Pharma’s Cutting Edge

NEJM — Detection of Mutations in EGFR in Circulating Lung-Cancer Cells (Sub Req)

Look to history for a sense of the import of today’s medical advances. 

Most authorities recognize TR Ashworth, writing in the Australian Medical Jorunal, as making the first discovery of cells in the blood similar to those in patients’ solid tumors (post-mortem).  That was in 1869.  I couldn’t find the original article online, but the citation is: [Ashworth TR (1869) A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aus Med J 14: 146–149, as referenced in this minireview.]

Surely, shortly after word of this discovery spread, scientists began pondering ways of exploiting this knowledge to diagnose and track the progression of cancer.  But a huge technological gulf separated the idea of using circulating tumor cells for the benefit of cancer patients and its application in the clinic.  As you might imagine, the number of circulating tumor cells (CTCs) relative to the total number of circulating blood cells is relatively small, necessitating reliable tumor cell-enrichment and detection technologies to make diagnostic/theranostic use of CTCs.

Fast forward some 135 years from Ashworth’s initial discovery to the routine use of techniques to exploit it.  In January 2004, Veridex, a J&J company, received US FDA approval to market CellSearch, a device for magnetically labeling antibody-selected epithelial cells in a blood sample, for use in patients with metastatic breast cancer as an aid to monitoring response to treatment.  The theory behind the device and accompanying analysis of the BRCA CTCs is that the number of CTCs correlates (inversely) with response to treatment.  To my knowledge, this is the only such separation/analysis system available in the U.S. for non-experimental monitoring of response to therapy via CTCs.  It has now been approved for marketing for metastatic colon and prostate cancer in addition to BRCA.

Unfortunately for Veridex and for patients, the system has not been shown to affect outcomes in metastatic breast cancer, where it has been most thoroughly studied, leading ASCO to make the following practice recommendation:

The measurement of circulating tumor cells (CTCs) should not be used to make the diagnosis of breast cancer or to influence any treatment decisions in patients with breast cancer. Similarly, the use of the recently US Food and Drug Administration–cleared test for CTCs (CellSearch Assay; Veridex, Warren, NJ) in patients with metastatic breast cancer cannot be recommended until additional validation confirms the clinical value of this test.

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Above: NMR solution structure of exenatide from Ganfyd.org

 taspoglutide advancement announcement

Lead 6 results press release

52-week data from Duration-1 trial

A bit more excitement than usual surrounded this year’s recently completed ADA annual meeting, with a flurry of news surrounding the GLP-1 mimetics and their brethren, the DPP-IV inhibitors.

In my mind, the most interesting bit of news concerned progress on so-called exenatide LAR, a once-weekly formulation for sc injection of Amylin/Lilly exenatide.  According to Amylin’s website, the LAR program is being jointly managed by Amylin/Lilly.  However, Amylin hosted an Amylin-only event at ADA to discuss the development program, leading me to speculate that Lilly’s role in the drug’s development is strictly advisory/financial.  If you know otherwise, do chime in.

Regardless of whose pulling the strings, the program has progressed well into Phase 3clinical development, and Amylin shared the 30- and 52-week results from the first (Duration-1; see above link) of the large Phase 3 studies at the meeting.  I’ve supervised and reviewed lots of clinical trials of diabetes drugs, and I can tell you that the results with exenatide LAR thus far are potentially game-changing.

Sure, there’s a long way to go until registration:  more Phase 3 studies, including head to head with DPP-IV inhibitors, and a bridging program from the research formulation to the commercial form.  Amylin knows this; its management team strikes me as completely realistic and credible regarding the difficult tasks ahead.  I also appreciate the lack of hyperbole and cheerleading we used to get from the Ginger Graham-led team.  There’s no need for these distractions when your drug does the PR for you.

Let’s look at some of the drug characteristics and Phase 3 data that make me bullish about exenatide LAR’s potential impact on type 2 diabetes:

1.9% HbA1c drop from baseline with average BL A1c in low 8’s; an improvement compared with Byetta, although the improvement appears to be confined to those with worse control at baseline.  This is probably due to the better effect on FPG in the high-A1c subgroup.  Presumably high FPG drives the higher A1c, and the LAR is able to suppress overnight FPG better than regular exenatide. 

The A1c drop was extended to 52 weeks in the extension study, which offered LAR to all participants, indicating durability of effect to 1 year.  Many other therapies start to show waning effect on A1c at 1 year.

Both FPG and PPG were suppressed, and the PPG suppression appeared more “physiologic” than with regular exenatide.

Weight loss and cholesterol/SBP reduction were similar to regular exenatide; lipid effect maybe a bit stronger.

Well-tolerated with less nausea than regular exenatide.

Once weekly administration, with 94% of the injections self-administered in the clinical trial (i.e. easy to self-administer after brief education).  Issues regarding formulation consistsency will be worked out before launch.

Compliance likely to be at least as good as Byetta (twice daily exenatide), despite presumably larger gauge needle with higher rate of injection site symptoms (primarily itching), due to the need to inject only once a week.

