ASGT in San Diego

This year's annual meeting of the American Society of Gene Therapy is in San Diego.  I've been to several interesting talks thus far, and plan to post entries on a few. For now, here's an overview of some major (or some not so major) clinical developments in gene transfer that are being reported at this meeting.

1- Last year, I predicted that the first gene transfer applications were nearing licensure.  Not so fast.  Because of concurrent sessions, I was unable to attend the entire talk given by Robert Shaw of the British biotech company Ark Therapeutics.  Ark has developed a gene transfer approach, Cerepro, that uses adenovirus to treat malignant glioma (which is one of the most aggressive types of cancer).  Ark recently applied to the European drug regulatory authority, EMEA, for registration of Cerepro.  Why not FDA? Dunno (though the speaker stated that the review standards are more or less the same).  The data behind the product are less than earth shaking.  According to information available over the web [proviso- these data are from August 2008], the pivotal phase 3 study of Cerepro showed only a 42-day increase in survival for patients in the active drug arm.  And the product caused "increases" in hemiparesis, aphasia, and fever.

2- Another somewhat discouraging indication of the challenges in reaching licensure for gene transfer products was a session titled "late stage industry clinical trials."  To me, late stage means phase 3.  But three talks centered on phase 1/2 studies, and none presented phase 3 results.  The first talk was given by Ceregene on their Parkinson's disease product Cerepro. The product did not show any significant advantage over sham for their primary endpoint.  

3- Last year, the "buzz" at ASGT was the preliminary results from three studies testing AAV vectors for a form of congenital blindness, LCA. I also discussed the somewhat ethically controversial decision to move this study into children.  I will look forward to attending Jean Bennett's talk on Friday; her abstract reports that her LCA study has enrolled "9 children and young adults" ranging from age 8 to 26 years.  The abstract claims improvement in "subjective and objective" measures of vision.  To be continued... (photo credit: slack12, 2008)

A Cure? "Compassionate Use" and Drug Regulation

Are government bureaucrats keeping dying patients from getting access to possibly life saving drugs?  That's one way to read Margaret Talbot's story in the Sunday New York Times ("Fighting for a Last Chance at Life."  May 17, 2009).  Talbot describes how mother Kathy Thompson sought access to an unlicensed therapy Iplex for her Amyotrophic Lateral Sclerosis (ALS)- afflicted son, Joshua.  The drug, Iplex, was not licensed by FDA for use against ALS, and an almost identical drug had failed two randomized controlled trials in patients with ALS.

Buoyed by anecdotal patient reports on web forums, Thompson sought compassionate use access from the FDA and was rebuffed.  She ultimately engaged the Washington Legal Foundation to appeal FDA's rejection of Thompson's request for the drug. FDA relented, allowing the drug maker to run a trial of Iplex– recouping all costs from enrolled patients (about $100k/year).

There are a number of troubling features in this story.  First, the article (or, at least Thomspson) makes FDA out to be a bunch of heartless bastards. Some, like the Washington Legal Foundation, view FDA's stringency as an affront to the "civil liberties of American Business" (to paraphrase Haley Barbour). But let's remember that, for over a half a century, FDA has played a critical role in public health by keeping unproven drugs out of the pharmacy. Grants of compassionate use seriously weaken the ability of the state to collect evidence of a drug's safety and efficacy, because they make enrollment in clinical trials much more difficult. So there need to be some pretty compelling policy reasons- backed by persuasive evidence- to grant exemptions.

Second, the article states "Many are Campaigning for the chance to be treated with drugs whose safety and effectiveness is not yet known."  While Iplex itself hasn't been tested against ALS, its active ingredient has been tested in two large randomized controlled trials. Both failed to show any advantage over placebo.

Third, there's the business of allowing desperate patients to "buy" their slots in the trial approved by FDA. For starters, it's hard to imagine that a trial that included only "several dozen patients" is going to be of any use in measuring safety or efficacy (the two failed studies involved about 180 and 300 patients). As well, there is something unseemly about a "compassionate use" exemption that is priced at $100K.

ALS is an awful disease, and I feel for people like Thompson and her son. Surely, more and better care and research are needed for ALS sufferers. But where's the compassion in a program that ministers only all to the most wealthy and politically connected? More importantly, where's the compassion in undermining a system that ultimately protects us all from clinics that prey on the desperation of patients, and companies that sell unsafe, ineffective, and extremely expensive drugs? (photo credit: Monster 2007)

Basic Science and Pharmaceutical Productivity

One of the great paradoxes of contemporary medicine has been a seeming inverse relationship between investment in basic science and registration of novel new drugs by regulatory agencies. The delay between basic science discoveries and clinical applications can be very long; many promising drug candidates are called on the basis of laboratory discovery, but few are chosen.

Cancer drugs, in particular, have one of the highest rates of failure as measured by the probability that a new drug entering phase 1 clinical testing will prove promising enough to eventually be registered by the FDA. One 2004 report pegged this figure at about 5%.

