The Vision Thing: Update on LCA

Last year's "big ticket" item at ASGT was results from the first three patients in two gene transfer trials testing nearly identical products against a rare form of congenital blindness, Leber's Congenital Amaurosis (LCA). I previously blogged (here and here and here and elsewhere) on the controversial decision to move the intervention into children, given the novelty of the intervention, that the trial is primarily a safety study, and that blindness is not a fatal condition.

Today, Jean Bennett of University of Pennsylvania presented an update on the first three patients (previously reported in New England Journal of Medicine) plus results on the next three patients. Here's a synopsis. The first three patients continue to show dramatic improvement in objective measures like pupillometry (that is, their pupils are responding to flashes of light in a way that does not normally occur in patients with this form of blindness), and they show signs of improved vision.

The next three patients were children eight years or a bit older. Bennett showed dramatic footage of a child unable to find his way through a maze when using the uncorrected eye, and navigating a maze with relative ease with the corrected eye. She also showed data indicating retinal function in regions of the eye receiving vector. Improvements in vision were greater with the children than in the previous cohort- which she chalked up to the fact that retinal tissue was not as degenerated in younger patient-volunteers. The team did not observe any gene transfer-related adverse events.

The other two LCA trials were conspicuously missing from the meeting. Rumor has it that the Penn team has been far more successful recruiting patients with this rare disorder. Bennett flashed a slide at the beginning of her presentation showing that patients had been accrued from several continents- North America, Africa, Europe, and elsewhere. Patients in the second cohort, according to Bennett, are begging to have their second eye dosed. (photo credit: Ferran 2009).

Mice- Three Different Ones: Towards More Robust Preclinical Experiments

One of the most exciting and intellectually compelling talks thus far at the American Society of Gene Therapy meeting was Pedro Lowenstein's.  A preclinical researcher who works on gene transfer approaches to brain malignancies (among other things), Lowenstein asked the question: why do so many gene transfer interventions that look promising in the laboratory fail during clinical testing? His answer: preclinical studies lack "robustness."

In short,  first-in-human trials are typically launched on the basis of a pivotal laboratory study showing statistically significant differences between treatment and control arms. In addition to decrying the "p-value" fetish- in which researchers, journal editors, and granting agencies view "statistical significance" as having magical qualities- Lowenstein also urged preclinical researchers to test the "nuances" and "robustness" of their systems before moving into human studies.

He provided numerous provocative examples where a single preclinical study showed very impressive, "significant" effects on treating cancer in mice. When the identical intervention was tried with seemingly small variations (e.g. different mouse strains used, different gene promotors tried, etc.), the "significant effects" vanished.  In short, Lowenstein's answer to the question of why so many human trials fail to recapitulate major effects seen in laboratory studies is: we aren't designing and reviewing preclinical studies properly. Anyone (is there one?) who has followed this blog knows: I completely agree. This is an ethical issue in scientific clothing. (photo credit: Rick Eh, 2008)

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)