Wednesday, November 18, 2015

Uncertain Health in an Insecure World – 65


There is no human disease more feared than cancer in kids.

And among pediatric oncologists, there is no cancer more feared than childhood acute lymphoblastic leukemia (ALL). A rare disease, ALL affects 3,000 young persons in the U.S. annually, often beginning with fever and bruising, but quickly turning fatal if not aggressively treated at a specialized children’s hospital. After a bone marrow aspiration confirms the diagnosis, treatment involves complex chemotherapy, irradiation and stem cell transplant regimens. A shared sense of urgency to improve childhood leukemia mortality has created novel ALL therapies, which have turned around its poor prognosis into 98% remission and 90% ten-year survival rates at leading pediatric cancer centers.

Researchers are now borrowing upon this pediatric oncology urgency to promote precision medicine (PM) in other diseases.

Some ALL patients have the Philadelphia chromosome mutation (above), described in 1960 by Peter Nowell and David Hungerford at the University of Pennsylvania (below), who made the first direct link between a chromosomal abnormality and any malignancy. Recent research from the U.S. Pediatric Genome Project shows other gene mutations in the most deadly ALL subtype, early T-cell precursor (ETP), which may direct future PM tailored therapies.

Bert Vogelstein’s 2013 Science article describes the “march of mutations” through a genomic landscape which is the backdrop to the most common human cancers. Its “mountains” are genes altered in a high percentage of tumors (below), while the “hills” are infrequently altered genes. Over 140 cancer driver gene mutations have been described, with tumors typically expressing between two to eight such genes responsible for cell death, cell survival and healthy genome maintenance. Vogelstein’s construct of the diverse cancer genome is fostering the development of precisely targeted therapies.

In Boston last week, Siddhartha Muhkerjee (below), the author of The Emperor of All Maladies: A Biography of Cancer, spoke of his acute leukemia experiences as a pediatric cancer physician. He described how the human body “slouches towards cancer”, from one gene mutation to another. At a cellular level, even seemingly similar cancers differ from every other cancer in terms of their genetics and cell metabolism.

Fair warning from Sid – cancer biology is complex.

It includes organismal features – the physiology that keeps cancer cells alive; environmental features – the immunologic systems causing cancer cell destruction; and epigenetic features – the mechanisms that control cancer gene transcription into messenger RNA (mRNA).

Cancer is a “pathway disease.

Along the path to cancer (above), there are multiple switches opening and shutting cellular circuitry that largely exists like a massive iceberg below the water surface. New therapies must precisely target this submerged iceberg using personalized medicine approaches that are actionable.

Endogenous cellular sources of oxidative DNA damage via base pair and nucleotide excision – so-called single nucleotide polymorphisms or SNP’s – cause gene toxicity (i.e., genotoxicity) by inducing mutations in tumor-causing oncogenes and in tumor suppression genes. Exogenous viruses and chemical carcinogens can also promote mutations. 

The WHO’s International Agency for Research on Cancer (IARC, est. 1969) maintains a database on genotoxic and non-genotoxic carcinogens. Most carcinogens are also mutagens (i.e., changing human DNA). Of >900 likely candidates, some 100+ are classified by IARC as carcinogenic to humans. Because it takes years or decades for exposure to a carcinogen to cause cancer, making such cause & effect linkages can be complex. Landfills are quickly filling up with heavy metals and toxic chemicals that now permeate our ground water. But the last new human carcinogen was described >15 years ago, and only pre-natal ionizing radiation has been identified as a risk for ALL. 
Cells can be drugs, engineered and educated to attach to tumors and other benign diseases.

Synthetic biology can endow immune cells with new properties for treating ALL, and offers potential for treating some solid tumors. The widespread mutational burden of some diseases is a key to the success of a new class of immunotherapies called checkpoint inhibitors. Activated T-lymphocyes (T-cells) trying to kill tumor cells are neutralized when they attach to specific T-cell PD-1 or tumor cell PD-L1 receptors (above). This T-cell deactivation is prevented by the binding (below) of checkpoint inhibitors (i.e. Opdivo™ and Yervoy™ from Bristol Myers Squibb; Keytruda™ from Merck Sharp & Dohme), which have been effective in deadly metastatic melanoma, renal carcinoma and some lung cancers. It is feasible that similar approaches will work in the benign disease space and be used for tissue engineering.

Personalized medicine demands such precision.  
PM will not succeed if it is based on “n of 1” clinical trials. New drugs can only move forward into clinical use after phase-1/-2 safety studies are completed. The gold standard for phase-3 randomized clinical trial (RCT) informed treatment protocols is to balance therapeutic and toxic effects encountered in the average RCT study subject. But every cancer in every cancer patient is unique, so new “smart surrogate” clinical trials will be needed. PM-informed biological endpoints will replace standard RCT survival rates. So-called “basket trials” of regular cancer therapy plus T-cell activating/suppressing immunotherapy adjuvants are being designed.