The question is: will such discouragingly low figures hold for new classes of cancer drugs that are entering clinical testing? According to Ian Walker and Herbie Newell in the January issue of Nature Reviews Drug Discovery, maybe not. Walter and Newell examined pharmaceutical development databases to determine probabilities that a particular class of new cancer drugs– protein kinase inhibitors– will survive from phase 1 testing through to registration (the wonder drug Gleevec is in this class). They found that 53% of new kinase inhibitors that enter phase 1 trials are ultimately licensed. They conclude that their analysis "further demonstrate[s] the benefits of developing molecularly targeted therapeutics for cancer."

Here are some concerns about their analysis. First, their figures for success from phase 1 to registration for all cancer drugs (not just kinase inhibitors) are roughly three times previous estimates. This bears explaining. A second concern is that this may represent a particularly successful class of molecularly targeted agents. Third and crucially, according to a recent Nature Reviews–Cancer report, there are 11 different kinase inhibitors approved by the FDA. Eleven divided by the sample used in this paper– 137 kinase inhibitor drugs entering phase 1 testing– yields 8%– a number very similar to the 5% success rate that has been quoted elsewhere. Last, some kinase inhibitors are "me-toos" or at least, very closely related (e.g. panitumumab and cetexumab)

Too early, I say, to conclude that the way we are doing basic and preclinical science is beginning to bear fruit in terms of pharmaceutical productivity. (photo credit: Night Heron, Pull Chain, 2007)

Yellow Light on Gene Transfer Studies

Among the greatest heartbreaks in the field of gene transfer have been problems encountered in trials involving a rare, hereditary immune disorder, X-SCID (known popularly as "Bubble Boy" syndrome).  As is well known, a team of researchers based in Paris– and then in London– successfully reversed severe immunodeficiencies in 20 or so children using retroviral gene transfer starting around year 2000.  Shortly thereafter, however, the Paris team began observing rare leukemic disorders that were causally related to the gene transfer. To date, the Paris team has reported 4 cases of leukemia, with one leading to death. The London team has reported one leukemia.

In response to these events, the U.S. Recombinant DNA Advisory Committee (RAC) recommended that investigators only use retroviral gene transfer in the most severe situations– namely, where patients are ineligible for even high risk alternative care options like haploidentical stem cell transplantation.  RAC's recommendations were stricter than those in the U.K., which allowed children to enter a study even if they were candidates for haploidentical transplants.  

As reported in the current issue of Molecular Therapy, the RAC recently decided to liberalize its recommendations, allowing retroviral gene transfer in children who are eligible for halploidentical transplantation. RACs recommendations are still somewhat stricter than those of the UK, because the former recommends against retroviral gene transfer in children who are candidates for haploidentical transplantation but under 3.5 years age (children in this category respond better to haploidentical transplants). RAC additionally supported a similar trial involving a different vector that integrates its genome into the host's (lentiviral vectors, which are derived from HIV).

Is this gentle liberalization of standards justified?  Some will argue that the benefits of haploidentical transplantation are variable and undependable, and that since initial leukemias have been reported, researchers have made progress in improving the safety of their vectors. All this might be true, if one were evaluating this as a clinical judgment.

However, the judgment is better viewed through the lens of research rather than therapy. Though laboratory testing indicates that new retroviral and lentiviral vectors are safer than the old ones, there remain substantial uncertainties. For example, current assays for determining the oncogenicity of integrating vectors are not well worked out. Neither the new retroviral vectors nor lentiviral vectors have been used in blood stem cell gene transfer in a pediatric population. The effect of lentiviral vectors on gene sequences near their integrating sites remains poorly understood. In short, the null hypothesis of new trials is that these new vectors are no better than the old ones.

What's the safest way to refute this null hypothesis and confirm what many think, on laboratory evidence, will be the case? In my view, the safest approach– for patients as well as the field in general, which stands to lose much from another major toxicity– is to begin with the most narrow medical indication possible, which means excluding children who stand a chance of benefiting from standard (albeit suboptimal) care.  (photo credit: Jamelah 2007)

Toxic Waste?

Before testing new drugs in human beings, drug developers must first perform a series of safety tests in animals. Unfortunately, these preclinical toxicology studies are typically protected as trade secrets. In fact, many countries have laws that specifically bar drug regulators from releasing preclinical toxicology data submitted by drug developers.

Unless you take the extreme view that animal experimentation raises no ethical concerns, this represents a terrible waste of animals and a failure of researchers to enable the sacrifice of animals to enrich the bank of human knowledge. As an afterthought, it's worth mentioning that this also comes with certain opportunity costs for human beings, since such nondisclosure potentially 1-frustrates efforts by researchers to improve their knowledge about drug safety, 2- results in duplicative expenditure of human resources.

It needn't be this way, and the field of gene transfer shows one modest way toxicology data could be published and pooled. Since it was established, the National Gene Vector Laboratories, at Indiana University, have invited gene transfer researchers to submit summary data on toxicology studies to their database (the laboratory recently was eliminated and replaced with the National Gene Vector Biorepository-- NGVB for short). As described by NGVB director Ken Cornetta and project coordinator Lorraine Matheson in Molecular Therapy (April 2009), the database is intended to provide a resource for researchers so that they can cross-reference toxicology experiments in their FDA filings and avoid duplicative studies. The authors also envision the database as a resource for grant reviewers.

