Thursday, September 24, 2009

Unwarranted pessimism on IL28A/B & HCV?

I finally got around to reading the Nature News & Views article by Iadonato and Katze summarizing and opining on the recent quartet of papers linking genetic variation around IL26B and the response to standard therapy for Hepatitis C Virus. The N&V has at least one glaring flaw and also (IMHO) goes down the cliched route of concluding that the result will be clinically useless.

The four GWAS studies found the same cluster of SNPs around IL28B, nicely cross-validating the studies. One curious statement in the N&V is
Although all of the identified variants in the three studies lie in or near the IL28B gene, none of them has an obvious effect on the function of this gene, which encodes interferon-3, a growth factor with similarities to the interferon- preparations used as treatment.

Two of the papers provide direct evidence as to at least one effect of these SNPs; one showed that the SNPs are linked to the expression of both IL28B and the nearby related gene IL28A; the other looked only at IL28B. Lower expression of these loci was correlated with the genotype with worse prognosis.

The N&V goes on with some boilerplate pessimism about GWAS studies impact on medicine
The question remains, however, as to how readily these and other observations from GWAS can be translated into meaningful changes in patient care. The field of human genetics has described many associations between specific mutations and medically important outcomes, but rarely have these observations resulted in new therapies to treat disease or in major shifts in existing treatments. This failure is exemplified by the lack of clinical benefit that followed the cloning in 1989 of the gene responsible for cystic fibrosis11 — the first example of the use of molecular genetics to discover the cause of an otherwise poorly understood condition. Although some progress has been made in treating patients with cystic fibrosis, in the ensuing 20 years neither of the two newly approved drugs for this condition were developed using knowledge of the gene mutations that cause it. Apart from a few well-characterized beneficial mutations (for example, those resulting in resistance to HIV infection), genetics has been an inefficient tool for drug discovery.

So although these findings raise the tantalizing prospect of a more personalized approach to treating HCV by tailoring treatment to patients who are most likely to benefit, the reality is more sobering. Diagnostic testing to identify likely responders to interferon may be a future possibility, but clinical decision-making will be clouded by the fact that the effect of the advantageous variant is not absolute — not all carriers of the variant clear the virus, nor do all patients lacking the variant fail to benefit from treatment. Furthermore, there is currently no alternative to interferon therapy for the HCV-infected population.
. They also pile on with graphs showing the exponential growth of Genbank and dbSNP vs. the flat numbers for INDs (new drugs into trials) and NMEs (new approvals).

Of course, I could respond with the boilerplate response (found in at least one of the papers) that patients with the "poor response" genotype. And indeed, new HCV therapies are in the pipeline, perhaps most prominently a compound under development by Vertex. Understanding if these variants affect response to the new compounds now becomes an important research question.

But, it's also stunning that the N&V authors didn't suggest a rather obvious approach suggested by these papers. Not only do patients with the "high expression" genotype respond better to therapy, but this genotype also predicts spontaneous clearance of the virus. Furthermore, these loci encode secreted immune factors. So to me at least, this can be viewed as a classic protein replacement therapy candidate -- a subset of patients produce too little of a natural protein (or two natural proteins) and providing them with recombinant protein might provide therapeutic benefit. I suspect that whatever companies hold patent claims on IL28A & IL28B are contemplating just such a strategy. This is also in stark contrast to cystic fibrosis, where the affected protein is damaged rather than underexpressed and is a membrane protein not a secreted protein. By focusing on the general difficulty of converting genetic information to therapy rather than the specific circumstances of these papers, the N&V authors completely blew it.

IL28A & IL28B loci produce proteins classified as interferons and it is another interferon (alpha) which is a key part of the standard therapy. A more extreme version (or a bit of the flip side) of the protein shortage theory would posit that the sum of the interferons is important for response -- and perhaps also for side effects. If this were the case, then increasing the dose of alpha interferon in the "low expression" genotype (or better yet, actually typing patients white cells for expression of these proteins) might be a reasonable clinical approach. Given that interferon alpha is already approved, this is the sort of clinical experimentation that goes on all the time.

Yet another angle suggested by the "IL28A/B deficiency hypothesis" is that a viable therapeutic discovery approach is to find compounds which increase expression of IL28A and/or IL28B in leukocytes. This has been a successful strategy for generating new therapeutic hypotheses in oncology. Better yet, hints may already exist -- some enterprising student should search the Broad's Connection Map or other databases of expression data for cell lines treated with compounds to identify compounds which upregulate IL28A/B transcripts. A hit in such a search or a broader screen of already approved compounds could potentially rapidly lead to clinical experiments.

The one time I had an opportunity to write a N&V (as a grad student) I got writer's block and missed the boat. It will always irk me. But, perhaps it's better to blow a chance silently rather than write such an awful, unimaginative one which stuck to stock genomics negativity rather than creatively exploring the topic at hand.
Iadonato SP, & Katze MG (2009). Genomics: Hepatitis C virus gets personal. Nature, 461 (7262), 357-8 PMID: 19759611

Ge, D., Fellay, J., Thompson, A., Simon, J., Shianna, K., Urban, T., Heinzen, E., Qiu, P., Bertelsen, A., Muir, A., Sulkowski, M., McHutchison, J., & Goldstein, D. (2009). Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance Nature, 461 (7262), 399-401 DOI: 10.1038/nature08309

Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, & Carrington M (2009). Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature PMID: 19759533

the Hepatitis C Study, Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Müller T, Bahlo M, Stewart GJ, Booth DR, & George J (2009). IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nature genetics PMID: 19749758

Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, & Mizokami M (2009). Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nature genetics PMID: 19749757

(ugh: had a serious typo in the title on first posting; now fixed & revised)

1 comment:

Jason S Simon said...

Nice Post-a few points.
1. Zymogenetics holds the IP around IL-28B and therapeutic claims. Not sure what they're doing with that however...issues patents are fairly old, unlikely they have plans for a replacement therapy

2. An immediate use of a prognostic test would be to reduce the extensive time that most patients wait to begin IFN therapy (currently on average >52 weeks). If one tested "positive" (carry the beneficial allele), likely to initiate treatment more quickly after diagnosis and stay with treatment through adverse events rather than dose reduce...If one tests negative for beneficial allele, in the absence of novel therapies right now (until HCV protease inhibitors approved...), perhaps patients would still initiate IFN sooner, but stop treatment with less regret at 16 weeks if no 2 log drop in viral load is seen.

3. I'm not sure increased dose of IFN will be of use. SPRI ran IDEAL (the trial We got the DNA from to collaborate with Goldstein) as an FDA commitment study to examine 1.5mg/kg v 1.0 mg/kg weight based dosing v Roche's IFN. The result of that trial (published in NEJM the day the Nature paper came out online) showed no difference in response between the 3 regimens. Given the difficulty of the regimen at high dose, I doubt people can go much beyond the currently approved doses without significant SAEs.

BTW, I designed the PGx study when I was at SGP, initiated the collaboration with Duke and am an author on the Nature paper.