Such molecularly-informed drug trials should always be guided by good clinical medicine.

The Roche Group acquired the remaining 40% of Genentech in 2009 for US$46.8B. On November 10, 2015 the FDA approved Cotellic™ (Roche-Genentech) for the treatment of BRAF V600E or V600K mutation-positive advanced melanoma (below), in combination with Zelboraf™. The phase-3 coBRIM study, started in 2012, combined Cotellic’s inhibition of MEK (a protein kinase like that above, phosphorylates the ERK gene regulating programmed cell death) and Zelboraf’s BRAF (a proto-oncogene making B-Raf protein that directs cell growth) in order to delay the onset of tumor resistance seen after BRAF inhibition alone. The endpoint used in this gene-targeted PM regimen was progression-free survival.

It worked!

Today, Roche-Genentech has >20 anti-cancer molecules (i.e., drugs) in its pipeline, and is committed to the treatment of children.

PM approaches are urgently needed for all cancers.

In July 2015, the National Cancer Institute (NCI) Molecular Analysis for Therapy Choice (MATCH) launched a nationwide phase-2 clinical trial to sequence the tumor biopsies of 3,000 patients, and match findings against a 143 cancer driver gene panel. NCI-MATCH (above) will bring diverse Big Pharma companies (including some that haven’t yet completed M&A transactions!; see post #63) together in PM-directed sub-studies to jointly develop novel clinical treatment protocols involving their otherwise proprietary blockbuster drugs.

We in the Square are heartened by all this urgency, and by the coming together of market competitors to extend the lives of our patients, not just their drug patents.

Thursday, November 12, 2015

Uncertain Health in an Insecure World – 64

Either Good or Bad

In Act 2 Scene 2 of Hamlet, the Prince of Denmark laments to his spies, Guldenstern and Rosencrantz, that “… there is nothing either good or bad, but that thinking makes it so.” This statement, the fourteenth century equivalent of the modern, “Psych!”, revealed a Hamlet deeply troubled by murder, incest and ghosts in the Danish royal family. He adapts to all these negatives by putting on a mask of “antic disposition” – feigning madness as he walks the corridors of Elsinore castle.

Not so long ago, in his 2012 book Bad Pharma, author Ben Goldacre (below) nobly took on medical journal publication bias towards studies with “positive” results over those with “negative” outcomes. Former U.S. Food & Drug Administration (FDA) official Henry Miller responded to Goldacre’s angry antics, correctly pointing out that many negative studies are simply statistically underpowered – as such, they should best be called “unsuccessful” or “inconclusive”.

A truly negative clinical trial is one that shows a new treatment is actually inferior to standard therapy. In fact, the FDA often approves new drugs on the basis of non-inferiority compared to a standard treatment. Of course, an underpowered study that demonstrates non-inferiority might actually prove to be negative if adequately powered to conclusively disprove the null hypothesis (i.e., that a new drug is the same as a standard drug or a placebo). 

Goldacre’s book and medical literature meta-analyses provoked a lot of soul searching in the research and regulatory sectors.

For example, a 2012 Nature article showed that the results of 47 of 53 published molecular biology papers couldn’t be reproduced by another scientist. The following year, noted that half of all clinical trials go unpublished and many omit key details, despite U.S. FDA rules requiring all results be submitted to the database (above).  A recent New England Journal of Medicine article (March 12, 2015) by Duke University investigators showed that only 13.4% of >200,000 clinical trials reported since 2000 published summary data within one year of completion. Two-thirds of these studies were funded by industry; industry funding increased the likelihood of timely reporting. 

Has any of this existential angst about publications changed practice at the point-of-care?

When medical practitioners use new drugs to treat chronic diseases – infections, diabetes, hypertension, arthritis and cancer – they experience responses in their clinic patients (below) that are not the same as those in clinical trial subjects. Why? Because clinical trials are highly managed protocols carried out on carefully selected cohorts, they may not predict the responses of patients who are less adherent and more heterogeneous.

Before becoming generic in 2012, some 50,000,000 Americans had used the anti-platelet drug clopidogrel (Plavix™) for cardiovascular illnesses at an average cost of $200 per month. Since 2008, the FDA has monitored the value of dual anti-platelet therapy (DAPT) with both aspirin and clopidogrel after drug-eluting stents are placed in blocked coronary arteries. Last week, an FDA meta-analysis of multiple clinical trials concluded that DAPT, “does not save lives, reduce heart attacks, or result in lower risk of stent thrombosis.” Such FDA-mandated post-marketing surveillance in general populations often causes early enthusiasm based on randomized clinical trials (RCT’s) to wane. This late-breaking medical news makes patients, like my mother who nearly bled out on DAPT, MAD!