The database contains 27 toxicology studies in all. This number seems small when you consider the volume of gene transfer studies pursued since the database was established. The fact that every institution that has contributed to the database is a nonprofit suggests that the private sector has not taken an interest in this worthy resource. One question I have is how many private companies have used data contained in this databank in their FDA filings (this should be easy to determine).

These questions aside, other fields should create similar resources to pool data and create opportunities for data linkage. I would go so far as to say that ethics policies should require that, at a minimum, such summary data be published on a public database. The failure to do so seem a toxic waste for animals, scientists, funders, and patients alike.  (photo credit: drp, Waste Not, 2004)

The Biotechnology of Neglect

What can the biotechnology industry do for neglected diseases (infectious diseases that, because they primarily afflict low-income countries, are not heavily researched in the public or private sector)? Biotechnology enthusiasts might answer "everything," ignoring the dearth of research and development incentives for small biotechnology firms, much less the major challenges presented by the manufacture, distribution, purchase, and administration of biotechnology products. Critics might answer "nothing," drawing attention to the existing availability of simple, low cost interventions against diarrheal diseases, tuberculosis, etc..

A recent article puts forward a series of proposals on the biotechnology sector and neglected disease. In the April 2009 issue of Nature Biotechnology (Leveraging biotech's drug discovery expertise for neglected diseases), authors Joanna Lowell and Christopher Earl (of BIO Ventures for Global Health) argue that biotechnology companies can play a "pivotal role" in developing small-molecule drugs against neglected diseases. Noting that many neglected diseases involve drug targets that are similar to those for high-income country diseases, Lowell and Earl suggest that companies can simultaneously advance their primary objectives while supporting development of drugs for neglected diseases.  

They offer several reasons why biotechnology companies might do so. First is "the chance to prove technology platforms."  Companies might "leverage" philanthropic support to test biologic pathways of relevance to drugs targeting more affluent markets (I will note, without comment, that such a proposal would need to think through justice concerns). Second is employee morale: initiating such research is an important way of attracting and retaining talented and idealistic scientists. Third is "sustaining underutilized discovery platforms." Once companies have discovered a lead compound, drug discovery platforms can potentially languish.  Using this dormant capacity helps companies maintain their drug discovery platforms so that they will be available in the future.

I leave it to readers to decide the soundness of the proposals. On the one hand, the idea that biotechnology companies can derive benefits from pursuing neglected disease research seems plausible, as does the notion that the biotechnology sector has much to offer low-income countries (curiously, the article centers on small molecule drugs rather than vaccines). The authors cite a number of examples to support their claims, and BIO Ventures for Global Health has received a "seal of approval" (e.g. generous funding) from the Bill and Melinda Gates Foundation.

On the other hand, are struggling biotechnologies likely to embrace this-- especially given today's credit markets? One can be forgiven for wondering whether this is merely a PR ploy for a biotechnology industry that has sought contentious policies like strong intellectual property protections.  BIO Ventures for Global Health is, after all, an arm of the biotechnology trade association, BIO.  (photo credit: ViaMoi, Neglect, 2007)

Guinea Pig Nation?

Here is an irresistible news headline: "Public Policy That Makes Test Subjects of Us All."(New York Times, April 6, 2009). Then you open to the story only to discover, to your disappointment, that the piece is written by John Tierney, probably the most uninformed and underqualified members of the NYTimes staff.

His argument is ridiculous: that the New York City mayor's initiative to "pressure" the food industry to cut salt amounts to a big experiment that would normally have to undergo IRB review and informed consent (never mind that the initiative is not an experiment designed to further knowledge.  Never mind that the initiative is not aimed at generalizable knowledge, or that public health initiatives grounded in a state-based interest that are enacted by elected leaders have the "consent of the governed").

But in the most recent issue of JAMA, a news story (Bridget M. Kuehn, "Rare Neurological Condition Linked to Newer Monoclonal Antibody Biologics," April 8, 2009) reminds us that, in some small sense, licensure of novel biologics makes guinea pigs of us all.  The report describes how FDA recently issued an advisory on the psoriasis drug efalizumab after reports emerged that it may be associated with a risk of developing a rare and fatal brainwasting disease (progressive multifocal leukoencephalopathy, or PML).  FDA had previously issued warnings on two similar, immunomodulating drugs, and established a restricted distribution system for a third (natalizumab-- for multiple sclerosis).

In the case of natalizumab, cases of PML occurred in pre-marketing clinical trials.  For the other drugs, knowledge of the risk emerged only after drug licensing.  Risk of PML was totally unexpected, and is a reminder of the high degree of uncertainty surrounding interventions directed at the immune system.  

Premarketing clinical trials are statistically powered only to detect common, "signature" adverse events.  As we move into an era of biologics-based pharmaceuticals (and accelerated approval), expect that many adverse events will only be discovered once a drug is in widespread use.  Robust systems of pharmacovigilence will be especially critical (photo credit: Peter Guthrie, 2006).