Once weekly injections will make the drug attractive to somewhat better-controlled patients, for whom injections are rejected as an option now.  How much more attractive awaits real-world experience, but I speculate–an educated guess–that the acceptance will be much greater than either insulin or a once-daily formulation of GLP-1 analog.  Still, I think the role is later in the disease right now, with the DPP-IV drugs dominating the early/better-controlled patient group, along with the other oral meds. 

What I think we’ll see with LAR in the marketplace (whenever that may be; we should know more by the end of this year) is that the average duration of diabetes and average A1c prior to therapy will both drop substantially relative to Byetta within a year of the LAR’s launch.  Eventually, LAR should totally supplant Byetta, and also steal some of the volume share still held by the SUs, the TZD’s, insulins, and some held by the DPP-IVs.  Like I said–game-changing.

Meanwhile, as I teased above Novo is looking like it has a real drug with its once-daily liraglutide, potentially a strong competitor to Byetta.  But remember that liraglutide is an NME; it’s got a scaredy-cat FDA in the US and a diabetes NME-unfriendly EMEA in Europe it must face before selling a thing.  Once it makes its way onto the major markets, exenatide LAR will be breathing down its neck.  Liraglutide may be able to compete for Byetta patients, but I don’t see how once daily therapy can compete with once-weekly, especially when the API in the once-weekly has an enormous amount of patient experience and clinical research behind it.

As for Ipsen/Roche (see above linked press release), they’re pressing forward for now.  They’ve really got their work cut out for them.  A straightforward “me-too” type of development program is unlikely to reap them the ROI they seek.  They’ll need to be creative in Phase 3, and focus on the unmet medical and practical needs that (might) remain after exenatide LAR hits the market. 

Finally an editorial plea, in light of the recent ACCORD and ADVANCE trial results, which suggest that drugs that carry a risk of hypoglycemia are likely not appropriate for strict glycemic control in advanced type 2 diabetes, I urge Lilly and Amylin to provide financial support for a large study of Exenatide LAR with cardiovascular endpoints to be started as soon as feasible.  It is likely our nearest best hope to reduce the risk of CV events (or at least not increase them) in older diabetics, while maintaining glycemia close to normal to prevent microvascular disease.  US government support for such a study is realistic. 

In December 2006, I described my initial impressions of Google Patent Search beta, a free USPTO patent search engine, powered by Google.  As you’ll read, I wasn’t thrilled with this early release.

So, how has Google fared with some time–nearly 17 months–to marinate its patent search engine?

First off, Google hasn’t promoted the service out of beta yet.  I don’t know how Google decides to promote a new tool to production, but I have to think that many thousands of searches have been made with it since beta testing began, and they’ve had plenty of time to work out the kinks.  Beta schmeta…is it good enough to recommend?

Once again, I’ll compare Google Patent Search directly to the USPTO search engine, as Google has not yet added international patents. 

The Google search interface has been improved and provides simple form field searching for patent number, inventor, assignee, classification code (US and international), issue date, and filing date.  Google’s advanced search operators also work, including the “-” for NOT and “OR”.

The USPTO quick search allows search of all these fields plus some two dozen more, and their advanced search interface allows all of these delimiters to be accessed simultaneously, albeit using a complex syntax.  If you’re doing serious patent research, Google’s search interface will simply not provide you with enough search specificity to meet your needs.

For simple searches, the USPTO quick search and Google Patent advanced search interfaces are similar in user-friendliness and utility.  (The basic Google Patent search has very limited utility.)  So, the key differentiators will be result accuracy and result presentation.

Last time I looked at the Google service, it offered results in a list sorted by relevance-according-to-Google.  In my mind, this made the service virtually useless for industry-based searchers.  Google has since added in a date sorting.  I would have preferred having a patent number sorting option, but date at least makes the search worth doing.

As for relevance, I’m still scratching my head with Google.  It seems to return results in some quasi-random way.  For instance, search the exact phrase (in quotes) “Eli Lilly” the field assignee name, using the entire USPTO issued patent database (quick search) or Google Patent Search (advanced search).  The USPTO returns 3,793 hits dating back to 1971.  Google returns only 527 issued patents dated to 1976, and very strangely, only 461 filings of any status (issued plus applications combined–yes this number is lower than issued patnets alone!), and just 46 patent applications (USPTO returns 94 applications).

Clearly, there is something amiss with Google’s Patent Search.  It really does behave as a beta product, despite its protracted time in use.   It has some potential advantages to the USPTO search in theory, claiming, for example, full-content access to all US issued patents, whereas the USPTO offers full-text access only as far back as 1976.  But it remains fatally flawed for all research purposes except cherry-picking individual patents by number, when you are certain the patent number is correct.

Phase 2 Gemini Study Top-line Results Described

This morning Alnylam presented top-line results from its Phase 2 POC study of anti-RSV RNAi therapy, known as ALN-RSV01, demonstrating an effect of the therapy in experimental upper respiratory RSV infection.