Today, there is nothing “rotten in the state of Denmark”, a modern Nordic country of some 5,678,348 souls.

Denmark is home to a global diabetes pharmaceutical giant, Novo Nordisk (NVO), headquartered in Bagsv√¶rd. Although the prevalence of diabetes in Denmark is low (above) and less than that in Europe (52M) and around the world (387M) – this 90-year old company has intentionally focused its R&D efforts on diabetes care. Its long-acting insulin, Levemir™, has been a big seller. In late September 2015 (below), the FDA approved NVO’s longer-acting Tresiba™, after “head-to-head” studies versus Sanofi’s market leader that showed Tresiba™ was non-inferior to Lantus™.

Another progressive Denmark-based firm, Genomic Expression, is becoming a first-mover in the field of companion diagnostics by making RNA sequencing (OneRNA™) gene expression targets actionable in oncology patients. In addition to high initial cancer therapy failure rates, the inconvenient truth is that only one in four current cancer treatments prolong life. OneRNA™ is a precision medicine (PM) approach that identifies a positive chance of treatment response in triple-negative breast cancer and other diseases.

Full disclosure – I have brilliant professional colleagues who work at both of these highly progressive Danish firms.

On the verge of despair amid negative and/or irreproducible RCT’s, in July 2015 along comes The Economist’s brilliant data shop with a clinical trial simulator  This interactive "run a trial" exercise (above) makes the point that there is a critical need to fix a situation where only regulators see all the good and bad data (below, left). The selective publication of only positive clinical trial results is highly flawed (below, right). When doctors only see what under-reporting Big Pharma and clinical trialists want them to see, there is a 14.1% distortion!

To be or not to be?… that is the question.” Patients need to stop flying blind related to the applicability of RCT’s to their healthcare. 

What Institute for Systems Biology founder Roy Hood calls “dense dynamic personalized data clouds” offer the potential for individualized PM, instead of relying on averaged data responses from RCT patient cohorts. In the wake of 2012’s rotten revelations, it will be good when “N of 1” data-driven PM care trumps that based on notoriously underpowered and inconclusive clinical trials. 

So when it comes to, “the heart-ache, and the thousand natural shocks that flesh is heir to…”, here’s “the rub...

Unlike Hamlet, who was unable to escape “the many confines, wards, and dungeons” of Denmark, we in the Square think it good to face such real-world clinical drug trial ambiguities, then shuffle them off from our medical practice thoughts and troubled treatment failure dreams. 

Anything else is antics, amid a modern Shakespearean tragedy.

Tuesday, November 3, 2015

Uncertain Health in an Insecure World – 63

“Too Big to Fail?”

On Halloween eve 2015, the U.S. Federal Reserve proposed that the banks "too big to fail" in 2008 set aside billions in long-term debt reserves as a cushion against scary financial failures.These same banks were saved 7 years ago by the government to protect the longer term public interests.

Until the Fed’s latest spooky move is ratified, the big U.S. banks and large global banks’ U.S. subsidiaries must demonstrate that they can pass annual “stress tests” and write “living wills” stating how they would safely be wound down in the process of restructuring. If there’s a complete bank failure, their bondholders, not the taxpayers, would be on the hook.

So, while this financial sector has dramatically concentrated since 2008, it is also heavily regulated to protect the public interests.

What, and who, regulates the healthcare and big pharma sector?

Also on Halloween eve 2015 came scary news that the tenth largest U.S. company, Pfizer, was seeking a merger with Irish Botox and Restasis maker, Allergan PLC. It would be the biggest market cap combo of an already big year (US$216B + US$113B) – a blockbuster deal for two blockbuster drug makers! Pfizer revenues have been declining since cholesterol-lowering Lipitor came off patent protection in 2011. But its >80 pipeline drugs and new products for breast cancer (Ibrance) and blood clots (Eliquis) are signals of pent up growth.

High U.S. corporate taxes are the main reason for Pfizer-Allergan merger & acquisition talks.

The effective tax rate for Pfizer is 25%, while Allergan’s rate is 15%. Pfizer CEO Ian Read (above) says that Pfizer is competing against foreign companies “with one hand tied behind our back”. Mr. Read has called U.S. tax rates “highly disadvantageous to American multinational high-tech businesses.” The proposed deal would move Pfizer headquarters from New York (below) to Dublin, and likely cost many U.S. jobs.

Recognizing their tax problem, last year Pfizer attempted a “tax inversion” takeover of U.K. based AstraZeneca PLC. The move was blocked by AZ’s board in the face of intense U.K. political opposition. The capacity of U.S. drug companies to get around the current tax regulations requires certain conditions be met – shareholders of the newly created overseas entity must own >40% of the combined entity. This makes the only remaining hurdle the price of shares involved in the transaction: on Oct. 29, 2015, Pfizer shares (PFE, below left) closed below $35 and Allergan shares (ACT) traded above $310 (below right).

