Pharma’s Cutting Edge

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 »

As you might have noticed, I’m finding it increasingly difficult to keep up a weekly or even biweekly posting schedule lately.  It’s not for a lack of interest I assure you. 

I’m revisiting the year-end best-of list that was popular last year (everyone loves a ranking, but I refuse to author a hot or not post!).  So, without further ado, these are my totally subjective picks for the best pharmaceutical (including biopharmaceutical/biologics) innovations this past year.  Only drugs eligible for sale in the US or EU after January 1st, 2007 are eligible.

1. TIE: maraviroc (Selzentry, Pfizer) and raltegravir (Isentress, Merck).  Two NMEs that attack HIV-1 via novel mechansims tie for first place in this year’s best-of list, despite the relatively modest fanfare that greeted their arrivals.

Maraviroc is the first in a class of drugs called chemokine (C-C motif) receptor 5 (CCR5) co-receptor antagonists that are designed to interfere with white blood cell entry of HIV via CCR5. CCR5 is likely the most physiologically important co-receptor during natural infection, and at least 50% to 60% of treatment-experienced infected patients harbor CCR5-using viruses.  When added to optimized therapy in clinically advanced patients, maraviroc led to virologic responses in roughly twice as many patients relative to placebo.

Raltegravir is the first in a class of antiretroviral agents known as HIV-integrase strand transfer inhibitor (HIV-1 INSTII) that are designed to slow HIV-1 progression by blocking the integrase enzyme required for viral insertion into human DNA.  It is approved for clinically advanced patients with evidence of viral replication and multi-drug resistant HIV-1.  Like maraviroc, raltegavir was tested as add-on to optimized therapy and resulted in similar virologic response rates relative to placebo.  However, Merck has the PR advantage over Pfizer.  Here’s a representative quote for Isentress, courtesy of SFGate.com: “This drug looks more potent than virtually anything we have ever seen.” (UCSF Professor Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology)  I found no similar effusiveness over Selzentry, but rest assured that both drugs represent welcome advances in AIDS treatment and deserve to share top innovation honors this year.

2.  Lapatinib (Tykerb, GSK).  Lapatinib is a small molecule, orally-active tyrosine kinase inhibitor (TKI) that targets both erbB1 (EGF) and erbB2 (Her2/neu) receptors. Its dual mode of action distinguishes it from other marketed small-molecule TKIs, such as gefitinib (Iressa) and erlotinib (Tarceva), which target just EGFR, and the monoclonal antibody trastuzumab (Herceptin), which targets just Her2/neu. In theory, dual TK inhibition might diminish drug resistance  arising from single TK inhibition.  In practice, we just don’t know.  The pivotal trial tested lapatinib combination therapy with capecitibine versus capecitabine alone in women whose Her2/neu-overexpressing breast cancer had progressed after therapy with taxanes, anthracycline, and Herceptin.  I’ve read several different reports of the results of this study, probably because the interim results were published in the NEJM, and updated results were used by FDA to support approval.  Furthermore, FDA relied both on the investigator-reported and independent assessments of TTP.  The bottom line is that lapatinib did NOT “nearly double” TTP, as you might have read; rather, addition of lapatinib increased TTP by 33-40% over capecitabine alone and had no effect on survival.  Still, lapatinib represents the best option for women with Her2-overexpressing breast cancer whose disease has progressed despite chemotherapy and Herceptin and holds promise for earlier disease stages as well.

3.  Eculizumab (Soliris, Alexion).  Eculizumab is a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation.  It is the first complement activation inhibitor approved for human use and is also the first drug indicated for Paroxsymal Nocturnal Hemoglobinuria (PNH), a rare, complement-mediated disease characterized by red blood cell destruction.  Eculizumab was approved for its ability to stabilize hemoglobin (49% versus 0% with placebo) and reduce transfusion requirements (mean 3 U versus 11 U with placebo) in PNH.  Eculizumab represents a tremendous clinical advance for PNH and represents clinical proof-of-concept for inhibition of complement activation generally.  Its downside is its exorbitant cost of nearly $400k per year, which keeps this innovation out of my top 3.

