Pharma’s Cutting Edge

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.

This is destined to be one of the key HIV papers of this decade, if not longer.

–Robert Gallo

I’m a real fan of unconventional thinking and scientists who are unafraid of venturing outside of their comfort zones.  So, when I read the story of the discovery of new potential drug targets against HIV in Science recently, I was thrilled.  I believe the full article behind the news piece requires a subscription; if you have one it’s worth at least a quick read-through.

Stephen Elledge is a pioneer in the use of “forward genetics” to screen for host factors that influence (suppress and or promote) the malignant phenotype (see this for an example of his group’s creative scientific approach).  In Elledge’s brand of forward genetics applied to cancer target screening, he and his team apply massive pools of interfering RNA to cells of various types to determine whether blocking endogenous gene transcription modulates the malignant cell phenotype. 

In the recent Science paper, Elledge and his collaborators used the same approach with a foreign invader–HIV.  I don’t know whose idea that was, but it was brilliant, and I give Elledge lots of credit for not shying away from a complex, costly, time-consuming HIV study despite his previous lack of experience working with the virus.  In short, the labs grew transformed epithelial cells (HeLa) transfected with some 21,000 pools of siRNAs in pools of 4 siRNAs per gene (i.e. siRNAs against all expressed human genes with transcription-suppresion redundancy to help gaurd against false positives and negatives) and then infected the cells with HIV-1.  When HIV-1 was able to replicate despite host-gene transcription inhibition, the scientists could conclude that the host gene probably wasn’t important for HIV replication, but if HIV replication was disrupted, they could surmise that a host protein involved in HIV replication had been discovered.  As you’ll read, the group found 273 host proteins that HIV relies upon for replication, only 36 of which had been previously discovered, thus explaining how HIV is able to so effectively parasitize its human hosts despite having a genome of just 9000 RNA bases.

As this is a scientific paper, the authors themselves have respectfully avoided aggrandizing this work and their screening approach in general, but this type of study is potentially very clinically relevant in the near-should be a more fruitful strategy to eliminate the virus from the body.  This is because HIV can easily mutate in the face of selection pressure from drugs targeting its own proteins, but it will be much harder for HIV to mutate to circumvent a blockade of a host target (or two) that it requires for reproduction. 

The accompanying news story expresses some skepticism from a Novartis researcher regarding the ease of discovering drugs targeting HDFs and the willingness of pharma to fund such work.  I frankly can’t understand such skepticism, but perhaps the story excerpted the interview in order to provide a bit of contrast to the enthusiasm from Dr. Gallo that opened the piece.  Yes, the HDFs are mostly internal cellular targets, and yes, they probably have some important roles to play in normal host functions, but let’s remember that we already use lots of drugs that fit this description, particularly in oncology, and although side effects are common, so are benefits.  As for pharma funding the work needed to capitalize on this work, let’s remember that it’s one thing to gauge the suits’ interests in the face of established pathway opportunities, and it’s quite another to anticipate their interest in the face of potential therapeutic breakthroughs with large commercial potential.   In my mind, this is a must-do opportunity for any company with virology capabilities and experience.  From a platform perspective, I’d be surprised if most large discovery outfits aren’t already taking advantage of genome-wide functional screening to identify the host factors enabling invaders to live at our expense, whether those invaders be infectious organisms or our own cells gone awry.

Genitope’s Webcast

A week ago Genitope reported the results of a pivotal Phase 3 trial for its only clinical candidate, the idiotype-specific, personalized active immunotherapy for Non-Hodgkin’s Lymphoma, known as MyVax.  I’ve been interested in this budding therapy since around the time the company went public in early 2004, which roughly coincided with the start of the Phase 3 study.  That was back when I was testing my proclivity for biotech equity analysis, so I began following the company.  

I remember being impressed with the long clinical experience with this form of personalized therapy, which dates back some two decades and which was nurtured by no less than Dr. Ronald Levy of Stanford (who you might know as one of the founders of IDEC Pharmaceuticals and a pioneer of immunotherapy for cancer, lymphoma in particular; see this profile).  Based largely on the Phase 2 experience of Dr. Levy and others, which included a convincing number of long-term remissions with MyVax and MyVax-similar idiotype immunotherapy, I recommended investors buy Genitope stock.  I think the stock was just under $10/share then.

My feelings about the stock and the likelihood of a successful Phase 3 study changed dramatically after a second planned interim analysis of efficacy of the MyVax Phase 3 study failed to demonstrate superiority of the therapeutic vaccine over control measured as progression-free survival, but I’m getting ahead of myself.

Backing up to the beginning of the Phase 3 study, its purpose was to test the ability of MyVax to prolong PFS in patients with newly diagnosed NHL who had received one course of chemotherapy  After a 6-month rest, patients with at least a partial response to the course of chemo were randomly assigned to therapy with either MyVax immunizations (recombinant, cancer-specific idiotype protein conjugated to KLH) + GM-CSF or KLH + GM-CSF.  Multiple immunizations were given and PFS, along with a number of biomarkers, was determined.

As mentioned, a second planned interim analysis for efficacy was perfomed in July 2006.  Based on my own accrual and hazard rate assumptions, I had expected that sufficient evidence of efficacy would be seen to allow stopping the trial at that point.  However, the trial was continued.  I suspected then that the study would miss its primary endpoint.  Full planned follow-up was completed earlier this month and, as you’ll see from the market reaction, the study missed its primary endpoint.

What interests me about this story is less the ostensibly failed study and more the way Genitope spun the news into a positive story about MyVax.  “Simply put,” said CEO Dan Denney Jr., “MyVax works.”  Dr. Denney went on to explain that the primary endpoint was missed because the KLH arm did better than expected, with some patients mounting an immune response that caused prolonged PFS.  However, a secondary endpoint that was “highly statistically significant” showed that MyVax prolonged PFS in a subgroup of the subjects who mounted a “positive immune response” to the therapy when compared with those who did not mount such a response to MyVax. Read the rest of this entry »