The math isn’t the only thing getting harder for the Viagra-maker.  
In March 2015, Allergan successfully competed with Quebec-based Valeant Pharmaceuticals for the purchase of California-based Actavis, but only after Actavis pulled off a “white knight” purchase of Allergan. Allergan revenues grew this year by an estimated 10%, despite selling its generic drug business to Israel’s Teva for US$40.5B.

While such big pharma M&A activity raises share prices, this hyperactivity is breeding contempt.

For example, Valeant has grown by voraciously acquiring 150 mature off-patent drug companies since 2008, then using its specialty pharmacies to increase drug prices by 200-500% (above), abruptly inflating its sales revenues. Pfizer CEO Read called Valeant’s acquisitive business model a non-sustainable “dead end” for new drug R&D. But Valeant has handsomely rewarded Wall Street investment banks >US$500M since 2012 to close its M&A deals.

Only GE, Allergan, AT&T and Dell Inc. have paid more Wall Street fees than Valeant since 2012!

One major Valeant shareholder, Bill Ackman (above), is also founder and CEO of the hedge fund Pershing Square Capital Management. His investor-oriented point-of-view recently saw him characterize Valeant as “a very early stage Berkshire Hathaway”, based on its aggressive M&A style. Last week, a disruptive report from short-selling Citron Research called Valeant “the pharmaceutical Enron”. Others have called Valeant “a conglomerate”, like ITT Corp., implying that it should be forced to split itself up. To avoid this, Valeant began “severing all ties” with some of its specialty pharmacies like Philidor Rx Services. In nearly the same breath, Ackman spoke of joining forces with Amazon CEO Jeff Bezos to spawn mail order services, touting that “specialty pharmacy is the future of the industry.”

Valeant CEO Mike Pearson (above), an American running the company from its north Montreal headquarters, has been staying quiet since 2014 when Ackman outed him as a billionaire, based on the fact that Pearson owned 10.6 million Valeant shares (VRX). Ackman has also lauded the business synergy between senior management’s shareholdings and the company’s long-term share price performance.

But for most Valeant investors, this kind of bottom line alignment does not remove their risk.

There is no golden parachute for Valeant’s common shareholders, who have seen share prices drop 40% in the last week (above), reminding Canadian investors of the collapse of R.I.M./Blackberry Ltd. (2012-2013) and bankruptcy of Nortel Networks Corp. (2009). Pershing Square Capital has already seen $1.5 B in paper losses from Valeant in 2015. Citron Research just projected that there is a real risk of Valeant shares going to US$0. Quebec’s Authorit√© des Marches Financiers regulators are investigating “worrisome” allegations. 

Whatever the currency exchange rates, US$0 and CDN$0 are the same price per share.
Is it any wonder that current public sentiment towards the big pharma sector is so negative?

One observer commented that they should “run before the torches and pitchforks show up.” Of course, U.S. presidential candidates like Hillary Clinton are joining the fray, with her spokesperson saying “there is a lot more work to be done to stop them”. Donald Trump believes that Pfizer’s move is just another reason to overhaul to the U.S. tax code, “so companies will be coming to America, not looking for ways to leave.”  Well before the recent Valeant “phantom sales” scandal, U.S. presidential candidate Bernie Sanders (below) began a government investigation of the company’s extreme price hikes.

According to Thomson Reuters, the accelerated 2015 rate of healthcare and pharma sector M&A has already set a historical high of US$448B! Last week, other major market-changing deals saw Walgreens Boots Alliance Inc. purchase Rite Aid Corp. (below), while health insurers Aetna and Humana Inc. merged, as did Anthem Inc. and Cigna Corp.

These big pharma and healthcare sector M&A’s raise big questions.

       Do these deals stimulate economies, or simply churn the public markets and cost jobs?
Does the U.S. need to build a Trump-like tax wall to protect this business sector?
Is it time for greater government regulation to prevent more conglomeration?
The public wants affordable drug prices, and resents price gouging behaviors. Patients benefit from new blockbuster drugs that require expensive R&D. There will never be a national Viagra or Botox or Liptor or Restasis shortage crisis severe enough to require direct government funds infusion. 

But what and who protect the long term public interests amid such M&A hyperactivity?

The what is markets that punish deceptive behaviors out of bounds with regulations, and reward creativity in business practices within the rules.

The who is the regulators and policymakers. Unfortunately, these market controllers take time to connect the dots, and may be swayed by perverse incentives to look the other way.  

We in the Square know that company failure is natural selection in the business world. And just like in bad Halloween movies, bad CEO's should be the serial ax murderer's first victims.