4. Ixabepilone (Ixempra, BMS).  Ixabepilone is the first approved epothilone analog.  Epothilones are microtubule inhibitors found naturally in a myxobacterium.  BMS developed ixabepilone first as treatment for advanced breast cancer, testing it as monotherapy and in combination with capecitabine.  Both indications were approved in the US, with ixabepilone demonstrating improved progression-free survival in the combination therapy study (5.7 vs. 4.1 months) and objective tumor response (median response time of 6 months in up to 18% of subjects) as monotherapy.  Ixabepilone and other epothilones are currently being studied for other advanced cancers, includeing hormone-refractory prostate cancer.

5. Temsirolimus (Torisel, Wyeth).  A metabolic parent of Wyeth’s immunosuppresant sirolimus (Rapamune), temsirolimus is an mTOR inhibitor that arrests the cell cycle at G1 in kindey tumor cells in vitro.  In its pivotal studies in previously untreated advanced renal cancer, temsirolimus improved overall and progression-free survival versus interferon-alpha alone (10.9 vs. 7.3 months and 5.5 vs. 3.1 months, respectively).  More mTOR inhibitors will follow in the footsteps of temsirolimus in the years ahead, and, along with PI3/Akt inhibitors, should be important advances in the treatment of a wide variety of cancers.

6. Aliskerin (Tekturna/Rasilez, Novartis).  Aliskerin, the first approved renin inhibitor, is probably best known for the story of its development, which I won’t recount here.  Aliskerin inhibits the renin-angiotensin-aldosterone axis without increasing bradykinin, circumventing bradykinin-induced cough and angioedema that is a problem with inhibitors of downstream RAAS effectors.  We can’t have too many useful treatments for hypertension and heart failure.

7. Ambrisentan (Letairis, Gilead).  Ambrisentan is the second approved Endothelin A receptor antagonist following bosentan (Tracleer, Actelion, which is also an Endothelin B antagonist) for treatment of pulmonary artery hypertension (PAH).  Both are oral therapies.  So, what puts ambrisentan on this list?  It’s more convenient (once-daily versus twice) and has the potential for fewer drug interactions (Tracleer induces 3A4 and 2C9, reducing the plasma concentration of sildenafil, used to treat PAH).  It’s also shown to be safe in patients who have discontinued Tracleer due to elevated hepatic enzymes.  Neither ambrisentan nor bosentan has powerful efficacy, however, and there have been no head-to-head studies.

Honorable Mention:  Protein C Concentrate (Ceprotin, Baxter).  Baxter studied nearly every patient with severe inherited Protein C deficiency during the long development of Ceprotin.

NEJM — Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes

Following up Oct 24th’s post reporting on the news of Phase 1 trial suspensions of prasugrel to adjust dosage, we have today’s results of the TRITON-TIMI 38 Phase 3 pivotal trial of prasugrel vs. clopidogrel, published online in the NEJM to coincide with a presentation at the AHA annual meeting.

The editorial accompanying the detailed trial results, written by Deepak Bhatt of the Cleveland Clinic, sums up the study findings and implications nicely and sheds some light on the decision to study the antiplatelet pharmacodynamic effects at lower doses in subgroups of patients with differing baseline risks for serious bleeding:

The degrees of reduction in all these important ischemic events were substantial and robust [~19% in the primary efficacy endpoint, up to 52% for reduction in stent thrombosis with drug-eluting stents]. Beyond  comparing one drug with another, the TRITON–TIMI 38 study validates the hypothesis that greater degrees of adenosine diphosphate–mediated platelet inhibition are indeed associated with a greater suppression of clinical ischemic events. This is a major scientific contribution to our understanding of antiplatelet therapy….

Of concern, however, was the excess in TIMI major bleeding not related to coronary-artery bypass grafting that was life-threatening in the prasugrel group (1.4%, vs. 0.9% in the clopidogrel group; P=0.01), even fatally so (0.4% vs. 0.1%, P=0.002)….Thus, there is a price to pay for greater platelet inhibition and the accompanying reduction in ischemic events: higher rates of serious bleeding. In TRITON–TIMI 38, for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel…..[I]n a “real-world” setting, such as in an elderly patient with multiple coexisting conditions, the risk of major bleeding and even fatal bleeding may be increased to an even greater degree than was seen in TRITON–TIMI 38. Correspondingly,the benefits may also be greater in actual practice….