The intent of thes study was to determine whether relatively high doses of ALNRSV-01 delivered intranasally to experimentally infected healthy volunteers could reduce local viral load.  The volunteers were given two doses of the drug (one per day) prior to being nasally inoculated with roughly 10,000 viral particles (much higher than the typical natural infection load).  Then they were given further treatments of ALN-RSV01 or a matching placebo for an additional three days after inoculation; all told volunteers were quarantined for 12 days (yikes).  In order to ensure a reasonable rate of infection, potential volunteers were screened for anti-RSV antibodies.  Those with clinically relevant titers of antibodies were excluded from the study, necessitating the screening of 1,000 people to enroll 88 (double yikes). 

The rate of infection (primary endpoint, by plaque assay), viral load measures, and clinical symptoms were assessed.  In a nutshell, the therapy reduced the rate of viral infection by a number of measures and the primary endpoint was met.  Trends were seen in viral load measures but not in symptoms, which were modest in any case. 

This was a robust demonstration that RNAi delivered locally (and prophylactically) can reduce (but not eliminate) viral infection.  In that respect, it is valuable as a proof of concept in humans for topically delivered RNAi acting against viral cells directly at the site of inoculation.  I don’t think it should be construed as a proper POC of systemically delivered RNAi under any circumstances, nor for topically delivered RNAi directed against endogenous gene expression.  So, RNAi is still in its infancy, clinically speaking, but it’s showing signs of life. 

Investors on the conference call were interested in what this study might mean for the future of this particular therapy.  I think Alnylam’s management were appropriately circumspect when addressing the issue.  If I were an investor (I’m not), I’d be relieved that this important first hurdle has been cleared, but I’d also have to admit to myself that this therapy is still a long way from proving itself in naturally infected kids and fragile adults with RSV pneumonia.  Alnylam mentioned that the next Phase 2 will be a study of adults with naturally occurring RSV infection, presumably upper respiratory infection.  In that setting, ALN-RSV01 won’t be given a headstart over the virus–treatment won’t begin until clinical symptoms have appeared–and effects on symptoms would be helpful to guide future studies and gain investor confidence.  So, like any other drug, we’ll have to see.  But at least now there’s a decent reason to watch.

A few years back, as a consultant, I was asked by GTX to take a look at their unreleased Phase 2 ACAPODENE (toremifene citrate 80 mg) data and to make some recommendations and predictions for Phase 3.  I remember being very bullish on the prospects for this therapy and finding very little for the company to worry about.  They seemed appropriately restrained in their own optimism, so I wasn’t too concerned about them under-powering Phase 3 by assuming too much efficacy.  As it turns out, Phase 2 basically told the same story that GTx is now reporting from their top-line Phase 3 results that tested the drug in men with prostate cancer who’d undergone androgen deprivation therapy (ADT). 

Toremifene, you might know, is a SERM, like its kissing chemical cousin tamoxifen.  For years, the drug–marketed by Orion as Fareston–at lower doses has been used to treatment hormone-responsive postmenopausal breast cancer patients, as its antiestrogenic activity inhibits estrogen-driven cancer cell growth. 

Now, toremifene’s estrogen-like effects in bone and on lipid metabolism, which were always suspected of being a bit stronger than those of tamoxifen, are being exploited in men to inhibit excessive bone resorption and correct the dyslipidemia caused by ADT.  The data released by GTx suggest that the drug worked quite well in both respects, with a modest (~2x) early increase in the risk of VTE, a known risk of SERMs in women.  Data on hot flashes are pending, but you can expect to hear of an increased risk of hot flashes as well; I’m guessing 4x over placebo for the first year, with few med discontinuations due to them.  No news on stroke risk, which is good news.

This is potentially a very inspiring story for those of us who still feel positive about the value of this industry.  Were high-dose toremifene repurposed by a large company, we’d soon be reading criticisms about anticonsumer lifecycle management strategies and a persistent lack of innovation alongside the news of its clinical success (you know, to balance out any good feelings industry proponents might be having).  But that’s what is so great about this situation.  We won’t have to hear these criticisms alongside the good news, because GTx is a small company, largely backed by one guy (JR Hyde, of AutoZone notoriety) with deep pockets, who believed in his people (most notably Mitch Steiner and Marc Hanover) and their ability to bring this drug along without the help from big pharma.  That was gutsy, some might say crazy, but I think most Americans will appreciate the story.

That GTx are likely to have found an important new therapy without the need for medicinal chemistry to create something brand new is a beautiful example of how innovations should be judged by the value they offer and not by the mechanisms through which ideas become reality.  Should ACAPODENE make it to the market, it will be a triumph of ingenuity and entrepreneurial spirit.  We need more stories like this.  I’m sure patients with serious illness would agree.

I’ll update this story when we see further data and learn of regulatory progress.  I anticipate priority review at FDA.

Disclosures:  As indicated, I received consulting revenue from GTx several years ago; none since then.  I own no stock in their company.