~250,000 annual cases in the US alone) but has not yet been broadly cracked by a targeted therapeutic. (Iressa had approval, and Xalkori has approval for use in a very small %age of patients. Tarceva and Avastin both have approval, but clinicians are skeptical and the economic argument is suspect.)

But we have every reason to believe that NSCLC can be impacted by targeting EGFR and/or VEGF - Sutent (Pfizer's competitor to Nexavar) is also in late stage NSCLC trials, and a variety of not-yet-approved targeted therapies are also likely to try to impact NSCLC. Because of the large number of annual cases, and the need to audition as a thrid-line therapy, perhaps we're just setting the the bar too high or setting these trials up for failure.



(please pardon the upcoming rant)

Independent of the judgement on Nexavar in NSCLC, I am very disappointed at the FDA mandate of a placebo arm for oncology trials using late-stage, terminal patients such as the Nexavar trial discussed above. I fully appreciate that to run the most scientifically bullet-proof trial requires a control arm, but what is the humanity in dosing late-stage cancer patients with a placebo? Not only are you potentially generating false hope for the patient and their family, it seems utterly wasteful. With nearly a million cases of NSCLC every year, and decades of data tracking patient outcomes, don't we know by now what the OS and PFS are for NSCLC patients at a given stage?

I'd like to see an FDA/NCI-led project to calculate baseline survival expectation across the most lethal cancers, with these standards to serve as stand-ins for placebo arms. I'm not suggesting relaxing approval standards (I will in a minute), but instead normalizing for humanitarian reasons and economic reasons. Even better, such an FDA/NCI study would be a springboard to genomic-level understanding of outcomes.

Eliminating the placebo arm of trials of late-stage cancer patients would immediately double the base of trials-eligible patients - something very important as on of the hardest things of trial design is recruitment. (The Nexavar NSCLC trial was based on ~700 patients recruited at ~150 locations. Imagine what a pain it is to manage numbers like this, and how much $$$ could be saved if ~350 patients were not needed.)

The two reasons that the use of placebo arms continue (other than seeking perfection in experiments) are that

1) for many drug/disease combination, the survival benefit may be tiny (4.5 months versus 3), to the point of being very difficult to detect.

2) regulators have a negative biased (against approval), mostly for CYA reasons. No one ever got fired at the FDA for being too picky with approvals, while a sure way to get fired at the FDA is to be too permissive.

Combining these two arguments raises the bar for drug approvals. To obviate this, I would make the survival standards generated by the FDA/NIH (discussed above) a simple hurdle - if a drug clears the baseline hurdle survival rate or just ties it, approval is automatic, in contrast to the current approach of requiring placebo arms in order to demonstrate the statistical significance of the trial outcomes.

(Yes, I did just argue against a fundamental aspect of data analysis, but we're talking about cancer here. We need more shots on goal, and more importantly, more learning. We don't really learn anything from a placebo arm patient when we already have millions of data points in our databases.)

(end rant)

DNA, RNA, and….XNA?

A UK team synthesized DNA-like and RNA-like chemicals with similar properties, though using never seen-before chemistry to act as the structure for the nucleobase genetic information. (In other words, traditional A's, G's, T's. and C's, but novel structures in place of the ribose or deoxyribose sugar scaffolding. Good scientific over views can be found here or here.)

The resulting molecules are referred to as XNA - xeno nucleic acids. The implications of XNAs are profound, and I'm not even counting the conclusion that it now seems that life need not be based on DNA or RNA. (I can't wait to see how the evolutionists and creationists spin this news.)

The UK team's research represents the dawn of a new research modality or at least a re-definition of the science of biochemistry. XNAs could be a new source of therapeutic compounds or a source of new biomaterials. XNAs could be a key component of quantum computing (it would seem that XNAs could represent organic memory storage).

My first thought, as I contemplate how to explain the significance of XNAs to a non-bio-geek, is to suggest a mainstream analogy: DNA & RNA are traditional operating systems that we have grown up with and almost mastered, like Linux or Windows. The development of XNA is like the establishment of a different but ubiquitous operating system like Java. Like Java, XNA could enable exciting new applications in a breadth of industries or operating systems.

I think XNAs will kickstart a wave of interest in chemistry and synthetic biology research, not just in traditional biochemistry groups, but probably as far afield as NASA (XNAs as an analog for extraterrestrial life?) and Dow Chemical (why synthesize a chemical when you can express it?)

A couple of questions to chew over as a result:

1) while XNAs represent a change in the basics of life's chemistry, is an improvement possible, or has evolutionary biology optimized our chemistry?

2) what does this mean for large synthetic biology ventures like Intrexon? Their existing IP likely just became less relevant (or valuable), but their core capabilities are now more relevant. (I'm probably getting ahead of things - the XNA technology is still a long way from commercialization.)

3) what groups will be the first to incorporate XNA in their grant proposals? Will it be drug discovery groups, who would consider XNA another lead class on the order of siRNA or aptamers or will it be chemical engineers?

4) what can be down to mitigate the inevitable new, larger, louder round of synthetic biology fear-mongering among bioethicists and bio-Luddites, as XNAs could possibly do very bad things - intentionally or unintentionally.


Of course, XNA was not the biggest scientific advance this week. That prize goes to the research team who discovered the cause of brain freeze. I wonder if the research was underwritten by Slupree Corp.