Thursday, March 27, 2008

Low Summit: Setbacks in HIV Vaccine Research

March 26 NYTimes and Washington Post ran stories about a "summit meeting" of HIV vaccine researchers at the NIH. According to the reports, the meeting was prompted by a widely publicized study in which a highly promising Merck HIV vaccine candidate proved ineffective in a large placebo controlled study. Even more disturbing is an analysis indicating that the vaccine might have increased seroconversion rates in volunteers who received the vaccine.

Interestingly, news reports have not tagged this as a setback for gene transfer– perhaps because it does not involve genetic modification of a recipient's tissues. But the vaccine involved strategies– namely, genetically modified adenoviruses– that conventionally fall under the rubric of gene transfer. This counts as yet another reminder of the profound uncertainties and complexities surrounding gene transfer translational research. Over the next week, I'll continue my commentary on this event. (photo credit: ciao chow 2007)

Tuesday, March 25, 2008

Misfolding Proteins, MisLede-ing Headlines?

On March 14th, the Guardian reported on a recent advance using gene transfer against a degenerative brain condition called spinalcerebellar ataxia.  The condition belongs to a class of diseases that also includes Huntington's disease, and as the report indicates, the study could prove useful for many other degenerative brain disorders.

The lede begins "Scientists are a step closer to curing a severe inherited brain-wasting disease using gene therapy."  Without diminishing the value of the study, readers should interpret the story with caution.  Among the limitations of studies like these, two stand out.  First, perhaps more than any single class of diseases, those involving neurodegenerative diseases have the highest failure rate in terms of preclinical findings translating into clinical applications.  Second, most brain degenerative diseases involve multiple brain regions.  But most gene transfer strategies, while thinking globally, target locally.  As such, they seem unlikely to halt progression of disease in regions of the brain that are not specifically targeted. (photo credit: moon rhythm 2006)

Friday, March 21, 2008

Little Orphan Ending

...At any rate, the NEJM article describes four bills as having been introduced in the U.S. Congress in 2007 to expedite approval of follow-on protein products.  None reached the floor.  The article cheerfully concludes "despite failures of the bills... [they] collectively represent important first steps that should help stimulate further discourse... and signal an end to the de facto permanent patent that a recombinant protein therapeutic currently enjoys."  In the meantime, its a hard knock life for persons with ultra-rare disorders.   (photo credit: dishevld 2007)

Thursday, March 20, 2008

A Fruity Defense?

...Another reason why drugs like Cerezyme are so expensive is because it is very difficult for generic drug companies to license follow-on (that is, generic) drugs under existing drug regulations. In the March 17 issue of New England Journal of Medicine, two Boston-based researchers review the legal and regulatory environment for generic protein-drugs.

Under the Hatch-Waxman Act, drug manufacturers can market generic versions of a drug provided a sponsor can show bioequivalence. But because of a quirk in the history of drug regulation, products regulated as biologicals can not follow the conventional path to generic approval.  The biotechnology industry opposes licensure on the basis of bioequivalence, arguing that "the process is the product." Does this sound familiar to anyone? It might be a plausible position: different manufacturing processes can alter protein folding or post-translational modifications, which in turn can affect immunogenicity and pharmacokinetics. But it directly contradicts the biotechnology industry's position that GM foods should be regulated as products, not processes. (photo credit: Steelepop 2006)

Wednesday, March 19, 2008

The Cost of Orphan Upkeep

Why is Cerezyme so expensive? One reason is that it targets an ultra-rare disease. Drug companies generally avoid developing products for such "orphan diseases" because there is little consumer demand. To spur development of orphan drugs, the U.S. and other countries have enacted legislation granting market exclusivity (in the U.S., seven years) for orphan drug products. 

Gene transfer products aimed at genetic diseases will likely have orphan disease status, which should prompt us to think carefully about how access to this promising technology platform will be e(i)nsured. (photo credit: klynslis, 2007)

Tuesday, March 18, 2008

Wardens of the Orphanage

...the other NYTimes article on Cerezyme concerned Genzyme's cultivation of relationships with the small Gaucher's disease population.  The article described Genzyme as employing a staff of 50 to help patients negotiate insurance coverage for their products.  Genzyme has also established treatment centers and built a stable of Gaucher's specialists.  Said one Gaucher's specialist, Genzyme has "monopoloized the disease itself, not just the medicine."  (image credit: George Cruikshank, c. 1837)

Monday, March 17, 2008

Cutting Recombinant Protein Pills?

On March 16, the NYTimes ran two stories on Cerezyme, an expensive protein-based drug used to treat a rare genetic disorder, Gaucher's disease. Both articles covered issues that might be emblematic of those that will be encountered when gene transfer applications are commercialized.

One article described uncertainties clinicians face in establishing the appropriate dose for Cerezyme. At $350K/year to treat a typical adult, lowering doses can have important economic benefits for patients. But with the drug licensed at a particular dose level, reliable clinical evidence on response at lower dose is not available. And Genzyme isn't about to run trials testing whether Gaucher's patients can get away with less of their product. Similar issues are raised by the treatment of wet age-related macular degeneration (AMD), where some ophthalmologists use Avastin off-label at a fraction of the cost of Lucentis, which is licensed for AMD. So are Gaucher's physicians practicing substandard medicine by considering their patients' pocketbooks, or are they treating the whole patient instead of the disease? (photocredit: banner from Genzyme website (

More on orphan drugs in the next few posts...

Monday, March 10, 2008

Gimme (and 'em) More

What are the benefits of participating in a clinical trial? Ethicists have tended to divide benefits into three categories: direct, collateral, and aspirational. The first involves medical benefits flowing from the study intervention; the second, from increased medical monitoring. The third refers to the benefits that flow to society from the knowledge gained.

But are aspirational benefits external to the individual? That is, do they flow to society exclusively, or do they accrue to individuals who participate in studies– a sort of satisfaction that comes from having "given back" to society?

This Sunday's NYTimes featured an article by David Leonhardt, titled "What Makes People Give?"  The article describes some emerging findings from a branch of economics concerned with philanthropic behavior. One area of bioethics that calls out for further empirical and analytic research is what might be called corporal philanthropy. What makes people give their bodies? And to what extent is it ethical to harness these motivations, or perhaps even to prime them, in order to induce them to give more?

Thursday, March 6, 2008

Verma Wins Vilcek Prize

Inder Verma has won the Vilcek Foundation annual award for, among other things, his work in gene transfer (for those of you who, like me, enjoy contemporary music, this year's other recipient was Oswaldo Golijov– an eclectic Argentine-born composer).

As a former editor of Molecular Therapy and in other writings, Verma has often offered thoughtful and circumspect commentary on gene transfer. I leave you with a few quotes. From a 2005 interview in the journal Gene Therapy: "the big problem in gene therapy will be immunology. We don't know whether the vector is immunogenic, or more importantly, whether the transgene is immunogenic...."  Same interview: "there has to be more... back and forth [between clinicians and basic science researchers]. That hasn't happened as much as I would have liked to have seen." From an editorial in Molecular Therapy, 2001: "new and highly experimental technologies have inherent risks and uncertainties.  Scientists must find a balance between excitement and eagerness, problem and promises, and hopes and hypes.  The reality is that the timeline of promises kept is unpredictable, but the reaction to unfulfilled expectations is predictable." (photo credit: Salk Institute, Aaronbflickr 2007)