Bottom line:  Prasugrel more effectively prevents acute coronary syndromes than clopidgrel at its approved dosage, probably by stronger ADP-mediated platelet inhibition at the one size-fits-all dose of prasugrel studied.  However, one-size-fits-all appears to be an undesirable approach to this form of therapy, as evidenced by the significantly higher bleeding risk with prasugrel.  A more personalized approach, perhaps to the level of an individual patient, is necessary to improve on the efficacy of clopidogrel in the real world.  Thus, further clinical study of prasugrel , perhaps in conjunction with a point-of-care theranostic, will be needed to guide its tailored prescription.  That said,  I see nothing in these results that would preclude FDA approval of prasugrel now, without further clinical study, albeit with limitations on its use to low bleeding-risk patients.  Realistically, though, Lilly and DaiichiSankyo must perform additional studies to justify prescription of prasugrel to broader populations of patients and reap the financial rewards they are seeking.

Hey…sorry for the layoff time here at Pharma’s Cutting Edge.  You can breathe a bit easier now that I’m back.  Pun intended.

I’ve covered Exubera’s peri-approval and launch highlights in these pages, so now that Pfizer has pulled its marketing plug amidst ridiculously low sales of the first inhalable insulin I figured I’d a retrospective of those posts to aid the research of lessons-gatherers near and far.

In April 2007, I waxed philosophic as Exubera was hanging on by a thread:

Recognize in yourself your reluctance to change your opinion as evidence mounts to the contrary; the strength of your unwillingness to change your mind is proportional to the strength of your held opinion.  This is hardly a novel insight, as published evidence supporting it dates to at least the 1950’s.  In behavioral circles, it’s known as attitude strength, or as I like to call it, stubborness.  You might not be able to overcome your stubborness, but you might be more willing to hedge your bets if you can admit to it.

Following the launch of Exubera in July 2006, I set the stage for one of the moore interesting drug launches of the last few years:

This will certainly be one of the more interesting product launches in diabetes care ever. I’m intrigued by competing factors clinicians, patients, and third-party payers will weigh when deciding to use/reimburse for the drug: convenience (multiple injections vs. multiple inhalations; syringes and needles vs. an inhalation device), dose tailoring (extreme flexibility vs. limited flexibility), cost (3x to 5x higher for Exubera), toxicity (an increased risk of lung toxicity and lung function testing before use for Exubera), and Pfizer’s powerful position in the industry.

In May  2006 I extensively reviewed the drubbing Pfizer took from the UK’s nice.  As it turned out, apparently, NICE’s views of the relative quality-of-life benefits of Exubera were shared by doctors and their patients in the U.S:

It’s always a tall order to demonstrate ICE [incremental cost-effectiveness] for a new therapy with similar average efficacy as older therapies. Toss in the fact that the new therapy must cost two to three times as much as older therapies in order to meet profit margin requirements, and economists are faced with a nearly untenable situation. It’s rarely in the company’s best interests today to take extraordinary risks to demonstrate ICE convincingly prior to first launch if the risks aren’t necessary to gain marketing approval and at least Tier 3 coverage in the U.S., understanding that reimbursement in countries like UK is unlikely.

Following approval of Exubera in the U.S., I reviewed the contents of its prescribing information for physicians (i.e. its label):

Patients with Underlying Lung Diseases: Unlike the smoking contraindication, lung diseases present a risk to the patient that has not been quantified. Unstable lung disease is a contraindication due to altered absorption of insulin. The average clinician will be confused between a stable and an unstable lung disease, as am I. The risk management program will need to address this source of confusion. Look for this imprecise labeling as a potential area for product liability issues to arise.

Prior to the review by FDA’s EMDAC in September 2005, I discussed some of the briefing information regarding pulmonary safety:

One has to wonder how Pfizer plans to manage the liability risk of Exubera. They’ve appropriately proposed a raft of post-marketing studies designed to better quantify the clinical risks of the drug in a variety of patients, but at the same time they have suggested that Exubera is safe to use in patients with mild to moderate asthma or COPD, in contrast to the internal FDA pulmonary consultant’s review, which indicated that current data were insufficient to draw such a conclusion. This leads me to believe that Pfizer is planning to fight to avoid a contraindication to use in such patients, clearly an anti-conservative position.